Intestinal macrophages at the crossroad between diet, inflammation, and cancer: International Journal of Molecular Sciences

G. Caprara; P. Allavena; M. Erreni

doi:10.3390/ijms21144825

Intestinal macrophages at the crossroad between diet, inflammation, and cancer: International Journal of Molecular Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte–macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Original language	English
Pages (from-to)	1-31
Number of pages	31
Journal	Int. J. Mol. Sci.
Volume	21
Issue number	14
DOIs	https://doi.org/10.3390/ijms21144825
Publication status	Published - 2020

Keywords

Colorectal cancer
Diet
Gut
Inflammation
Intestine
Macrophage
Microbiota
Tumor-associated macrophage
alphaVbeta5 integrin
B7 antigen
CD40 antigen
chemokine receptor CCR2
chemokine receptor CX3CR1
fractalkine
interleukin 10
interleukin 10 receptor
interleukin 6
interleukin 8
monocyte chemotactic protein 1
omega 3 fatty acid
retinol
saturated fatty acid
short chain fatty acid
toll like receptor 2
trace element
transcription factor RUNX3
transforming growth factor beta
vitamin D
cell differentiation
colorectal cancer
diet therapy
dietary fiber
down regulation
environmental factor
gene expression
human
immune response
inflammatory bowel disease
intestine cell
intestine flora
intestine infection
macrophage
missense mutation
nonhuman
processed meat
protein expression
protein localization
red meat
Review
tissue repair
tumor associated leukocyte
upregulation
Western diet

Access to Document

10.3390/ijms21144825

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087761334&doi=10.3390%2fijms21144825&partnerID=40&md5=219d13cb0cfdfde012d239e65543392d

Fingerprint Dive into the research topics of 'Intestinal macrophages at the crossroad between diet, inflammation, and cancer: International Journal of Molecular Sciences'. Together they form a unique fingerprint.

Cite this

@article{95fbd777ac1946a488c341b8ccf5b0c5,

title = "Intestinal macrophages at the crossroad between diet, inflammation, and cancer: International Journal of Molecular Sciences",

abstract = "Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte–macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies. {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

keywords = "Colorectal cancer, Diet, Gut, Inflammation, Intestine, Macrophage, Microbiota, Tumor-associated macrophage, alphaVbeta5 integrin, B7 antigen, CD40 antigen, chemokine receptor CCR2, chemokine receptor CX3CR1, fractalkine, interleukin 10, interleukin 10 receptor, interleukin 6, interleukin 8, monocyte chemotactic protein 1, omega 3 fatty acid, retinol, saturated fatty acid, short chain fatty acid, toll like receptor 2, trace element, transcription factor RUNX3, transforming growth factor beta, vitamin D, cell differentiation, colorectal cancer, diet therapy, dietary fiber, down regulation, environmental factor, gene expression, human, immune response, inflammatory bowel disease, intestine cell, intestine flora, intestine infection, macrophage, missense mutation, nonhuman, processed meat, protein expression, protein localization, red meat, Review, tissue repair, tumor associated leukocyte, upregulation, Western diet",

