TY - JOUR
T1 - A Specific Mutation in Muc2 Determines Early Dysbiosis in Colitis-Prone Winnie Mice
AU - Liso, Marina
AU - De Santis, Stefania
AU - Verna, Giulio
AU - Dicarlo, Manuela
AU - Calasso, Maria
AU - Santino, Angelo
AU - Gigante, Isabella
AU - Eri, Rajaraman
AU - Raveenthiraraj, Sathuwarman
AU - Sobolewski, Anastasia
AU - Palmitessa, Valeria
AU - Lippolis, Antonio
AU - Mastronardi, Mauro
AU - Armentano, Raffaele
AU - Serino, Grazia
AU - De Angelis, Maria
AU - Chieppa, Marcello
N1 - Funding Information:
From the *National Institute of Gastroenterology “S. de Bellis,” Institute of Research, Castellana Grotte (BA), Italy; †Department of Pharmacy, School of Pharmacy, University of Salerno, Fisciano (SA), Italy; ‡Department of Soil, Plant and Food Sciences, University of Bari, Bari, Italy; §Institute of Sciences of Food Production C.N.R., Unit of Lecce, Lecce, Italy; ¶Mucosal Biology, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia; ‖School of Pharmacy University of East Anglia, Norwich Research Park, Norwich, UK; **Department of Immunology and Cell Biology, European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy aEqual contribution Conflicts of Interest: The authors declare no financial or commercial conflicts of interest. Supported by:This work was supported by the Italian Ministry of Health GR-2011-02347991, GR-2009-1470633, the Ricerca Corrente 2016 and PON “2014-2020 E FSC –C.P. ARS01_01220” – BIOMIS.
Publisher Copyright:
© 2020 Crohn's & Colitis Foundation. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3/4
Y1 - 2020/3/4
N2 - Background: Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is a multifactorial disorder characterized by chronic inflammation and altered gut barrier function. Dysbiosis, a condition defined by dysregulation of the gut microbiome, has been reported in patients with IBD and in experimental models of colitis. Although several factors have been implicated in directly affecting gut microbial composition, the genetic determinants impacting intestinal dysbiosis in IBD remain relatively unknown. Methods: We compared the microbiome of normal, uninflamed wild-type (WT) mice with that of a murine model of UC (ie, Winnie strain). Winnie mice possess a missense mutation in Muc2 that manifests in altered mucus production as early as 4 weeks of age, with ensuing colonic inflammation. To better address the potential role of mutant Muc2 in promoting dysbiosis in Winnie mice, we evaluated homozygous mutant mice (Winnie-/-) with their WT littermates that, after weaning from common mothers, were caged separately according to genotype. Histologic and inflammatory status were assessed over time, along with changes in their respective microbiome compositions. Results: Dysbiosis in Winnie mice was already established at 4 weeks of age, before histologic evidence of gut inflammatory changes, in which microbial communities diverged from that derived from their mothers. Furthermore, dysbiosis persisted until 12 weeks of age, with peak differences in microbiome composition observed between Winnie and WT mice at 8 weeks of age. The relative abundance of Bacteroidetes was greater in Winnie compared with WT mice. Verrucomicrobia was detected at the highest relative levels in 4-week-old Winnie mice; in particular, Akkermansia muciniphila was among the most abundant species found at 4 weeks of age. Conclusions: Our results demonstrate that mutant genetic determinants involved in the complex regulation of intestinal homeostasis, such as that observed in Winnie mice, are able to promote early gut dysbiosis that is independent from maternal microbial transfer, including breastfeeding. Our data provide evidence for intestinal dysbiosis attributed to a Muc2-driven mucus defect that leads to colonic inflammation and may represent an important target for the design of future interventional studies.
AB - Background: Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is a multifactorial disorder characterized by chronic inflammation and altered gut barrier function. Dysbiosis, a condition defined by dysregulation of the gut microbiome, has been reported in patients with IBD and in experimental models of colitis. Although several factors have been implicated in directly affecting gut microbial composition, the genetic determinants impacting intestinal dysbiosis in IBD remain relatively unknown. Methods: We compared the microbiome of normal, uninflamed wild-type (WT) mice with that of a murine model of UC (ie, Winnie strain). Winnie mice possess a missense mutation in Muc2 that manifests in altered mucus production as early as 4 weeks of age, with ensuing colonic inflammation. To better address the potential role of mutant Muc2 in promoting dysbiosis in Winnie mice, we evaluated homozygous mutant mice (Winnie-/-) with their WT littermates that, after weaning from common mothers, were caged separately according to genotype. Histologic and inflammatory status were assessed over time, along with changes in their respective microbiome compositions. Results: Dysbiosis in Winnie mice was already established at 4 weeks of age, before histologic evidence of gut inflammatory changes, in which microbial communities diverged from that derived from their mothers. Furthermore, dysbiosis persisted until 12 weeks of age, with peak differences in microbiome composition observed between Winnie and WT mice at 8 weeks of age. The relative abundance of Bacteroidetes was greater in Winnie compared with WT mice. Verrucomicrobia was detected at the highest relative levels in 4-week-old Winnie mice; in particular, Akkermansia muciniphila was among the most abundant species found at 4 weeks of age. Conclusions: Our results demonstrate that mutant genetic determinants involved in the complex regulation of intestinal homeostasis, such as that observed in Winnie mice, are able to promote early gut dysbiosis that is independent from maternal microbial transfer, including breastfeeding. Our data provide evidence for intestinal dysbiosis attributed to a Muc2-driven mucus defect that leads to colonic inflammation and may represent an important target for the design of future interventional studies.
KW - dysbiosis
KW - inflammatory bowel disease (IBD)
KW - microbiome
KW - murine model of ulcerative colitis (UC)
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U2 - 10.1093/ibd/izz279
DO - 10.1093/ibd/izz279
M3 - Article
C2 - 31748792
AN - SCOPUS:85081088411
VL - 26
SP - 546
EP - 556
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
SN - 1078-0998
IS - 4
ER -