author = "G. Caprara and P. Allavena and M. Erreni",

note = "Cited By :5 Export Date: 2 March 2021 Correspondence Address: Erreni, M.; Unit of Advanced Optical Microscopy, via Manzoni 56, Italy; email: marco.erreni@humanitasresearch.it Chemicals/CAS: fractalkine, 199619-66-4; interleukin 8, 114308-91-7; retinol, 68-26-8, 82445-97-4; toll like receptor 2, 203811-81-8 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 21147 Funding text 1: Funding: This research was funded by AIRC 5 × 1000 grant no. 21147 to Alberto Mantovani. References: Bain, C.C., Mowat, A.M., Macrophages in intestinal homeostasis and inflammation (2014) Immunol. Rev, 260, pp. 102-117. , [CrossRef]; van Furth, R., Cohn, Z.A., The origin and kinetics of mononuclear phagocytes (1968) J. Exp. Med, 128, pp. 415-435. , [CrossRef]; Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F., Stanley, E.R., Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010) Science, 330, pp. 841-845. , [CrossRef] [PubMed]; Bain, C.C., Bravo-Blas, A., Scott, C.L., Perdiguero, E.G., Geissmann, F., Henri, S., Malissen, B., Mowat, A.M., Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice (2014) Nat. Immunol, 15, pp. 929-937. , [CrossRef] [PubMed]; De Schepper, S., Verheijden, S., Aguilera-Lizarraga, J., Viola, M.F., Boesmans, W., Stakenborg, N., Voytyuk, I., Dierckx de Casterle, I., Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis (2018) Cell, 175, pp. 400-415. , e413. [CrossRef] [PubMed]; Bain, C.C., Scott, C.L., Uronen-Hansson, H., Gudjonsson, S., Jansson, O., Grip, O., Guilliams, M., Mowat, A.M., Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors (2013) Mucosal. Immunol, 6, pp. 498-510. , [CrossRef] [PubMed]; Serbina, N.V., Pamer, E.G., Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2 (2006) Nat. Immunol, 7, pp. 311-317. , [CrossRef]; Tamoutounour, S., Henri, S., Lelouard, H., de Bovis, B., de Haar, C., van der Woude, C.J., Woltman, A.M., Sichien, D., CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis (2012) Eur. J. Immunol, 42, pp. 3150-3166. , [CrossRef]; Schridde, A., Bain, C.C., Mayer, J.U., Montgomery, J., Pollet, E., Denecke, B., Milling, S.W.F., Henri, S., Tissue-specific differentiation of colonic macrophages requires TGFbeta receptor-mediated signaling (2017) Mucosal. Immunol, 10, pp. 1387-1399. , [CrossRef]; Bain, C.C., Schridde, A., Origin, Differentiation, and Function of Intestinal Macrophages (2018) Front. Immunol, 9, p. 2733. , [CrossRef]; Bujko, A., Atlasy, N., Landsverk, O.J.B., Richter, L., Yaqub, S., Horneland, R., Oyen, O., Stunnenberg, H.G., Transcriptional and functional profiling defines human small intestinal macrophage subsets (2018) J. Exp. Med, 215, pp. 441-458. , [CrossRef]; Bernardo, D., Marin, A.C., Fernandez-Tome, S., Montalban-Arques, A., Carrasco, A., Tristan, E., Ortega-Moreno, L., Caminero-Fernandez, R., Human intestinal pro-inflammatory CD11c(high)CCR2(+)CX3CR1(+) macrophages, but not their tolerogenic CD11c(-)CCR2(-)CX3CR1(-) counterparts, are expanded in inflammatory bowel disease (2018) Mucosal. Immunol, 11, pp. 1114-1126. , [CrossRef]; Shaw, T.N., Houston, S.A., Wemyss, K., Bridgeman, H.M., Barbera, T.A., Zangerle-Murray, T., Strangward, P., Tamoutounour, S., Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression (2018) J. Exp. Med, 215, pp. 1507-1518. , [CrossRef]; Fiocchi, C., What is “physiological” intestinal inflammation and how does it differ from “pathological” inflammation? (2008) Inflamm. Bowel. Dis, 14, pp. S77-S78. , (Suppl. 2), [CrossRef] [PubMed]; Niess, J.H., Adler, G., Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions (2010) J. Immunol, 184, pp. 2026-2037. , [CrossRef] [PubMed]; Na, Y.R., Stakenborg, M., Seok, S.H., Matteoli, G., Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD (2019) Nat. Rev. Gastroenterol. Hepatol, 16, pp. 531-543. , [CrossRef] [PubMed]; Ryan, G.R., Dai, X.M., Dominguez, M.G., Tong, W., Chuan, F., Chisholm, O., Russell, R.G., Stanley, E.R., Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis (2001) Blood, 98, pp. 74-84. , [CrossRef]; Dai, X.M., Zong, X.H., Sylvestre, V., Stanley, E.R., Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1 (2004) Blood, 103, pp. 1114-1123. , [CrossRef] [PubMed]; Sehgal, A., Donaldson, D., Pridans, C., Sauter, K., Hume, D., Mabbott, N., The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (2018) Nat. Commun, 9, p. 1272. , [CrossRef]; Cummings, R., Barbet, G., Bongers, G., Hartmann, B., Gettler, K., Muniz, L., Furtado, G., Blander, J., Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs (2016) Nature, 539, pp. 565-569. , [CrossRef]; Ueda, Y., Kayama, H., Jeon, S.G., Kusu, T., Isaka, Y., Rakugi, H., Yamamoto, M., Takeda, K., Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10 (2010) Int. Immunol, 22, pp. 953-962. , [CrossRef] [PubMed]; Zigmond, E., Bernshtein, B., Friedlander, G., Walker, C.R., Yona, S., Kim, K.W., Brenner, O., Muller, W., Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis (2014) Immunity, 40, pp. 720-733. , [CrossRef]; Girard-Madoux, M.J., Ober-Blobaum, J.L., Costes, L.M., Kel, J.M., Lindenbergh-Kortleve, D.J., Brouwers-Haspels, I., Heikema, A.P., Clausen, B.E., IL-10 control of CD11c+ myeloid cells is essential to maintain immune homeostasis in the small and large intestine (2016) Oncotarget, 7, pp. 32015-32030. , [CrossRef] [PubMed]; Shouval, D.S., Biswas, A., Goettel, J.A., McCann, K., Conaway, E., Redhu, N.S., Mascanfroni, I.D., Ibourk, M., Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function (2014) Immunity, 40, pp. 706-719. , [CrossRef] [PubMed]; Schenk, M., Bouchon, A., Birrer, S., Colonna, M., Mueller, C., Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine (2005) J. Immunol, 174, pp. 517-524. , [CrossRef]; Yona, S., Kim, K.W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Misharin, A., Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis (2013) Immunity, 38, pp. 79-91. , [CrossRef]; Medina-Contreras, O., Geem, D., Laur, O., Williams, I., Lira, S., Nusrat, A., Parkos, C., Denning, T., CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice (2011) J. Clin. Investig, 121, pp. 4787-4795. , [CrossRef]; Marelli, G., Belgiovine, C., Mantovani, A., Erreni, M., Allavena, P., Non-redundant role of the chemokine receptor CX3CR1 in the anti-inflammatory function of gut macrophages (2017) Immunobiology, 222, pp. 463-472. , [CrossRef]; Bernshtein, B., Curato, C., Ioannou, M., Thaiss, C., Gross-Vered, M., Kolesnikov, M., Wang, Q., Harmelin, A., IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response (2019) Sci. Immunol, 4, pp. 1-14. , [CrossRef]; Longman, R., Diehl, G., Victorio, D., Huh, J., Galan, C., Miraldi, E., Swaminath, A., Littman, D., CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22 (2014) J. Exp. Med, 211, pp. 1571-1583. , [CrossRef]; Zhou, L., Chu, C., Teng, F., Bessman, N., Goc, J., Santosa, E., Putzel, G., Baldassano, R., Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2 (2019) Nature, 568, pp. 405-409. , [CrossRef]; Leonardi, I., Li, X., Semon, A., Li, D., Doron, I., Putzel, G., Bar, A., McGovern, D.P.B., CX3CR1(+) mononuclear phagocytes control immunity to intestinal fungi (2018) Science, 359, pp. 232-236. , [CrossRef] [PubMed]; Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B., Jung, S., Transepithelial pathogen uptake into the small intestinal lamina propria (2006) J. Immunol, 176, pp. 2465-2469. , [CrossRef] [PubMed]; Chieppa, M., Rescigno, M., Huang, A., Germain, R., Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement (2006) J. Exp. Med, 203, pp. 2841-2852. , [CrossRef] [PubMed]; Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S., Amit, I., Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment (2014) Cell, 159, pp. 1312-1326. , [CrossRef]; Fadok, V.A., Bratton, D.L., Konowal, A., Freed, P.W., Westcott, J.Y., Henson, P.M., Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF (1998) J. Clin. Investig, 101, pp. 890-898. , [CrossRef]; Cho, I., Blaser, M.J., The human microbiome: At the interface of health and disease. Nature reviews (2012) Genetics, 13, pp. 260-270. , [CrossRef]; Rescigno, M., The microbiota revolution: Excitement and caution (2017) Eur. J. Immunol, 47, pp. 1406-1413. , [CrossRef]; Muller, P., Matheis, F., Mucida, D., Gut macrophages: Key players in intestinal immunity and tissue physiology (2020) Curr. Opin. Immunol, 62, pp. 54-61. , [CrossRef]; Franchi, L., Kamada, N., Nakamura, Y., Burberry, A., Kuffa, P., Suzuki, S., Shaw, M.H., Nunez, G., NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense (2012) Nat. Immunol, 13, pp. 449-456. , [CrossRef]; Hayashi, A., Sato, T., Kamada, N., Mikami, Y., Matsuoka, K., Hisamatsu, T., Hibi, T., Ohteki, T., A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice (2013) Cell Host Microbe, 13, pp. 711-722. , [CrossRef]; Kim, M., Galan, C., Hill, A., Wu, W., Fehlner-Peach, H., Song, H., Schady, D., Longman, R., Critical Role for the Microbiota in CX (2018) Immunity, 49, pp. 151-163. , e155. [CrossRef]; Mortha, A., Chudnovskiy, A., Hashimoto, D., Bogunovic, M., Spencer, S.P., Belkaid, Y., Merad, M., Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis (2014) Science, 343, p. 1249288. , [CrossRef]; Hubbard, T.D., Murray, I.A., Nichols, R.G., Cassel, K., Podolsky, M., Kuzu, G., Tian, Y., Patterson, A.D., Dietary Broccoli Impacts Microbial Community Structure and Attenuates Chemically Induced Colitis in Mice in an Ah receptor dependent manner (2017) J. Funct. Foods, 37, pp. 685-698. , [CrossRef]; Chang, P.V., Hao, L., Offermanns, S., Medzhitov, R., The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition (2014) Proc. Natl. Acad. Sci. USA, 111, pp. 2247-2252. , [CrossRef]; Scott, N.A., Andrusaite, A., Andersen, P., Lawson, M., Alcon-Giner, C., Leclaire, C., Caim, S., Connolly, J.P.R., Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis (2018) Sci. Transl. Med, 10, p. eaao4755. , [CrossRef]; Russell, W.R., Hoyles, L., Flint, H.J., Dumas, M.E., Colonic bacterial metabolites and human health (2013) Curr. Opin. Microbiol, 16, pp. 246-254. , [CrossRef]; Maslowski, K.M., Mackay, C.R., Diet, gut microbiota and immune responses (2011) Nat. Immunol, 12, pp. 5-9. , [CrossRef]; Liu, H., Wang, J., He, T., Becker, S., Zhang, G., Li, D., Ma, X., Butyrate: A Double-Edged Sword for Health? (2018) Adv. Nutr, 9, pp. 21-29. , [CrossRef]; Andou, A., Hisamatsu, T., Okamoto, S., Chinen, H., Kamada, N., Kobayashi, T., Hashimoto, M., Takeda, T., Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages (2009) Gastroenterology, 136, pp. 564-574. , e562. [CrossRef]; Ochi, T., Feng, Y., Kitamoto, S., Nagao-Kitamoto, H., Kuffa, P., Atarashi, K., Honda, K., Kamada, N., Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine (2016) Sci. Rep, 6, p. 27634. , [CrossRef]; Li, P., Yin, Y.L., Li, D., Kim, S.W., Wu, G., Amino acids and immune function (2007) Br. J. Nutr, 98, pp. 237-252. , [CrossRef] [PubMed]; Statovci, D., Aguilera, M., MacSharry, J., Melgar, S., The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces (2017) Front. Immunol, 8, p. 838. , [CrossRef] [PubMed]; Wang, S., Ye, Q., Zeng, X., Qiao, S., Functions of Macrophages in the Maintenance of Intestinal Homeostasis (2019) J. Immunol. Res, 2019, p. 1512969. , [CrossRef] [PubMed]; Sirisinha, S., The pleiotropic role of vitamin A in regulating mucosal immunity (2015) Asian Pac. J. Allergy Immunol, 33, pp. 71-89; Manicassamy, S., Pulendran, B., Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages (2009) Semin. Immunol, 21, pp. 22-27. , [CrossRef]; McDaniel, K.L., Restori, K.H., Dodds, J.W., Kennett, M.J., Ross, A.C., Cantorna, M.T., Vitamin A-Deficient Hosts Become Nonsymptomatic Reservoirs of Escherichia coli-Like Enteric Infections (2015) Infect. Immun, 83, pp. 2984-2991. , [CrossRef]; Bai, A., Lu, N., Guo, Y., Liu, Z., Chen, J., Peng, Z., All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis (2009) J. Leukoc. Biol, 86, pp. 959-969. , [CrossRef]; Wang, X., Allen, C., Ballow, M., Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages (2007) J. Clin. Immunol, 27, pp. 193-200. , [CrossRef]; Yamada, H., Mizuno, S., Ross, A.C., Sugawara, I., Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis (2007) J. Nutr, 137, pp. 2696-2700. , [CrossRef]; Anand, P.K., Kaul, D., Downregulation of TACO gene transcription restricts mycobacterial entry/survival within human macrophages (2005) FEMS Microbiol. Lett, 250, pp. 137-144. , [CrossRef]; Zhang, Y., Leung, D.Y., Richers, B.N., Liu, Y., Remigio, L.K., Riches, D.W., Goleva, E., Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1 (2012) J. Immunol, 188, pp. 2127-2135. , [CrossRef]; Fabri, M., Stenger, S., Shin, D.M., Yuk, J.M., Liu, P.T., Realegeno, S., Lee, H.M., Sieling, P.A., Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages (2011) Sci. Transl. Med, 3, p. 104ra102. , [CrossRef]; Pouillon, L., Travis, S., Bossuyt, P., Danese, S., Peyrin-Biroulet, L., Head-to-head trials in inflammatory bowel disease: Past, present and future (2020) Nat. Rev. Gastroenterol. Hepatol, 17, pp. 365-376. , [CrossRef]; Schenk, M., Bouchon, A., Seibold, F., Mueller, C., TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases (2007) J. Clin. Investig, 117, pp. 3097-3106. , [CrossRef]; Thiesen, S., Janciauskiene, S., Uronen-Hansson, H., Agace, W., H{\"o}gerkorp, C., Spee, P., H{\aa}kansson, K., Grip, O., CD14(hi)HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn{\textquoteright}s disease (2014) J. Leukoc. Biol, 95, pp. 531-541. , [CrossRef]; Vos, A., Wildenberg, M., Arijs, I., Duijvestein, M., Verhaar, A., de Hertogh, G., Vermeire, S., Hommes, D., Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro (2012) Inflamm. Bowel Dis, 18, pp. 401-408. , [CrossRef]; Dige, A., Magnusson, M., {\"O}hman, L., Hvas, C., Kelsen, J., Wick, M., Agnholt, J., Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn{\textquoteright}s disease (2016) Scand. J. Gastroenterol, 51, pp. 692-699. , [CrossRef]; Kamada, N., Hisamatsu, T., Okamoto, S., Chinen, H., Kobayashi, T., Sato, T., Sakuraba, A., Koganei, K., Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis (2008) J. Clin. Investig, 118, pp. 2269-2280. , [CrossRef]; Takada, Y., Hisamatsu, T., Kamada, N., Kitazume, M., Honda, H., Oshima, Y., Saito, R., Chinen, H., Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset (2010) J. Immunol, 184, pp. 2671-2676. , [CrossRef]; Platt, A., Bain, C., Bordon, Y., Sester, D., Mowat, A., An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation (2010) J. Immunol, 184, pp. 6843-6854. , [CrossRef] [PubMed]; Schippers, A., Muschaweck, M., Clahsen, T., Tautorat, S., Grieb, L., Tenbrock, K., Ga{\ss}ler, N., Wagner, N., β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon (2016) Mucosal. Immunol, 9, pp. 527-538. , [CrossRef] [PubMed]; Ingersoll, M., Spanbroek, R., Lottaz, C., Gautier, E., Frankenberger, M., Hoffmann, R., Lang, R., Tacke, F., Comparison of gene expression profiles between human and mouse monocyte subsets (2010) Blood, 115, pp. e10-e19. , [CrossRef]; Smith, P., Smythies, L., Shen, R., Greenwell-Wild, T., Gliozzi, M., Wahl, S., Intestinal macrophages and response to microbial encroachment (2011) Mucosal. Immunol, 4, pp. 31-42. , [CrossRef] [PubMed]; Asano, K., Takahashi, N., Ushiki, M., Monya, M., Aihara, F., Kuboki, E., Moriyama, S., Qiu, C., Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes (2015) Nat. Commun, 6, p. 7802. , [CrossRef]; Li, Q., Wang, D., Hao, S., Han, X., Xia, Y., Li, X., Chen, Y., Qiu, C., CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis (2017) Front. Immunol, 8, p. 669. , [CrossRef]; Rugtveit, J., Bakka, A., Brandtzaeg, P., Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD) (1997) Clin. Exp. Immunol, 110, pp. 104-113. , [CrossRef]; Carlsen, H., Yamanaka, T., Scott, H., Rugtveit, J., Brandtzaeg, P., The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propria (2006) Inflamm. Bowel Dis, 12, pp. 1013-1024. , [CrossRef]; Ahrens, R., Waddell, A., Seidu, L., Blanchard, C., Carey, R., Forbes, E., Lampinen, M., Stringer, K., Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis (2008) J. Immunol, 181, pp. 7390-7399. , [CrossRef]; Waddell, A., Ahrens, R., Steinbrecher, K., Donovan, B., Rothenberg, M., Munitz, A., Hogan, S., Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11 (2011) J. Immunol, 186, pp. 5993-6003. , [CrossRef]; Man, A., Gicheva, N., Regoli, M., Rowley, G., De Cunto, G., Wellner, N., Bassity, E., Nicoletti, C., CX3CR1+ Cell-Mediated Salmonella Exclusion Protects the Intestinal Mucosa during the Initial Stage of Infection (2017) J. Immunol, 198, pp. 335-343. , [CrossRef] [PubMed]; Dunay, I.R., Damatta, R.A., Fux, B., Presti, R., Greco, S., Colonna, M., Sibley, L.D., Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii (2008) Immunity, 29, pp. 306-317. , [CrossRef] [PubMed]; Zheng, Y., Valdez, P., Danilenko, D., Hu, Y., Sa, S., Gong, Q., Abbas, A., de Sauvage, F., Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens (2008) Nat. Med, 14, pp. 282-289. , [CrossRef] [PubMed]; Manta, C., Heupel, E., Radulovic, K., Rossini, V., Garbi, N., Riedel, C., Niess, J., CX(3)CR1(+) macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium (2013) Mucosal. Immunol, 6, pp. 177-188. , [CrossRef] [PubMed]; Hardbower, D., Singh, K., Asim, M., Verriere, T., Olivares-Villag{\'o}mez, D., Barry, D., Allaman, M., Piazuelo, M., EGFR regulates macrophage activation and function in bacterial infection (2016) J. Clin. Investig, 126, pp. 3296-3312. , [CrossRef]; Grainger, J., Wohlfert, E., Fuss, I., Bouladoux, N., Askenase, M., Legrand, F., Koo, L., Belkaid, Y., Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection (2013) Nat. Med, 19, pp. 713-721. , [CrossRef]; Allen, J., Wynn, T., Evolution of Th2 immunity: A rapid repair response to tissue destructive pathogens (2011) PLoS Pathog, 7, p. e1002003. , [CrossRef]; Wolff, M., Broadhurst, M., Loke, P., Helminthic therapy: Improving mucosal barrier function (2012) Trends Parasitol, 28, pp. 187-194. , [CrossRef]; Wynn, T., Vannella, K., Macrophages in Tissue Repair, Regeneration, and Fibrosis (2016) Immunity, 44, pp. 450-462. , [CrossRef]; Maizels, R., Hewitson, J., Smith, K., Susceptibility and immunity to helminth parasites (2012) Curr. Opin. Immunol, 24, pp. 459-466. , [CrossRef]; Chen, F., Liu, Z., Wu, W., Rozo, C., Bowdridge, S., Millman, A., Van Rooijen, N., Gause, W., An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection (2012) Nat. Med, 18, pp. 260-266. , [CrossRef] [PubMed]; Borthwick, L., Barron, L., Hart, K., Vannella, K., Thompson, R., Oland, S., Cheever, A., Fisher, A., Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis (2016) Mucosal. Immunol, 9, pp. 38-55. , [CrossRef] [PubMed]; Bowcutt, R., Bell, L., Little, M., Wilson, J., Booth, C., Murray, P., Else, K., Cruickshank, S., Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris (2011) Parasite Immunol, 33, pp. 411-420. , [CrossRef] [PubMed]; Jenkins, S., Ruckerl, D., Cook, P., Jones, L., Finkelman, F., van Rooijen, N., MacDonald, A., Allen, J., Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation (2011) Science, 332, pp. 1284-1288. , [CrossRef]; Little, M., Hurst, R., Else, K., Dynamic changes in macrophage activation and proliferation during the development and resolution of intestinal inflammation (2014) J. Immunol, 193, pp. 4684-4695. , [CrossRef]; Lauber, K., Bohn, E., Krober, S.M., Xiao, Y.J., Blumenthal, S.G., Lindemann, R.K., Marini, P., Baksh, S., Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal (2003) Cell, 113, pp. 717-730. , [CrossRef]; Gude, D.R., Alvarez, S.E., Paugh, S.W., Mitra, P., Yu, J., Griffiths, R., Barbour, S.E., Spiegel, S., Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal (2008) FASEB J, 22, pp. 2629-2638. , [CrossRef]; Truman, L.A., Ford, C.A., Pasikowska, M., Pound, J.D., Wilkinson, S.J., Dumitriu, I.E., Melville, L., Nibbs, R., CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis (2008) Blood, 112, pp. 5026-5036. , [CrossRef]; Zigmond, E., Varol, C., Farache, J., Elmaliah, E., Satpathy, A.T., Friedlander, G., Mack, M., Murphy, K.M., Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells (2012) Immunity, 37, pp. 1076-1090. , [CrossRef]; Vong, L., Ferraz, J.G., Panaccione, R., Beck, P.L., Wallace, J.L., A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis (2010) Proc. Natl. Acad. Sci. USA, 107, pp. 12023-12027. , [CrossRef]; Kong, D., Shen, Y., Liu, G., Zuo, S., Ji, Y., Lu, A., Nakamura, M., Breyer, R.M., PKA regulatory IIalpha subunit is essential for PGD2-mediated resolution of inflammation (2016) J. Exp. Med, 213, pp. 2209-2226. , [CrossRef]; Chinen, T., Komai, K., Muto, G., Morita, R., Inoue, N., Yoshida, H., Sekiya, T., Takayanagi, R., Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance (2011) Nat. Commun, 2, p. 190. , [CrossRef] [PubMed]; Libioulle, C., Louis, E., Hansoul, S., Sandor, C., Farnir, F., Franchimont, D., Vermeire, S., Dixon, A., Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4 (2007) PLoS Genet, 3, p. e58. , [CrossRef] [PubMed]; Uranga, J.A., Lopez-Miranda, V., Lombo, F., Abalo, R., Food, nutrients and nutraceuticals affecting the course of inflammatory bowel disease (2016) Pharmacol. Rep, 68, pp. 816-826. , [CrossRef] [PubMed]; Christ, A., Lauterbach, M., Latz, E., Western Diet and the Immune System: An Inflammatory Connection (2019) Immunity, 51, pp. 794-811. , [CrossRef] [PubMed]; Shoelson, S.E., Herrero, L., Naaz, A., Obesity, inflammation, and insulin resistance (2007) Gastroenterology, 132, pp. 2169-2180. , [CrossRef]; Mozaffarian, D., Hao, T., Rimm, E.B., Willett, W.C., Hu, F.B., Changes in diet and lifestyle and long-term weight gain in women and men (2011) N. Engl. J. Med, 364, pp. 2392-2404. , [CrossRef] [PubMed]; Tanoue, T., Honda, K., Induction of Treg cells in the mouse colonic mucosa: A central mechanism to maintain host-microbiota homeostasis (2012) Semin. Immunol, 24, pp. 50-57. , [CrossRef]; Buc, M., Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis (2013) Mediators Inflamm, 2013, p. 963748. , [CrossRef] [PubMed]; Darfeuille-Michaud, A., Boudeau, J., Bulois, P., Neut, C., Glasser, A.L., Barnich, N., Bringer, M.A., Colombel, J.F., High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn{\textquoteright}s disease (2004) Gastroenterology, 127, pp. 412-421. , [CrossRef]; Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermudez-Humaran, L.G., Gratadoux, J.J., Blugeon, S., Corthier, G., Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients (2008) Proc. Natl. Acad. Sci. USA, 105, pp. 16731-16736. , [CrossRef] [PubMed]; Sun, P., Wang, H., He, Z., Chen, X., Wu, Q., Chen, W., Sun, Z., Ma, D., Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages (2017) Oncotarget, 8, pp. 74649-74660. , [CrossRef]; Lee, J.Y., Plakidas, A., Lee, W.H., Heikkinen, A., Chanmugam, P., Bray, G., Hwang, D.H., Differential modulation of Toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids (2003) J. Lipid Res, 44, pp. 479-486. , [CrossRef] [PubMed]; Moreira, A.P., Texeira, T.F., Ferreira, A.B., Peluzio Mdo, C., Alfenas Rde, C., Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia (2012) Br. J. Nutr, 108, pp. 801-809. , [CrossRef]; Lee, J.Y., Ye, J., Gao, Z., Youn, H.S., Lee, W.H., Zhao, L., Sizemore, N., Hwang, D.H., Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids (2003) J. Biol. Chem, 278, pp. 37041-37051. , [CrossRef]; Barbalho, S.M., Goulart Rde, A., Quesada, K., Bechara, M.D., de Carvalho Ade, C., Inflammatory bowel disease: Can omega-3 fatty acids really help? (2016) Ann. Gastroenterol, 29, pp. 37-43. , [PubMed]; Buckley, C.D., Gilroy, D.W., Serhan, C.N., Proresolving lipid mediators and mechanisms in the resolution of acute inflammation (2014) Immunity, 40, pp. 315-327. , [CrossRef]; Dalli, J., Serhan, C.N., Pro-Resolving Mediators in Regulating and Conferring Macrophage Function (2017) Front. Immunol, 8, p. 1400. , [CrossRef]; Gobbetti, T., Dalli, J., Colas, R.A., Federici Canova, D., Aursnes, M., Bonnet, D., Alric, L., Hansen, T.V., Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection (2017) Proc. Natl. Acad. Sci. USA, 114, pp. 3963-3968. , [CrossRef]; Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., Miglioli, M., Effect of an enteric-coated fish-oil preparation on relapses in Crohn{\textquoteright}s disease (1996) N. Engl. J. Med, 334, pp. 1557-1560. , [CrossRef]; Barbosa, D.S., Cecchini, R., El Kadri, M.Z., Rodriguez, M.A., Burini, R.C., Dichi, I., Decreased oxidative stress in patients with ulcerative colitis supplemented with fish oil omega-3 fatty acids (2003) Nutrition, 19, pp. 837-842. , [CrossRef]; Romano, C., Cucchiara, S., Barabino, A., Annese, V., Sferlazzas, C., Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn{\textquoteright}s disease: A double-blind, randomized, placebo-controlled study (2005) World J. Gastroenterol, 11, pp. 7118-7121. , [CrossRef] [PubMed]; Bento, A.F., Claudino, R.F., Dutra, R.C., Marcon, R., Calixto, J.B., Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice (2011) J. Immunol, 187, pp. 1957-1969. , [CrossRef] [PubMed]; Vernia, P., Gnaedinger, A., Hauck, W., Breuer, R.I., Organic anions and the diarrhea of inflammatory bowel disease (1988) Dig. Dis. Sci, 33, pp. 1353-1358. , [CrossRef] [PubMed]; Frank, D.N., St Amand, A.L., Feldman, R.A., Boedeker, E.C., Harpaz, N., Pace, N.R., Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases (2007) Proc. Natl. Acad. Sci. USA, 104, pp. 13780-13785. , [CrossRef] [PubMed]; Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., Verbeke, K., A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis (2014) Gut, 63, pp. 1275-1283. , [CrossRef]; Vieira, E.L., Leonel, A.J., Sad, A.P., Beltrao, N.R., Costa, T.F., Ferreira, T.M., Gomes-Santos, A.C., Cara, D.C., Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis (2012) J. Nutr. Biochem, 23, pp. 430-436. , [CrossRef]; Dicarlo, M., Teti, G., Verna, G., Liso, M., Cavalcanti, E., Sila, A., Raveenthiraraj, S., Serino, G., Quercetin Exposure Suppresses the Inflammatory Pathway in Intestinal Organoids from Winnie Mice (2019) Int. J. Mol. Sci, 20, p. 5771. , [CrossRef]; Weisshof, R., Chermesh, I., Micronutrient deficiencies in inflammatory bowel disease (2015) Curr. Opin. Clin. Nutr. Metab. Care, 18, pp. 576-581. , [CrossRef]; Burkholder, P.R., McVeigh, I., Synthesis of Vitamins by Intestinal Bacteria (1942) Proc. Natl. Acad. Sci. USA, 28, pp. 285-289. , [CrossRef]; Simmons, J.D., Mullighan, C., Welsh, K.I., Jewell, D.P., Vitamin D receptor gene polymorphism: Association with Crohn{\textquoteright}s disease susceptibility (2000) Gut, 47, pp. 211-214. , [CrossRef] [PubMed]; Liu, W., Chen, Y., Golan, M.A., Annunziata, M.L., Du, J., Dougherty, U., Kong, J., Pekow, J., Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis (2013) J. Clin. Investig, 123, pp. 3983-3996. , [CrossRef] [PubMed]; Ryz, N.R., Patterson, S.J., Zhang, Y., Ma, C., Huang, T., Bhinder, G., Wu, X., Sham, H.P., Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses (2012) Am. J. Physiol. Gastrointest. Liver Physiol, 303, pp. G1299-G1311. , [CrossRef] [PubMed]; Ooi, J.H., Li, Y., Rogers, C.J., Cantorna, M.T., Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis (2013) J. Nutr, 143, pp. 1679-1686. , [CrossRef] [PubMed]; Shiraishi, E., Iijima, H., Shinzaki, S., Nakajima, S., Inoue, T., Hiyama, S., Kawai, S., Hayashi, Y., Vitamin K deficiency leads to exacerbation of murine dextran sulfate sodium-induced colitis (2016) J. Gastroenterol, 51, pp. 346-356. , [CrossRef]; Michielan, A., D{\textquoteright}Inca, R., Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut (2015) Mediators Inflamm, 2015, p. 628157. , [CrossRef]; Lyons, C.L., Kennedy, E.B., Roche, H.M., Metabolic Inflammation-Differential Modulation by Dietary Constituents (2016) Nutrients, 8, p. 247. , [CrossRef]; Rodrigues, V.S., Milanski, M., Fagundes, J.J., Torsoni, A.S., Ayrizono, M.L., Nunez, C.E., Dias, C.B., Coy, C.S., Serum levels and mesenteric fat tissue expression of adiponectin and leptin in patients with Crohn{\textquoteright}s disease (2012) Clin. Exp. Immunol, 170, pp. 358-364. , [CrossRef]; Pietsch, J., Batra, A., Stroh, T., Fedke, I., Glauben, R., Okur, B., Zeitz, M., Siegmund, B., Toll-like receptor expression and response to specific stimulation in adipocytes and preadipocytes: On the role of fat in inflammation (2006) Ann. N. Y. Acad. Sci, 1072, pp. 407-409. , [CrossRef]; Schwingshackl, L., Hoffmann, G., Mediterranean dietary pattern, inflammation and endothelial function: A systematic review and meta-analysis of intervention trials (2014) Nutr. Metab. Cardiovasc. Dis, 24, pp. 929-939. , [CrossRef]; Caprara, G., Diet and longevity: The effects of traditional eating habits on human lifespan extension (2018) Med. J. Nutr. Metab, 11, pp. 261-294. , [CrossRef]; Ghosh, T.S., Rampelli, S., Jeffery, I.B., Santoro, A., Neto, M., Capri, M., Giampieri, E., Turroni, S., Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: The NU-AGE 1-year dietary intervention across five European countries (2020) Gut, 69, pp. 1218-1228. , [CrossRef]; Meslier, V., Laiola, M., Roager, H.M., De Filippis, F., Roume, H., Quinquis, B., Giacco, R., Pons, N., Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake (2020) Gut, 69, pp. 1258-1268. , [CrossRef] [PubMed]; Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., Allavena, P., Tumour-associated macrophages as treatment targets in oncology (2017) Nat. Rev. Clin. Oncol, 14, pp. 399-416. , [CrossRef]; Kiss, M., Van Gassen, S., Movahedi, K., Saeys, Y., Laoui, D., Myeloid cell heterogeneity in cancer: Not a single cell alike (2018) Cell. Immunol, 330, pp. 188-201. , [CrossRef] [PubMed]; DeNardo, D.G., Ruffell, B., Macrophages as regulators of tumour immunity and immunotherapy (2019) Nat. Rev. Immunol, 19, pp. 369-382. , [CrossRef] [PubMed]; De Palma, M., Lewis, C., Macrophage regulation of tumor responses to anticancer therapies (2013) Cancer Cell, 23, pp. 277-286. , [CrossRef] [PubMed]; Geissmann, F., Gordon, S., Hume, D.A., Mowat, A.M., Randolph, G.J., Unravelling mononuclear phagocyte heterogeneity (2010) Nat. Rev. Immunol, 10, pp. 453-460. , [CrossRef]; Gordon, S., Pluddemann, A., Martinez Estrada, F., Macrophage heterogeneity in tissues: Phenotypic diversity and functions (2014) Immunol. Rev, 262, pp. 36-55. , [CrossRef]; Locati, M., Curtale, G., Mantovani, A., Diversity, Mechanisms, and Significance of Macrophage Plasticity (2020) Annu. Rev. Pathol, 15, pp. 123-147. , [CrossRef]; Mosser, D., Edwards, J., Exploring the full spectrum of macrophage activation (2008) Nat. Rev. Immunol, 8, pp. 958-969. , [CrossRef] [PubMed]; Sica, A., Mantovani, A., Macrophage plasticity and polarization: In vivo veritas (2012) J. Clin. Investig, 122, pp. 787-795. , [CrossRef] [PubMed]; Sica, A., Erreni, M., Allavena, P., Porta, C., Macrophage polarization in pathology (2015) Cell. Mol. Life Sci, 72, pp. 4111-4126. , 26. [CrossRef]; Pollard, J., Tumour-educated macrophages promote tumour progression and metastasis (2004) Nat. Rev. Cancer, 4, pp. 71-78. , [CrossRef]; Balkwill, F., Charles, K., Mantovani, A., Smoldering and polarized inflammation in the initiation and promotion of malignant disease (2005) Cancer Cell, 7, pp. 211-217. , [CrossRef] [PubMed]; Condeelis, J., Pollard, J., Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis (2006) Cell, 124, pp. 263-266. , [CrossRef]; Noy, R., Pollard, J., Tumor-associated macrophages: From mechanisms to therapy (2014) Immunity, 41, pp. 49-61. , [CrossRef]; Ruffell, B., Coussens, L.M., Macrophages and therapeutic resistance in cancer (2015) Cancer Cell, 27, pp. 462-472. , [CrossRef]; Cassetta, L., Pollard, J.W., Targeting macrophages: Therapeutic approaches in cancer (2018) Nat. Rev. Drug Discov, 17, pp. 887-904. , [CrossRef]; Long, A., Lundsmith, E., Hamilton, K., Inflammation and Colorectal Cancer (2017) Curr. Colorectal. Cancer Rep, 13, pp. 341-351. , [CrossRef]; Diet, Nutrition, Physical Activity, and Cancer: A Global Perspective. Continuous Update Project Expert Report 2018, , https://www.wcrf.org/sites/default/files/Summary-of-Third-Expert-Report-2018.pdf, World Cancer Research Fund/American Institute for Cancer Research. (accessed on 2 July 2020); Yahaya, M., Lila, M., Ismail, S., Zainol, M., Afizan, N., Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them (2019) J. Immunol. Res, 2019, p. 2368249. , [CrossRef] [PubMed]; Lynch, H., de la Chapelle, A., Hereditary colorectal cancer (2003) N. Engl. J. Med, 348, pp. 919-932. , [CrossRef] [PubMed]; Rustgi, A., The genetics of hereditary colon cancer (2007) Genes Dev, 21, pp. 2525-2538. , [CrossRef] [PubMed]; Gupta, R., Harpaz, N., Itzkowitz, S., Hossain, S., Matula, S., Kornbluth, A., Bodian, C., Ullman, T., Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: A cohort study (2007) Gastroenterology, 133, pp. 1099-1105. , discussion 1340–1341. [CrossRef] [PubMed]; Erreni, M., Bianchi, P., Laghi, L., Mirolo, M., Fabbri, M., Locati, M., Mantovani, A., Allavena, P., Expression of chemokines and chemokine receptors in human colon cancer (2009) Methods Enzymol, 460, pp. 105-121. , [CrossRef]; Erreni, M., Mantovani, A., Allavena, P., Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer (2011) Cancer Microenviron, 4, pp. 141-154. , [CrossRef] [PubMed]; Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Wind, P., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome (2006) Science, 313, pp. 1960-1964. , [CrossRef]; Laghi, L., Bianchi, P., Miranda, E., Balladore, E., Pacetti, V., Grizzi, F., Allavena, P., Santoro, A., CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: A longitudinal study (2009) Lancet Oncol, 10, pp. 877-884. , [CrossRef]; Angell, H., Bruni, D., Barrett, J., Herbst, R., Galon, J., The Immunoscore: Colon Cancer and Beyond (2020) Clin. Cancer Res, 26, pp. 332-339. , [CrossRef] [PubMed]; Galdiero, M., Bianchi, P., Grizzi, F., Di Caro, G., Basso, G., Ponzetta, A., Bonavita, E., Polentarutti, N., Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer (2016) Int. J. Cancer, 139, pp. 446-456. , [CrossRef]; Braster, R., B{\"o}gels, M., Beelen, R., van Egmond, M., The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential (2017) Immunobiology, 222, pp. 21-30. , [CrossRef] [PubMed]; Deng, L., Zhou, J., Sellers, R., Li, J., Nguyen, A., Wang, Y., Orlofsky, A., Pollard, J., A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis (2010) Am. J. Pathol, 176, pp. 952-967. , [CrossRef] [PubMed]; Popivanova, B., Kitamura, K., Wu, Y., Kondo, T., Kagaya, T., Kaneko, S., Oshima, M., Mukaida, N., Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis (2008) J. Clin. Investig, 118, pp. 560-570. , [CrossRef] [PubMed]; Afik, R., Zigmond, E., Vugman, M., Klepfish, M., Shimshoni, E., Pasmanik-Chor, M., Shenoy, A., Geiger, T., Tumor macrophages are pivotal constructors of tumor collagenous matrix (2016) J. Exp. Med, 213, pp. 2315-2331. , [CrossRef]; Pinto, M., Rios, E., Silva, A., Neves, S., Caires, H., Pinto, A., Dur{\~a}es, C., Santos, N., Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18 (2017) Biomaterials, 124, pp. 211-224. , [CrossRef]; Marelli, G., Erreni, M., Anselmo, A., Taverniti, V., Guglielmetti, S., Mantovani, A., Allavena, P., Heme-oxygenase-1 production by intestinal CX3CR1(+) macrophages helps to resolve inflammation and prevents carcinogenesis (2017) Cancer Res, 77, pp. 4472-4485. , [CrossRef]; Oosterling, S., van der Bij, G., Meijer, G., Tuk, C., van Garderen, E., van Rooijen, N., Meijer, S., van Egmond, M., Macrophages direct tumour histology and clinical outcome in a colon cancer model (2005) J. Pathol, 207, pp. 147-155. , [CrossRef]; Grossman, J., Nywening, T., Belt, B., Panni, R., Krasnick, B., DeNardo, D., Hawkins, W., Fields, R., Recruitment of CCR2 (2018) Oncoimmunology, 7, p. e1470729. , [CrossRef]; Cortese, N., Soldani, C., Franceschini, B., Barbagallo, M., Marchesi, F., Torzilli, G., Donadon, M., Macrophages in Colorectal Cancer Liver Metastases (2019) Cancers, 11, p. 633. , [CrossRef]; Forssell, J., Oberg, A., Henriksson, M., Stenling, R., Jung, A., Palmqvist, R., High macrophage infiltration along the tumor front correlates with improved survival in colon cancer (2007) Clin. Cancer Res, 13, pp. 1472-1479. , [CrossRef]; Zhou, Q., Peng, R., Wu, X., Xia, Q., Hou, J., Ding, Y., Zhou, Q., Wan, D., The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer (2010) J. Transl. Med, 8, p. 13. , [CrossRef] [PubMed]; Kang, J., Chen, J., Lee, C., Chang, J., Shieh, Y., Intratumoral macrophage counts correlate with tumor progression in colorectal cancer (2010) J. Surg. Oncol, 102, pp. 242-248. , [CrossRef]; Kwak, Y., Koh, J., Kim, D., Kang, S., Kim, W., Lee, H., Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer (2016) Oncotarget, 7, pp. 81778-81790. , [CrossRef] [PubMed]; Bailey, C., Negus, R., Morris, A., Ziprin, P., Goldin, R., Allavena, P., Peck, D., Darzi, A., Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer (2007) Clin. Exp. Metastasis, 24, pp. 121-130. , [CrossRef] [PubMed]; Malesci, A., Bianchi, P., Celesti, G., Basso, G., Marchesi, F., Grizzi, F., Di Caro, G., Palmqvist, R., Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer (2017) Oncoimmunology, 6, p. e1342918. , [CrossRef]; Pinto, M., Rios, E., Dur{\~a}es, C., Ribeiro, R., Machado, J., Mantovani, A., Barbosa, M., Oliveira, M., The Two Faces of Tumor-Associated Macrophages and Their Clinical Significance in Colorectal Cancer (2019) Front. Immunol, 10, p. 1875. , [CrossRef]; De Almeida, C.V., de Camargo, M.R., Russo, E., Amedei, A., Role of diet and gut microbiota on colorectal cancer immunomodulation (2019) World J. Gastroenterol, 25, pp. 151-162. , [CrossRef]; Raskov, H., Burcharth, J., Pommergaard, H.C., Linking Gut Microbiota to Colorectal Cancer (2017) J. Cancer, 8, pp. 3378-3395. , [CrossRef]; Ma, W., Mao, Q., Xia, W., Dong, G., Yu, C., Jiang, F., Gut Microbiota Shapes the Efficiency of Cancer Therapy (2019) Front. Microbiol, 10, p. 1050. , [CrossRef]; Ahn, J., Sinha, R., Pei, Z., Dominianni, C., Wu, J., Shi, J., Goedert, J.J., Yang, L., Human gut microbiome and risk for colorectal cancer (2013) J. Natl. Cancer Inst, 105, pp. 1907-1911. , [CrossRef]; Kunzmann, A.T., Proenca, M.A., Jordao, H.W., Jiraskova, K., Schneiderova, M., Levy, M., Liska, V., Vymetalkova, V., Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients (2019) Eur. J. Clin. Microbiol. Infect. Dis, 38, pp. 1891-1899. , [CrossRef] [PubMed]; Boleij, A., Hechenbleikner, E.M., Goodwin, A.C., Badani, R., Stein, E.M., Lazarev, M.G., Ellis, B., Wick, E.C., The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients (2015) Clin. Infect. Dis, 60, pp. 208-215. , [CrossRef] [PubMed]; Yu, L.C., Wei, S.C., Ni, Y.H., Impact of microbiota in colorectal carcinogenesis: Lessons from experimental models (2018) Intest. Res, 16, pp. 346-357. , [CrossRef]; Dai, Z., Coker, O.O., Nakatsu, G., Wu, W.K.K., Zhao, L., Chen, Z., Chan, F.K.L., Wong, S.H., Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers (2018) Microbiome, 6, p. 70. , [CrossRef] [PubMed]; Tilg, H., Adolph, T.E., Gerner, R.R., Moschen, A.R., The Intestinal Microbiota in Colorectal Cancer (2018) Cancer Cell, 33, pp. 954-964. , [CrossRef] [PubMed]; Thomas, A.M., Manghi, P., Asnicar, F., Pasolli, E., Armanini, F., Zolfo, M., Beghini, F., Pozzi, C., Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation (2019) Nat. Med, 25, pp. 667-678. , [CrossRef] [PubMed]; Song, M., Chan, A.T., Sun, J., Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) Gastroenterology, 158, pp. 322-340. , [CrossRef]; Murphy, E.A., Davis, J.M., McClellan, J.L., Carmichael, M.D., Quercetin{\textquoteright}s effects on intestinal polyp multiplicity and macrophage number in the Apc(Min/+) mouse (2011) Nutr. Cancer, 63, pp. 421-426. , [CrossRef]; Song, M., Garrett, W.S., Chan, A.T., Nutrients, foods, and colorectal cancer prevention (2015) Gastroenterology, 148, pp. 1244-1260. , e1216. [CrossRef]; Bae, S., Ulrich, C.M., Neuhouser, M.L., Malysheva, O., Bailey, L.B., Xiao, L., Brown, E.C., Cheng, T.Y., Plasma choline metabolites and colorectal cancer risk in the Women{\textquoteright}s Health Initiative Observational Study (2014) Cancer Res, 74, pp. 7442-7452. , [CrossRef]; Da Silva, M., Jaggers, G.K., Verstraeten, S.V., Erlejman, A.G., Fraga, C.G., Oteiza, P.I., Large procyanidins prevent bile-acid-induced oxidant production and membrane-initiated ERK1/2, p38, and Akt activation in Caco-2 cells (2012) Free Radic. Biol. Med, 52, pp. 151-159. , [CrossRef] [PubMed]; Bingham, S.A., Day, N.E., Luben, R., Ferrari, P., Slimani, N., Norat, T., Clavel-Chapelon, F., Boeing, H., Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): An observational study (2003) Lancet, 361, pp. 1496-1501. , [CrossRef]; Murphy, N., Norat, T., Ferrari, P., Jenab, M., Bueno-de-Mesquita, B., Skeie, G., Dahm, C.C., Tjonneland, A., Dietary fibre intake and risks of cancers of the colon and rectum in the European prospective investigation into cancer and nutrition (EPIC) (2012) PLoS ONE, 7, p. e39361. , [CrossRef] [PubMed]; Afrin, S., Giampieri, F., Gasparrini, M., Forbes-Hernandez, T.Y., Cianciosi, D., Reboredo-Rodriguez, P., Zhang, J., Atanasov, A.G., Dietary phytochemicals in colorectal cancer prevention and treatment: A focus on the molecular mechanisms involved (2020) Biotechnol. Adv, 38, p. 107322. , [CrossRef]; Ferrante, A.W., The immune cells in adipose tissue (2013) Diabetes Obes. Metab, 15, pp. 34-38. , (Suppl. 3), [CrossRef]; Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante, A.W., Obesity is associated with macrophage accumulation in adipose tissue (2003) J. Clin. Investig, 112, pp. 1796-1808. , [CrossRef] [PubMed]; McNelis, J.C., Olefsky, J.M., Macrophages, immunity, and metabolic disease (2014) Immunity, 41, pp. 36-48. , [CrossRef]; Day, S.D., Enos, R.T., McClellan, J.L., Steiner, J.L., Velazquez, K.T., Murphy, E.A., Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer (2013) Cytokine, 64, pp. 454-462. , [CrossRef] [PubMed]; Wunderlich, C.M., Ackermann, P.J., Ostermann, A.L., Adams-Quack, P., Vogt, M.C., Tran, M.L., Nikolajev, A., Theurich, S., Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment (2018) Nat. Commun, 9, p. 1646. , [CrossRef]; Bantel, H., Berg, C., Vieth, M., Stolte, M., Kruis, W., Schulze-Osthoff, K., Mesalazine inhibits activation of transcription factor NF-kappaB in inflamed mucosa of patients with ulcerative colitis (2000) Am. J. Gastroenterol, 95, pp. 3452-3457. , [CrossRef] [PubMed]; Giles, K., Ross, K., Rossi, A., Hotchin, N., Haslett, C., Dransfield, I., Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac (2001) J. Immunol, 167, pp. 976-986. , [CrossRef] [PubMed]; Ehrchen, J., Steinm{\"u}ller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Roth, J., Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes (2007) Blood, 109, pp. 1265-1274. , [CrossRef] [PubMed]; Mowat, C., Cole, A., Windsor, A., Ahmad, T., Arnott, I., Driscoll, R., Mitton, S., Younge, L., Guidelines for the management of inflammatory bowel disease in adults (2011) Gut, 60, pp. 571-607. , [CrossRef] [PubMed]; Oakley, R., Cidlowski, J., The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease (2013) J. Allergy Clin. Immunol, 132, pp. 1033-1044. , [CrossRef]; And{\'o}n, F., Digifico, E., Maeda, A., Erreni, M., Mantovani, A., Alonso, M., Allavena, P., Targeting tumor associated macrophages: The new challenge for nanomedicine (2017) Semin. Immunol, 34, pp. 103-113. , [CrossRef]; Zhang, X., Chen, Y., Hao, L., Hou, A., Chen, X., Li, Y., Wang, R., Ou, J., Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine (2016) Cancer Lett, 381, pp. 305-313. , [CrossRef]; Liu, Z., Xie, Y., Xiong, Y., Liu, S., Qiu, C., Zhu, Z., Mao, H., Wang, X., TLR 7/8 agonist reverses oxaliplatin resistance in colorectal cancer via directing the myeloid-derived suppressor cells to tumoricidal M1-macrophages (2020) Cancer Lett, 469, pp. 173-185. , [CrossRef]; Zhang, W., Gordon, M., Schultheis, A., Yang, D., Nagashima, F., Azuma, M., Chang, H., Sherrod, A., FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab (2007) J. Clin. Oncol, 25, pp. 3712-3718. , [CrossRef]; Halama, N., Zoernig, I., Berthel, A., Kahlert, C., Klupp, F., Suarez-Carmona, M., Suetterlin, T., Lasitschka, F., Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients (2016) Cancer Cell, 29, pp. 587-601. , [CrossRef]; Nakamura, K., Smyth, M.J., Myeloid immunosuppression and immune checkpoints in the tumor microenvironment (2020) Cell. Mol. Immunol, 17, pp. 1-12. , [CrossRef] [PubMed]",

year = "2020",

doi = "10.3390/ijms21144825",

language = "English",

volume = "21",

pages = "1--31",

journal = "Int. J. Mol. Sci.",

issn = "1661-6596",

publisher = "MDPI AG",

number = "14",

}

TY - JOUR

T1 - Intestinal macrophages at the crossroad between diet, inflammation, and cancer

T2 - International Journal of Molecular Sciences

AU - Caprara, G.

AU - Allavena, P.

AU - Erreni, M.

N1 - Cited By :5 Export Date: 2 March 2021 Correspondence Address: Erreni, M.; Unit of Advanced Optical Microscopy, via Manzoni 56, Italy; email: marco.erreni@humanitasresearch.it Chemicals/CAS: fractalkine, 199619-66-4; interleukin 8, 114308-91-7; retinol, 68-26-8, 82445-97-4; toll like receptor 2, 203811-81-8 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 21147 Funding text 1: Funding: This research was funded by AIRC 5 × 1000 grant no. 21147 to Alberto Mantovani. References: Bain, C.C., Mowat, A.M., Macrophages in intestinal homeostasis and inflammation (2014) Immunol. Rev, 260, pp. 102-117. , [CrossRef]; van Furth, R., Cohn, Z.A., The origin and kinetics of mononuclear phagocytes (1968) J. Exp. Med, 128, pp. 415-435. , [CrossRef]; Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F., Stanley, E.R., Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010) Science, 330, pp. 841-845. , [CrossRef] [PubMed]; Bain, C.C., Bravo-Blas, A., Scott, C.L., Perdiguero, E.G., Geissmann, F., Henri, S., Malissen, B., Mowat, A.M., Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice (2014) Nat. Immunol, 15, pp. 929-937. , [CrossRef] [PubMed]; De Schepper, S., Verheijden, S., Aguilera-Lizarraga, J., Viola, M.F., Boesmans, W., Stakenborg, N., Voytyuk, I., Dierckx de Casterle, I., Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis (2018) Cell, 175, pp. 400-415. , e413. [CrossRef] [PubMed]; Bain, C.C., Scott, C.L., Uronen-Hansson, H., Gudjonsson, S., Jansson, O., Grip, O., Guilliams, M., Mowat, A.M., Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors (2013) Mucosal. Immunol, 6, pp. 498-510. , [CrossRef] [PubMed]; Serbina, N.V., Pamer, E.G., Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2 (2006) Nat. Immunol, 7, pp. 311-317. , [CrossRef]; Tamoutounour, S., Henri, S., Lelouard, H., de Bovis, B., de Haar, C., van der Woude, C.J., Woltman, A.M., Sichien, D., CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis (2012) Eur. J. Immunol, 42, pp. 3150-3166. , [CrossRef]; Schridde, A., Bain, C.C., Mayer, J.U., Montgomery, J., Pollet, E., Denecke, B., Milling, S.W.F., Henri, S., Tissue-specific differentiation of colonic macrophages requires TGFbeta receptor-mediated signaling (2017) Mucosal. Immunol, 10, pp. 1387-1399. , [CrossRef]; Bain, C.C., Schridde, A., Origin, Differentiation, and Function of Intestinal Macrophages (2018) Front. Immunol, 9, p. 2733. , [CrossRef]; Bujko, A., Atlasy, N., Landsverk, O.J.B., Richter, L., Yaqub, S., Horneland, R., Oyen, O., Stunnenberg, H.G., Transcriptional and functional profiling defines human small intestinal macrophage subsets (2018) J. Exp. Med, 215, pp. 441-458. , [CrossRef]; Bernardo, D., Marin, A.C., Fernandez-Tome, S., Montalban-Arques, A., Carrasco, A., Tristan, E., Ortega-Moreno, L., Caminero-Fernandez, R., Human intestinal pro-inflammatory CD11c(high)CCR2(+)CX3CR1(+) macrophages, but not their tolerogenic CD11c(-)CCR2(-)CX3CR1(-) counterparts, are expanded in inflammatory bowel disease (2018) Mucosal. Immunol, 11, pp. 1114-1126. , [CrossRef]; Shaw, T.N., Houston, S.A., Wemyss, K., Bridgeman, H.M., Barbera, T.A., Zangerle-Murray, T., Strangward, P., Tamoutounour, S., Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression (2018) J. Exp. Med, 215, pp. 1507-1518. , [CrossRef]; Fiocchi, C., What is “physiological” intestinal inflammation and how does it differ from “pathological” inflammation? (2008) Inflamm. Bowel. Dis, 14, pp. S77-S78. , (Suppl. 2), [CrossRef] [PubMed]; Niess, J.H., Adler, G., Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions (2010) J. Immunol, 184, pp. 2026-2037. , [CrossRef] [PubMed]; Na, Y.R., Stakenborg, M., Seok, S.H., Matteoli, G., Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD (2019) Nat. Rev. Gastroenterol. Hepatol, 16, pp. 531-543. , [CrossRef] [PubMed]; Ryan, G.R., Dai, X.M., Dominguez, M.G., Tong, W., Chuan, F., Chisholm, O., Russell, R.G., Stanley, E.R., Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis (2001) Blood, 98, pp. 74-84. , [CrossRef]; Dai, X.M., Zong, X.H., Sylvestre, V., Stanley, E.R., Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1 (2004) Blood, 103, pp. 1114-1123. , [CrossRef] [PubMed]; Sehgal, A., Donaldson, D., Pridans, C., Sauter, K., Hume, D., Mabbott, N., The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (2018) Nat. Commun, 9, p. 1272. , [CrossRef]; Cummings, R., Barbet, G., Bongers, G., Hartmann, B., Gettler, K., Muniz, L., Furtado, G., Blander, J., Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs (2016) Nature, 539, pp. 565-569. , [CrossRef]; Ueda, Y., Kayama, H., Jeon, S.G., Kusu, T., Isaka, Y., Rakugi, H., Yamamoto, M., Takeda, K., Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10 (2010) Int. Immunol, 22, pp. 953-962. , [CrossRef] [PubMed]; Zigmond, E., Bernshtein, B., Friedlander, G., Walker, C.R., Yona, S., Kim, K.W., Brenner, O., Muller, W., Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis (2014) Immunity, 40, pp. 720-733. , [CrossRef]; Girard-Madoux, M.J., Ober-Blobaum, J.L., Costes, L.M., Kel, J.M., Lindenbergh-Kortleve, D.J., Brouwers-Haspels, I., Heikema, A.P., Clausen, B.E., IL-10 control of CD11c+ myeloid cells is essential to maintain immune homeostasis in the small and large intestine (2016) Oncotarget, 7, pp. 32015-32030. , [CrossRef] [PubMed]; Shouval, D.S., Biswas, A., Goettel, J.A., McCann, K., Conaway, E., Redhu, N.S., Mascanfroni, I.D., Ibourk, M., Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function (2014) Immunity, 40, pp. 706-719. , [CrossRef] [PubMed]; Schenk, M., Bouchon, A., Birrer, S., Colonna, M., Mueller, C., Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine (2005) J. Immunol, 174, pp. 517-524. , [CrossRef]; Yona, S., Kim, K.W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Misharin, A., Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis (2013) Immunity, 38, pp. 79-91. , [CrossRef]; Medina-Contreras, O., Geem, D., Laur, O., Williams, I., Lira, S., Nusrat, A., Parkos, C., Denning, T., CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice (2011) J. Clin. Investig, 121, pp. 4787-4795. , [CrossRef]; Marelli, G., Belgiovine, C., Mantovani, A., Erreni, M., Allavena, P., Non-redundant role of the chemokine receptor CX3CR1 in the anti-inflammatory function of gut macrophages (2017) Immunobiology, 222, pp. 463-472. , [CrossRef]; Bernshtein, B., Curato, C., Ioannou, M., Thaiss, C., Gross-Vered, M., Kolesnikov, M., Wang, Q., Harmelin, A., IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response (2019) Sci. Immunol, 4, pp. 1-14. , [CrossRef]; Longman, R., Diehl, G., Victorio, D., Huh, J., Galan, C., Miraldi, E., Swaminath, A., Littman, D., CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22 (2014) J. Exp. Med, 211, pp. 1571-1583. , [CrossRef]; Zhou, L., Chu, C., Teng, F., Bessman, N., Goc, J., Santosa, E., Putzel, G., Baldassano, R., Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2 (2019) Nature, 568, pp. 405-409. , [CrossRef]; Leonardi, I., Li, X., Semon, A., Li, D., Doron, I., Putzel, G., Bar, A., McGovern, D.P.B., CX3CR1(+) mononuclear phagocytes control immunity to intestinal fungi (2018) Science, 359, pp. 232-236. , [CrossRef] [PubMed]; Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B., Jung, S., Transepithelial pathogen uptake into the small intestinal lamina propria (2006) J. Immunol, 176, pp. 2465-2469. , [CrossRef] [PubMed]; Chieppa, M., Rescigno, M., Huang, A., Germain, R., Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement (2006) J. Exp. Med, 203, pp. 2841-2852. , [CrossRef] [PubMed]; Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S., Amit, I., Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment (2014) Cell, 159, pp. 1312-1326. , [CrossRef]; Fadok, V.A., Bratton, D.L., Konowal, A., Freed, P.W., Westcott, J.Y., Henson, P.M., Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF (1998) J. Clin. Investig, 101, pp. 890-898. , [CrossRef]; Cho, I., Blaser, M.J., The human microbiome: At the interface of health and disease. Nature reviews (2012) Genetics, 13, pp. 260-270. , [CrossRef]; Rescigno, M., The microbiota revolution: Excitement and caution (2017) Eur. J. Immunol, 47, pp. 1406-1413. , [CrossRef]; Muller, P., Matheis, F., Mucida, D., Gut macrophages: Key players in intestinal immunity and tissue physiology (2020) Curr. Opin. Immunol, 62, pp. 54-61. , [CrossRef]; Franchi, L., Kamada, N., Nakamura, Y., Burberry, A., Kuffa, P., Suzuki, S., Shaw, M.H., Nunez, G., NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense (2012) Nat. Immunol, 13, pp. 449-456. , [CrossRef]; Hayashi, A., Sato, T., Kamada, N., Mikami, Y., Matsuoka, K., Hisamatsu, T., Hibi, T., Ohteki, T., A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice (2013) Cell Host Microbe, 13, pp. 711-722. , [CrossRef]; Kim, M., Galan, C., Hill, A., Wu, W., Fehlner-Peach, H., Song, H., Schady, D., Longman, R., Critical Role for the Microbiota in CX (2018) Immunity, 49, pp. 151-163. , e155. [CrossRef]; Mortha, A., Chudnovskiy, A., Hashimoto, D., Bogunovic, M., Spencer, S.P., Belkaid, Y., Merad, M., Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis (2014) Science, 343, p. 1249288. , [CrossRef]; Hubbard, T.D., Murray, I.A., Nichols, R.G., Cassel, K., Podolsky, M., Kuzu, G., Tian, Y., Patterson, A.D., Dietary Broccoli Impacts Microbial Community Structure and Attenuates Chemically Induced Colitis in Mice in an Ah receptor dependent manner (2017) J. Funct. Foods, 37, pp. 685-698. , [CrossRef]; Chang, P.V., Hao, L., Offermanns, S., Medzhitov, R., The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition (2014) Proc. Natl. Acad. Sci. USA, 111, pp. 2247-2252. , [CrossRef]; Scott, N.A., Andrusaite, A., Andersen, P., Lawson, M., Alcon-Giner, C., Leclaire, C., Caim, S., Connolly, J.P.R., Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis (2018) Sci. Transl. Med, 10, p. eaao4755. , [CrossRef]; Russell, W.R., Hoyles, L., Flint, H.J., Dumas, M.E., Colonic bacterial metabolites and human health (2013) Curr. Opin. Microbiol, 16, pp. 246-254. , [CrossRef]; Maslowski, K.M., Mackay, C.R., Diet, gut microbiota and immune responses (2011) Nat. Immunol, 12, pp. 5-9. , [CrossRef]; Liu, H., Wang, J., He, T., Becker, S., Zhang, G., Li, D., Ma, X., Butyrate: A Double-Edged Sword for Health? (2018) Adv. Nutr, 9, pp. 21-29. , [CrossRef]; Andou, A., Hisamatsu, T., Okamoto, S., Chinen, H., Kamada, N., Kobayashi, T., Hashimoto, M., Takeda, T., Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages (2009) Gastroenterology, 136, pp. 564-574. , e562. [CrossRef]; Ochi, T., Feng, Y., Kitamoto, S., Nagao-Kitamoto, H., Kuffa, P., Atarashi, K., Honda, K., Kamada, N., Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine (2016) Sci. Rep, 6, p. 27634. , [CrossRef]; Li, P., Yin, Y.L., Li, D., Kim, S.W., Wu, G., Amino acids and immune function (2007) Br. J. Nutr, 98, pp. 237-252. , [CrossRef] [PubMed]; Statovci, D., Aguilera, M., MacSharry, J., Melgar, S., The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces (2017) Front. Immunol, 8, p. 838. , [CrossRef] [PubMed]; Wang, S., Ye, Q., Zeng, X., Qiao, S., Functions of Macrophages in the Maintenance of Intestinal Homeostasis (2019) J. Immunol. Res, 2019, p. 1512969. , [CrossRef] [PubMed]; Sirisinha, S., The pleiotropic role of vitamin A in regulating mucosal immunity (2015) Asian Pac. J. Allergy Immunol, 33, pp. 71-89; Manicassamy, S., Pulendran, B., Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages (2009) Semin. Immunol, 21, pp. 22-27. , [CrossRef]; McDaniel, K.L., Restori, K.H., Dodds, J.W., Kennett, M.J., Ross, A.C., Cantorna, M.T., Vitamin A-Deficient Hosts Become Nonsymptomatic Reservoirs of Escherichia coli-Like Enteric Infections (2015) Infect. Immun, 83, pp. 2984-2991. , [CrossRef]; Bai, A., Lu, N., Guo, Y., Liu, Z., Chen, J., Peng, Z., All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis (2009) J. Leukoc. Biol, 86, pp. 959-969. , [CrossRef]; Wang, X., Allen, C., Ballow, M., Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages (2007) J. Clin. Immunol, 27, pp. 193-200. , [CrossRef]; Yamada, H., Mizuno, S., Ross, A.C., Sugawara, I., Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis (2007) J. Nutr, 137, pp. 2696-2700. , [CrossRef]; Anand, P.K., Kaul, D., Downregulation of TACO gene transcription restricts mycobacterial entry/survival within human macrophages (2005) FEMS Microbiol. Lett, 250, pp. 137-144. , [CrossRef]; Zhang, Y., Leung, D.Y., Richers, B.N., Liu, Y., Remigio, L.K., Riches, D.W., Goleva, E., Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1 (2012) J. Immunol, 188, pp. 2127-2135. , [CrossRef]; Fabri, M., Stenger, S., Shin, D.M., Yuk, J.M., Liu, P.T., Realegeno, S., Lee, H.M., Sieling, P.A., Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages (2011) Sci. Transl. Med, 3, p. 104ra102. , [CrossRef]; Pouillon, L., Travis, S., Bossuyt, P., Danese, S., Peyrin-Biroulet, L., Head-to-head trials in inflammatory bowel disease: Past, present and future (2020) Nat. Rev. Gastroenterol. Hepatol, 17, pp. 365-376. , [CrossRef]; Schenk, M., Bouchon, A., Seibold, F., Mueller, C., TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases (2007) J. Clin. Investig, 117, pp. 3097-3106. , [CrossRef]; Thiesen, S., Janciauskiene, S., Uronen-Hansson, H., Agace, W., Högerkorp, C., Spee, P., Håkansson, K., Grip, O., CD14(hi)HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn’s disease (2014) J. Leukoc. Biol, 95, pp. 531-541. , [CrossRef]; Vos, A., Wildenberg, M., Arijs, I., Duijvestein, M., Verhaar, A., de Hertogh, G., Vermeire, S., Hommes, D., Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro (2012) Inflamm. Bowel Dis, 18, pp. 401-408. , [CrossRef]; Dige, A., Magnusson, M., Öhman, L., Hvas, C., Kelsen, J., Wick, M., Agnholt, J., Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn’s disease (2016) Scand. J. Gastroenterol, 51, pp. 692-699. , [CrossRef]; Kamada, N., Hisamatsu, T., Okamoto, S., Chinen, H., Kobayashi, T., Sato, T., Sakuraba, A., Koganei, K., Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis (2008) J. Clin. Investig, 118, pp. 2269-2280. , [CrossRef]; Takada, Y., Hisamatsu, T., Kamada, N., Kitazume, M., Honda, H., Oshima, Y., Saito, R., Chinen, H., Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset (2010) J. Immunol, 184, pp. 2671-2676. , [CrossRef]; Platt, A., Bain, C., Bordon, Y., Sester, D., Mowat, A., An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation (2010) J. Immunol, 184, pp. 6843-6854. , [CrossRef] [PubMed]; Schippers, A., Muschaweck, M., Clahsen, T., Tautorat, S., Grieb, L., Tenbrock, K., Gaßler, N., Wagner, N., β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon (2016) Mucosal. Immunol, 9, pp. 527-538. , [CrossRef] [PubMed]; Ingersoll, M., Spanbroek, R., Lottaz, C., Gautier, E., Frankenberger, M., Hoffmann, R., Lang, R., Tacke, F., Comparison of gene expression profiles between human and mouse monocyte subsets (2010) Blood, 115, pp. e10-e19. , [CrossRef]; Smith, P., Smythies, L., Shen, R., Greenwell-Wild, T., Gliozzi, M., Wahl, S., Intestinal macrophages and response to microbial encroachment (2011) Mucosal. Immunol, 4, pp. 31-42. , [CrossRef] [PubMed]; Asano, K., Takahashi, N., Ushiki, M., Monya, M., Aihara, F., Kuboki, E., Moriyama, S., Qiu, C., Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes (2015) Nat. Commun, 6, p. 7802. , [CrossRef]; Li, Q., Wang, D., Hao, S., Han, X., Xia, Y., Li, X., Chen, Y., Qiu, C., CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis (2017) Front. Immunol, 8, p. 669. , [CrossRef]; Rugtveit, J., Bakka, A., Brandtzaeg, P., Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD) (1997) Clin. Exp. Immunol, 110, pp. 104-113. , [CrossRef]; Carlsen, H., Yamanaka, T., Scott, H., Rugtveit, J., Brandtzaeg, P., The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propria (2006) Inflamm. Bowel Dis, 12, pp. 1013-1024. , [CrossRef]; Ahrens, R., Waddell, A., Seidu, L., Blanchard, C., Carey, R., Forbes, E., Lampinen, M., Stringer, K., Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis (2008) J. Immunol, 181, pp. 7390-7399. , [CrossRef]; Waddell, A., Ahrens, R., Steinbrecher, K., Donovan, B., Rothenberg, M., Munitz, A., Hogan, S., Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11 (2011) J. Immunol, 186, pp. 5993-6003. , [CrossRef]; Man, A., Gicheva, N., Regoli, M., Rowley, G., De Cunto, G., Wellner, N., Bassity, E., Nicoletti, C., CX3CR1+ Cell-Mediated Salmonella Exclusion Protects the Intestinal Mucosa during the Initial Stage of Infection (2017) J. Immunol, 198, pp. 335-343. , [CrossRef] [PubMed]; Dunay, I.R., Damatta, R.A., Fux, B., Presti, R., Greco, S., Colonna, M., Sibley, L.D., Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii (2008) Immunity, 29, pp. 306-317. , [CrossRef] [PubMed]; Zheng, Y., Valdez, P., Danilenko, D., Hu, Y., Sa, S., Gong, Q., Abbas, A., de Sauvage, F., Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens (2008) Nat. Med, 14, pp. 282-289. , [CrossRef] [PubMed]; Manta, C., Heupel, E., Radulovic, K., Rossini, V., Garbi, N., Riedel, C., Niess, J., CX(3)CR1(+) macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium (2013) Mucosal. Immunol, 6, pp. 177-188. , [CrossRef] [PubMed]; Hardbower, D., Singh, K., Asim, M., Verriere, T., Olivares-Villagómez, D., Barry, D., Allaman, M., Piazuelo, M., EGFR regulates macrophage activation and function in bacterial infection (2016) J. Clin. Investig, 126, pp. 3296-3312. , [CrossRef]; Grainger, J., Wohlfert, E., Fuss, I., Bouladoux, N., Askenase, M., Legrand, F., Koo, L., Belkaid, Y., Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection (2013) Nat. Med, 19, pp. 713-721. , [CrossRef]; Allen, J., Wynn, T., Evolution of Th2 immunity: A rapid repair response to tissue destructive pathogens (2011) PLoS Pathog, 7, p. e1002003. , [CrossRef]; Wolff, M., Broadhurst, M., Loke, P., Helminthic therapy: Improving mucosal barrier function (2012) Trends Parasitol, 28, pp. 187-194. , [CrossRef]; Wynn, T., Vannella, K., Macrophages in Tissue Repair, Regeneration, and Fibrosis (2016) Immunity, 44, pp. 450-462. , [CrossRef]; Maizels, R., Hewitson, J., Smith, K., Susceptibility and immunity to helminth parasites (2012) Curr. Opin. Immunol, 24, pp. 459-466. , [CrossRef]; Chen, F., Liu, Z., Wu, W., Rozo, C., Bowdridge, S., Millman, A., Van Rooijen, N., Gause, W., An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection (2012) Nat. Med, 18, pp. 260-266. , [CrossRef] [PubMed]; Borthwick, L., Barron, L., Hart, K., Vannella, K., Thompson, R., Oland, S., Cheever, A., Fisher, A., Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis (2016) Mucosal. Immunol, 9, pp. 38-55. , [CrossRef] [PubMed]; Bowcutt, R., Bell, L., Little, M., Wilson, J., Booth, C., Murray, P., Else, K., Cruickshank, S., Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris (2011) Parasite Immunol, 33, pp. 411-420. , [CrossRef] [PubMed]; Jenkins, S., Ruckerl, D., Cook, P., Jones, L., Finkelman, F., van Rooijen, N., MacDonald, A., Allen, J., Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation (2011) Science, 332, pp. 1284-1288. , [CrossRef]; Little, M., Hurst, R., Else, K., Dynamic changes in macrophage activation and proliferation during the development and resolution of intestinal inflammation (2014) J. Immunol, 193, pp. 4684-4695. , [CrossRef]; Lauber, K., Bohn, E., Krober, S.M., Xiao, Y.J., Blumenthal, S.G., Lindemann, R.K., Marini, P., Baksh, S., Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal (2003) Cell, 113, pp. 717-730. , [CrossRef]; Gude, D.R., Alvarez, S.E., Paugh, S.W., Mitra, P., Yu, J., Griffiths, R., Barbour, S.E., Spiegel, S., Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal (2008) FASEB J, 22, pp. 2629-2638. , [CrossRef]; Truman, L.A., Ford, C.A., Pasikowska, M., Pound, J.D., Wilkinson, S.J., Dumitriu, I.E., Melville, L., Nibbs, R., CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis (2008) Blood, 112, pp. 5026-5036. , [CrossRef]; Zigmond, E., Varol, C., Farache, J., Elmaliah, E., Satpathy, A.T., Friedlander, G., Mack, M., Murphy, K.M., Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells (2012) Immunity, 37, pp. 1076-1090. , [CrossRef]; Vong, L., Ferraz, J.G., Panaccione, R., Beck, P.L., Wallace, J.L., A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis (2010) Proc. Natl. Acad. Sci. USA, 107, pp. 12023-12027. , [CrossRef]; Kong, D., Shen, Y., Liu, G., Zuo, S., Ji, Y., Lu, A., Nakamura, M., Breyer, R.M., PKA regulatory IIalpha subunit is essential for PGD2-mediated resolution of inflammation (2016) J. Exp. Med, 213, pp. 2209-2226. , [CrossRef]; Chinen, T., Komai, K., Muto, G., Morita, R., Inoue, N., Yoshida, H., Sekiya, T., Takayanagi, R., Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance (2011) Nat. Commun, 2, p. 190. , [CrossRef] [PubMed]; Libioulle, C., Louis, E., Hansoul, S., Sandor, C., Farnir, F., Franchimont, D., Vermeire, S., Dixon, A., Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4 (2007) PLoS Genet, 3, p. e58. , [CrossRef] [PubMed]; Uranga, J.A., Lopez-Miranda, V., Lombo, F., Abalo, R., Food, nutrients and nutraceuticals affecting the course of inflammatory bowel disease (2016) Pharmacol. Rep, 68, pp. 816-826. , [CrossRef] [PubMed]; Christ, A., Lauterbach, M., Latz, E., Western Diet and the Immune System: An Inflammatory Connection (2019) Immunity, 51, pp. 794-811. , [CrossRef] [PubMed]; Shoelson, S.E., Herrero, L., Naaz, A., Obesity, inflammation, and insulin resistance (2007) Gastroenterology, 132, pp. 2169-2180. , [CrossRef]; Mozaffarian, D., Hao, T., Rimm, E.B., Willett, W.C., Hu, F.B., Changes in diet and lifestyle and long-term weight gain in women and men (2011) N. Engl. J. Med, 364, pp. 2392-2404. , [CrossRef] [PubMed]; Tanoue, T., Honda, K., Induction of Treg cells in the mouse colonic mucosa: A central mechanism to maintain host-microbiota homeostasis (2012) Semin. Immunol, 24, pp. 50-57. , [CrossRef]; Buc, M., Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis (2013) Mediators Inflamm, 2013, p. 963748. , [CrossRef] [PubMed]; Darfeuille-Michaud, A., Boudeau, J., Bulois, P., Neut, C., Glasser, A.L., Barnich, N., Bringer, M.A., Colombel, J.F., High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease (2004) Gastroenterology, 127, pp. 412-421. , [CrossRef]; Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermudez-Humaran, L.G., Gratadoux, J.J., Blugeon, S., Corthier, G., Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients (2008) Proc. Natl. Acad. Sci. USA, 105, pp. 16731-16736. , [CrossRef] [PubMed]; Sun, P., Wang, H., He, Z., Chen, X., Wu, Q., Chen, W., Sun, Z., Ma, D., Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages (2017) Oncotarget, 8, pp. 74649-74660. , [CrossRef]; Lee, J.Y., Plakidas, A., Lee, W.H., Heikkinen, A., Chanmugam, P., Bray, G., Hwang, D.H., Differential modulation of Toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids (2003) J. Lipid Res, 44, pp. 479-486. , [CrossRef] [PubMed]; Moreira, A.P., Texeira, T.F., Ferreira, A.B., Peluzio Mdo, C., Alfenas Rde, C., Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia (2012) Br. J. Nutr, 108, pp. 801-809. , [CrossRef]; Lee, J.Y., Ye, J., Gao, Z., Youn, H.S., Lee, W.H., Zhao, L., Sizemore, N., Hwang, D.H., Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids (2003) J. Biol. Chem, 278, pp. 37041-37051. , [CrossRef]; Barbalho, S.M., Goulart Rde, A., Quesada, K., Bechara, M.D., de Carvalho Ade, C., Inflammatory bowel disease: Can omega-3 fatty acids really help? (2016) Ann. Gastroenterol, 29, pp. 37-43. , [PubMed]; Buckley, C.D., Gilroy, D.W., Serhan, C.N., Proresolving lipid mediators and mechanisms in the resolution of acute inflammation (2014) Immunity, 40, pp. 315-327. , [CrossRef]; Dalli, J., Serhan, C.N., Pro-Resolving Mediators in Regulating and Conferring Macrophage Function (2017) Front. Immunol, 8, p. 1400. , [CrossRef]; Gobbetti, T., Dalli, J., Colas, R.A., Federici Canova, D., Aursnes, M., Bonnet, D., Alric, L., Hansen, T.V., Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection (2017) Proc. Natl. Acad. Sci. USA, 114, pp. 3963-3968. , [CrossRef]; Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., Miglioli, M., Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease (1996) N. Engl. J. Med, 334, pp. 1557-1560. , [CrossRef]; Barbosa, D.S., Cecchini, R., El Kadri, M.Z., Rodriguez, M.A., Burini, R.C., Dichi, I., Decreased oxidative stress in patients with ulcerative colitis supplemented with fish oil omega-3 fatty acids (2003) Nutrition, 19, pp. 837-842. , [CrossRef]; Romano, C., Cucchiara, S., Barabino, A., Annese, V., Sferlazzas, C., Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn’s disease: A double-blind, randomized, placebo-controlled study (2005) World J. Gastroenterol, 11, pp. 7118-7121. , [CrossRef] [PubMed]; Bento, A.F., Claudino, R.F., Dutra, R.C., Marcon, R., Calixto, J.B., Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice (2011) J. Immunol, 187, pp. 1957-1969. , [CrossRef] [PubMed]; Vernia, P., Gnaedinger, A., Hauck, W., Breuer, R.I., Organic anions and the diarrhea of inflammatory bowel disease (1988) Dig. Dis. Sci, 33, pp. 1353-1358. , [CrossRef] [PubMed]; Frank, D.N., St Amand, A.L., Feldman, R.A., Boedeker, E.C., Harpaz, N., Pace, N.R., Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases (2007) Proc. Natl. Acad. Sci. USA, 104, pp. 13780-13785. , [CrossRef] [PubMed]; Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., Verbeke, K., A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis (2014) Gut, 63, pp. 1275-1283. , [CrossRef]; Vieira, E.L., Leonel, A.J., Sad, A.P., Beltrao, N.R., Costa, T.F., Ferreira, T.M., Gomes-Santos, A.C., Cara, D.C., Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis (2012) J. Nutr. Biochem, 23, pp. 430-436. , [CrossRef]; Dicarlo, M., Teti, G., Verna, G., Liso, M., Cavalcanti, E., Sila, A., Raveenthiraraj, S., Serino, G., Quercetin Exposure Suppresses the Inflammatory Pathway in Intestinal Organoids from Winnie Mice (2019) Int. J. Mol. Sci, 20, p. 5771. , [CrossRef]; Weisshof, R., Chermesh, I., Micronutrient deficiencies in inflammatory bowel disease (2015) Curr. Opin. Clin. Nutr. Metab. Care, 18, pp. 576-581. , [CrossRef]; Burkholder, P.R., McVeigh, I., Synthesis of Vitamins by Intestinal Bacteria (1942) Proc. Natl. Acad. Sci. USA, 28, pp. 285-289. , [CrossRef]; Simmons, J.D., Mullighan, C., Welsh, K.I., Jewell, D.P., Vitamin D receptor gene polymorphism: Association with Crohn’s disease susceptibility (2000) Gut, 47, pp. 211-214. , [CrossRef] [PubMed]; Liu, W., Chen, Y., Golan, M.A., Annunziata, M.L., Du, J., Dougherty, U., Kong, J., Pekow, J., Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis (2013) J. Clin. Investig, 123, pp. 3983-3996. , [CrossRef] [PubMed]; Ryz, N.R., Patterson, S.J., Zhang, Y., Ma, C., Huang, T., Bhinder, G., Wu, X., Sham, H.P., Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses (2012) Am. J. Physiol. Gastrointest. Liver Physiol, 303, pp. G1299-G1311. , [CrossRef] [PubMed]; Ooi, J.H., Li, Y., Rogers, C.J., Cantorna, M.T., Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis (2013) J. Nutr, 143, pp. 1679-1686. , [CrossRef] [PubMed]; Shiraishi, E., Iijima, H., Shinzaki, S., Nakajima, S., Inoue, T., Hiyama, S., Kawai, S., Hayashi, Y., Vitamin K deficiency leads to exacerbation of murine dextran sulfate sodium-induced colitis (2016) J. Gastroenterol, 51, pp. 346-356. , [CrossRef]; Michielan, A., D’Inca, R., Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut (2015) Mediators Inflamm, 2015, p. 628157. , [CrossRef]; Lyons, C.L., Kennedy, E.B., Roche, H.M., Metabolic Inflammation-Differential Modulation by Dietary Constituents (2016) Nutrients, 8, p. 247. , [CrossRef]; Rodrigues, V.S., Milanski, M., Fagundes, J.J., Torsoni, A.S., Ayrizono, M.L., Nunez, C.E., Dias, C.B., Coy, C.S., Serum levels and mesenteric fat tissue expression of adiponectin and leptin in patients with Crohn’s disease (2012) Clin. Exp. Immunol, 170, pp. 358-364. , [CrossRef]; Pietsch, J., Batra, A., Stroh, T., Fedke, I., Glauben, R., Okur, B., Zeitz, M., Siegmund, B., Toll-like receptor expression and response to specific stimulation in adipocytes and preadipocytes: On the role of fat in inflammation (2006) Ann. N. Y. Acad. Sci, 1072, pp. 407-409. , [CrossRef]; Schwingshackl, L., Hoffmann, G., Mediterranean dietary pattern, inflammation and endothelial function: A systematic review and meta-analysis of intervention trials (2014) Nutr. Metab. Cardiovasc. Dis, 24, pp. 929-939. , [CrossRef]; Caprara, G., Diet and longevity: The effects of traditional eating habits on human lifespan extension (2018) Med. J. Nutr. Metab, 11, pp. 261-294. , [CrossRef]; Ghosh, T.S., Rampelli, S., Jeffery, I.B., Santoro, A., Neto, M., Capri, M., Giampieri, E., Turroni, S., Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: The NU-AGE 1-year dietary intervention across five European countries (2020) Gut, 69, pp. 1218-1228. , [CrossRef]; Meslier, V., Laiola, M., Roager, H.M., De Filippis, F., Roume, H., Quinquis, B., Giacco, R., Pons, N., Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake (2020) Gut, 69, pp. 1258-1268. , [CrossRef] [PubMed]; Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., Allavena, P., Tumour-associated macrophages as treatment targets in oncology (2017) Nat. Rev. Clin. Oncol, 14, pp. 399-416. , [CrossRef]; Kiss, M., Van Gassen, S., Movahedi, K., Saeys, Y., Laoui, D., Myeloid cell heterogeneity in cancer: Not a single cell alike (2018) Cell. Immunol, 330, pp. 188-201. , [CrossRef] [PubMed]; DeNardo, D.G., Ruffell, B., Macrophages as regulators of tumour immunity and immunotherapy (2019) Nat. Rev. Immunol, 19, pp. 369-382. , [CrossRef] [PubMed]; De Palma, M., Lewis, C., Macrophage regulation of tumor responses to anticancer therapies (2013) Cancer Cell, 23, pp. 277-286. , [CrossRef] [PubMed]; Geissmann, F., Gordon, S., Hume, D.A., Mowat, A.M., Randolph, G.J., Unravelling mononuclear phagocyte heterogeneity (2010) Nat. Rev. Immunol, 10, pp. 453-460. , [CrossRef]; Gordon, S., Pluddemann, A., Martinez Estrada, F., Macrophage heterogeneity in tissues: Phenotypic diversity and functions (2014) Immunol. Rev, 262, pp. 36-55. , [CrossRef]; Locati, M., Curtale, G., Mantovani, A., Diversity, Mechanisms, and Significance of Macrophage Plasticity (2020) Annu. Rev. Pathol, 15, pp. 123-147. , [CrossRef]; Mosser, D., Edwards, J., Exploring the full spectrum of macrophage activation (2008) Nat. Rev. Immunol, 8, pp. 958-969. , [CrossRef] [PubMed]; Sica, A., Mantovani, A., Macrophage plasticity and polarization: In vivo veritas (2012) J. Clin. Investig, 122, pp. 787-795. , [CrossRef] [PubMed]; Sica, A., Erreni, M., Allavena, P., Porta, C., Macrophage polarization in pathology (2015) Cell. Mol. Life Sci, 72, pp. 4111-4126. , 26. [CrossRef]; Pollard, J., Tumour-educated macrophages promote tumour progression and metastasis (2004) Nat. Rev. Cancer, 4, pp. 71-78. , [CrossRef]; Balkwill, F., Charles, K., Mantovani, A., Smoldering and polarized inflammation in the initiation and promotion of malignant disease (2005) Cancer Cell, 7, pp. 211-217. , [CrossRef] [PubMed]; Condeelis, J., Pollard, J., Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis (2006) Cell, 124, pp. 263-266. , [CrossRef]; Noy, R., Pollard, J., Tumor-associated macrophages: From mechanisms to therapy (2014) Immunity, 41, pp. 49-61. , [CrossRef]; Ruffell, B., Coussens, L.M., Macrophages and therapeutic resistance in cancer (2015) Cancer Cell, 27, pp. 462-472. , [CrossRef]; Cassetta, L., Pollard, J.W., Targeting macrophages: Therapeutic approaches in cancer (2018) Nat. Rev. Drug Discov, 17, pp. 887-904. , [CrossRef]; Long, A., Lundsmith, E., Hamilton, K., Inflammation and Colorectal Cancer (2017) Curr. Colorectal. Cancer Rep, 13, pp. 341-351. , [CrossRef]; Diet, Nutrition, Physical Activity, and Cancer: A Global Perspective. Continuous Update Project Expert Report 2018, , https://www.wcrf.org/sites/default/files/Summary-of-Third-Expert-Report-2018.pdf, World Cancer Research Fund/American Institute for Cancer Research. (accessed on 2 July 2020); Yahaya, M., Lila, M., Ismail, S., Zainol, M., Afizan, N., Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them (2019) J. Immunol. Res, 2019, p. 2368249. , [CrossRef] [PubMed]; Lynch, H., de la Chapelle, A., Hereditary colorectal cancer (2003) N. Engl. J. Med, 348, pp. 919-932. , [CrossRef] [PubMed]; Rustgi, A., The genetics of hereditary colon cancer (2007) Genes Dev, 21, pp. 2525-2538. , [CrossRef] [PubMed]; Gupta, R., Harpaz, N., Itzkowitz, S., Hossain, S., Matula, S., Kornbluth, A., Bodian, C., Ullman, T., Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: A cohort study (2007) Gastroenterology, 133, pp. 1099-1105. , discussion 1340–1341. [CrossRef] [PubMed]; Erreni, M., Bianchi, P., Laghi, L., Mirolo, M., Fabbri, M., Locati, M., Mantovani, A., Allavena, P., Expression of chemokines and chemokine receptors in human colon cancer (2009) Methods Enzymol, 460, pp. 105-121. , [CrossRef]; Erreni, M., Mantovani, A., Allavena, P., Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer (2011) Cancer Microenviron, 4, pp. 141-154. , [CrossRef] [PubMed]; Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Wind, P., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome (2006) Science, 313, pp. 1960-1964. , [CrossRef]; Laghi, L., Bianchi, P., Miranda, E., Balladore, E., Pacetti, V., Grizzi, F., Allavena, P., Santoro, A., CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: A longitudinal study (2009) Lancet Oncol, 10, pp. 877-884. , [CrossRef]; Angell, H., Bruni, D., Barrett, J., Herbst, R., Galon, J., The Immunoscore: Colon Cancer and Beyond (2020) Clin. Cancer Res, 26, pp. 332-339. , [CrossRef] [PubMed]; Galdiero, M., Bianchi, P., Grizzi, F., Di Caro, G., Basso, G., Ponzetta, A., Bonavita, E., Polentarutti, N., Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer (2016) Int. J. Cancer, 139, pp. 446-456. , [CrossRef]; Braster, R., Bögels, M., Beelen, R., van Egmond, M., The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential (2017) Immunobiology, 222, pp. 21-30. , [CrossRef] [PubMed]; Deng, L., Zhou, J., Sellers, R., Li, J., Nguyen, A., Wang, Y., Orlofsky, A., Pollard, J., A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis (2010) Am. J. Pathol, 176, pp. 952-967. , [CrossRef] [PubMed]; Popivanova, B., Kitamura, K., Wu, Y., Kondo, T., Kagaya, T., Kaneko, S., Oshima, M., Mukaida, N., Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis (2008) J. Clin. Investig, 118, pp. 560-570. , [CrossRef] [PubMed]; Afik, R., Zigmond, E., Vugman, M., Klepfish, M., Shimshoni, E., Pasmanik-Chor, M., Shenoy, A., Geiger, T., Tumor macrophages are pivotal constructors of tumor collagenous matrix (2016) J. Exp. Med, 213, pp. 2315-2331. , [CrossRef]; Pinto, M., Rios, E., Silva, A., Neves, S., Caires, H., Pinto, A., Durães, C., Santos, N., Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18 (2017) Biomaterials, 124, pp. 211-224. , [CrossRef]; Marelli, G., Erreni, M., Anselmo, A., Taverniti, V., Guglielmetti, S., Mantovani, A., Allavena, P., Heme-oxygenase-1 production by intestinal CX3CR1(+) macrophages helps to resolve inflammation and prevents carcinogenesis (2017) Cancer Res, 77, pp. 4472-4485. , [CrossRef]; Oosterling, S., van der Bij, G., Meijer, G., Tuk, C., van Garderen, E., van Rooijen, N., Meijer, S., van Egmond, M., Macrophages direct tumour histology and clinical outcome in a colon cancer model (2005) J. Pathol, 207, pp. 147-155. , [CrossRef]; Grossman, J., Nywening, T., Belt, B., Panni, R., Krasnick, B., DeNardo, D., Hawkins, W., Fields, R., Recruitment of CCR2 (2018) Oncoimmunology, 7, p. e1470729. , [CrossRef]; Cortese, N., Soldani, C., Franceschini, B., Barbagallo, M., Marchesi, F., Torzilli, G., Donadon, M., Macrophages in Colorectal Cancer Liver Metastases (2019) Cancers, 11, p. 633. , [CrossRef]; Forssell, J., Oberg, A., Henriksson, M., Stenling, R., Jung, A., Palmqvist, R., High macrophage infiltration along the tumor front correlates with improved survival in colon cancer (2007) Clin. Cancer Res, 13, pp. 1472-1479. , [CrossRef]; Zhou, Q., Peng, R., Wu, X., Xia, Q., Hou, J., Ding, Y., Zhou, Q., Wan, D., The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer (2010) J. Transl. Med, 8, p. 13. , [CrossRef] [PubMed]; Kang, J., Chen, J., Lee, C., Chang, J., Shieh, Y., Intratumoral macrophage counts correlate with tumor progression in colorectal cancer (2010) J. Surg. Oncol, 102, pp. 242-248. , [CrossRef]; Kwak, Y., Koh, J., Kim, D., Kang, S., Kim, W., Lee, H., Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer (2016) Oncotarget, 7, pp. 81778-81790. , [CrossRef] [PubMed]; Bailey, C., Negus, R., Morris, A., Ziprin, P., Goldin, R., Allavena, P., Peck, D., Darzi, A., Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer (2007) Clin. Exp. Metastasis, 24, pp. 121-130. , [CrossRef] [PubMed]; Malesci, A., Bianchi, P., Celesti, G., Basso, G., Marchesi, F., Grizzi, F., Di Caro, G., Palmqvist, R., Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer (2017) Oncoimmunology, 6, p. e1342918. , [CrossRef]; Pinto, M., Rios, E., Durães, C., Ribeiro, R., Machado, J., Mantovani, A., Barbosa, M., Oliveira, M., The Two Faces of Tumor-Associated Macrophages and Their Clinical Significance in Colorectal Cancer (2019) Front. Immunol, 10, p. 1875. , [CrossRef]; De Almeida, C.V., de Camargo, M.R., Russo, E., Amedei, A., Role of diet and gut microbiota on colorectal cancer immunomodulation (2019) World J. Gastroenterol, 25, pp. 151-162. , [CrossRef]; Raskov, H., Burcharth, J., Pommergaard, H.C., Linking Gut Microbiota to Colorectal Cancer (2017) J. Cancer, 8, pp. 3378-3395. , [CrossRef]; Ma, W., Mao, Q., Xia, W., Dong, G., Yu, C., Jiang, F., Gut Microbiota Shapes the Efficiency of Cancer Therapy (2019) Front. Microbiol, 10, p. 1050. , [CrossRef]; Ahn, J., Sinha, R., Pei, Z., Dominianni, C., Wu, J., Shi, J., Goedert, J.J., Yang, L., Human gut microbiome and risk for colorectal cancer (2013) J. Natl. Cancer Inst, 105, pp. 1907-1911. , [CrossRef]; Kunzmann, A.T., Proenca, M.A., Jordao, H.W., Jiraskova, K., Schneiderova, M., Levy, M., Liska, V., Vymetalkova, V., Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients (2019) Eur. J. Clin. Microbiol. Infect. Dis, 38, pp. 1891-1899. , [CrossRef] [PubMed]; Boleij, A., Hechenbleikner, E.M., Goodwin, A.C., Badani, R., Stein, E.M., Lazarev, M.G., Ellis, B., Wick, E.C., The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients (2015) Clin. Infect. Dis, 60, pp. 208-215. , [CrossRef] [PubMed]; Yu, L.C., Wei, S.C., Ni, Y.H., Impact of microbiota in colorectal carcinogenesis: Lessons from experimental models (2018) Intest. Res, 16, pp. 346-357. , [CrossRef]; Dai, Z., Coker, O.O., Nakatsu, G., Wu, W.K.K., Zhao, L., Chen, Z., Chan, F.K.L., Wong, S.H., Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers (2018) Microbiome, 6, p. 70. , [CrossRef] [PubMed]; Tilg, H., Adolph, T.E., Gerner, R.R., Moschen, A.R., The Intestinal Microbiota in Colorectal Cancer (2018) Cancer Cell, 33, pp. 954-964. , [CrossRef] [PubMed]; Thomas, A.M., Manghi, P., Asnicar, F., Pasolli, E., Armanini, F., Zolfo, M., Beghini, F., Pozzi, C., Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation (2019) Nat. Med, 25, pp. 667-678. , [CrossRef] [PubMed]; Song, M., Chan, A.T., Sun, J., Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) Gastroenterology, 158, pp. 322-340. , [CrossRef]; Murphy, E.A., Davis, J.M., McClellan, J.L., Carmichael, M.D., Quercetin’s effects on intestinal polyp multiplicity and macrophage number in the Apc(Min/+) mouse (2011) Nutr. Cancer, 63, pp. 421-426. , [CrossRef]; Song, M., Garrett, W.S., Chan, A.T., Nutrients, foods, and colorectal cancer prevention (2015) Gastroenterology, 148, pp. 1244-1260. , e1216. [CrossRef]; Bae, S., Ulrich, C.M., Neuhouser, M.L., Malysheva, O., Bailey, L.B., Xiao, L., Brown, E.C., Cheng, T.Y., Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study (2014) Cancer Res, 74, pp. 7442-7452. , [CrossRef]; Da Silva, M., Jaggers, G.K., Verstraeten, S.V., Erlejman, A.G., Fraga, C.G., Oteiza, P.I., Large procyanidins prevent bile-acid-induced oxidant production and membrane-initiated ERK1/2, p38, and Akt activation in Caco-2 cells (2012) Free Radic. Biol. Med, 52, pp. 151-159. , [CrossRef] [PubMed]; Bingham, S.A., Day, N.E., Luben, R., Ferrari, P., Slimani, N., Norat, T., Clavel-Chapelon, F., Boeing, H., Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): An observational study (2003) Lancet, 361, pp. 1496-1501. , [CrossRef]; Murphy, N., Norat, T., Ferrari, P., Jenab, M., Bueno-de-Mesquita, B., Skeie, G., Dahm, C.C., Tjonneland, A., Dietary fibre intake and risks of cancers of the colon and rectum in the European prospective investigation into cancer and nutrition (EPIC) (2012) PLoS ONE, 7, p. e39361. , [CrossRef] [PubMed]; Afrin, S., Giampieri, F., Gasparrini, M., Forbes-Hernandez, T.Y., Cianciosi, D., Reboredo-Rodriguez, P., Zhang, J., Atanasov, A.G., Dietary phytochemicals in colorectal cancer prevention and treatment: A focus on the molecular mechanisms involved (2020) Biotechnol. Adv, 38, p. 107322. , [CrossRef]; Ferrante, A.W., The immune cells in adipose tissue (2013) Diabetes Obes. Metab, 15, pp. 34-38. , (Suppl. 3), [CrossRef]; Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante, A.W., Obesity is associated with macrophage accumulation in adipose tissue (2003) J. Clin. Investig, 112, pp. 1796-1808. , [CrossRef] [PubMed]; McNelis, J.C., Olefsky, J.M., Macrophages, immunity, and metabolic disease (2014) Immunity, 41, pp. 36-48. , [CrossRef]; Day, S.D., Enos, R.T., McClellan, J.L., Steiner, J.L., Velazquez, K.T., Murphy, E.A., Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer (2013) Cytokine, 64, pp. 454-462. , [CrossRef] [PubMed]; Wunderlich, C.M., Ackermann, P.J., Ostermann, A.L., Adams-Quack, P., Vogt, M.C., Tran, M.L., Nikolajev, A., Theurich, S., Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment (2018) Nat. Commun, 9, p. 1646. , [CrossRef]; Bantel, H., Berg, C., Vieth, M., Stolte, M., Kruis, W., Schulze-Osthoff, K., Mesalazine inhibits activation of transcription factor NF-kappaB in inflamed mucosa of patients with ulcerative colitis (2000) Am. J. Gastroenterol, 95, pp. 3452-3457. , [CrossRef] [PubMed]; Giles, K., Ross, K., Rossi, A., Hotchin, N., Haslett, C., Dransfield, I., Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac (2001) J. Immunol, 167, pp. 976-986. , [CrossRef] [PubMed]; Ehrchen, J., Steinmüller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Roth, J., Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes (2007) Blood, 109, pp. 1265-1274. , [CrossRef] [PubMed]; Mowat, C., Cole, A., Windsor, A., Ahmad, T., Arnott, I., Driscoll, R., Mitton, S., Younge, L., Guidelines for the management of inflammatory bowel disease in adults (2011) Gut, 60, pp. 571-607. , [CrossRef] [PubMed]; Oakley, R., Cidlowski, J., The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease (2013) J. Allergy Clin. Immunol, 132, pp. 1033-1044. , [CrossRef]; Andón, F., Digifico, E., Maeda, A., Erreni, M., Mantovani, A., Alonso, M., Allavena, P., Targeting tumor associated macrophages: The new challenge for nanomedicine (2017) Semin. Immunol, 34, pp. 103-113. , [CrossRef]; Zhang, X., Chen, Y., Hao, L., Hou, A., Chen, X., Li, Y., Wang, R., Ou, J., Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine (2016) Cancer Lett, 381, pp. 305-313. , [CrossRef]; Liu, Z., Xie, Y., Xiong, Y., Liu, S., Qiu, C., Zhu, Z., Mao, H., Wang, X., TLR 7/8 agonist reverses oxaliplatin resistance in colorectal cancer via directing the myeloid-derived suppressor cells to tumoricidal M1-macrophages (2020) Cancer Lett, 469, pp. 173-185. , [CrossRef]; Zhang, W., Gordon, M., Schultheis, A., Yang, D., Nagashima, F., Azuma, M., Chang, H., Sherrod, A., FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab (2007) J. Clin. Oncol, 25, pp. 3712-3718. , [CrossRef]; Halama, N., Zoernig, I., Berthel, A., Kahlert, C., Klupp, F., Suarez-Carmona, M., Suetterlin, T., Lasitschka, F., Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients (2016) Cancer Cell, 29, pp. 587-601. , [CrossRef]; Nakamura, K., Smyth, M.J., Myeloid immunosuppression and immune checkpoints in the tumor microenvironment (2020) Cell. Mol. Immunol, 17, pp. 1-12. , [CrossRef] [PubMed]

PY - 2020

Y1 - 2020

N2 - Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte–macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

AB - Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte–macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

KW - Colorectal cancer

KW - Diet

KW - Gut

KW - Inflammation

KW - Intestine

KW - Macrophage

KW - Microbiota

KW - Tumor-associated macrophage

KW - alphaVbeta5 integrin

KW - B7 antigen

KW - CD40 antigen

KW - chemokine receptor CCR2

KW - chemokine receptor CX3CR1

KW - fractalkine

KW - interleukin 10

KW - interleukin 10 receptor

KW - interleukin 6

KW - interleukin 8

KW - monocyte chemotactic protein 1

KW - omega 3 fatty acid

KW - retinol

KW - saturated fatty acid

KW - short chain fatty acid

KW - toll like receptor 2

KW - trace element

KW - transcription factor RUNX3

KW - transforming growth factor beta

KW - vitamin D

KW - cell differentiation

KW - colorectal cancer

KW - diet therapy

KW - dietary fiber

KW - down regulation

KW - environmental factor

KW - gene expression

KW - human

KW - immune response

KW - inflammatory bowel disease

KW - intestine cell

KW - intestine flora

KW - intestine infection

KW - macrophage

KW - missense mutation

KW - nonhuman

KW - processed meat

KW - protein expression

KW - protein localization

KW - red meat

KW - Review

KW - tissue repair

KW - tumor associated leukocyte

KW - upregulation

KW - Western diet

U2 - 10.3390/ijms21144825

DO - 10.3390/ijms21144825

M3 - Article

VL - 21

SP - 1

EP - 31

JO - Int. J. Mol. Sci.

JF - Int. J. Mol. Sci.

SN - 1661-6596

IS - 14

ER -