Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase

Sandra Angulo, Albert Morales, Silvio Danese, Laura Llacuna, Maria Carme Masamunt, Nicole Pultz, Maria Grazia Cifone, Claudio de Simone, Salvadora Delgado, Jordi Vila, Julián Panés, Curtis Donskey, Jose C. Fernández-Checa, Claudio Fiocchi, Miquel Sans

Research output: Contribution to journalArticle

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Abstract

Background: Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect. Methodology/Principal Findings: Neutral sphingomyelinase (NSMase) activity was measured in sonicates of the probiotic L. brevis (LB) and S. thermophilus (ST) and the non-probiotic E. coli (EC) and E. faecalis (EF). Lamina propria mononuclear cells (LPMC) were obtained from patients with Crohn's disease (CD) and Ulcerative Colitis (UC), and peripheral blood mononuclear cells (PBMC) from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS) generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB-induced apoptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase. Conclusions: These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics, and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics.

Original languageEnglish
Article numbere16953
JournalPLoS One
Volume6
Issue number3
DOIs
Publication statusPublished - 2011

Fingerprint

Sphingomyelin Phosphodiesterase
ceramides
Ceramides
Probiotics
probiotics
apoptosis
Apoptosis
Mucous Membrane
Escherichia coli
mononuclear leukocytes
cells
Blood
Chemical activation
Blood Cells
Crohn disease
colitis
Ulcerative Colitis
Reactive Oxygen Species
Crohn Disease
reactive oxygen species

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase. / Angulo, Sandra; Morales, Albert; Danese, Silvio; Llacuna, Laura; Masamunt, Maria Carme; Pultz, Nicole; Cifone, Maria Grazia; de Simone, Claudio; Delgado, Salvadora; Vila, Jordi; Panés, Julián; Donskey, Curtis; Fernández-Checa, Jose C.; Fiocchi, Claudio; Sans, Miquel.

In: PLoS One, Vol. 6, No. 3, e16953, 2011.

Research output: Contribution to journalArticle

Angulo, S, Morales, A, Danese, S, Llacuna, L, Masamunt, MC, Pultz, N, Cifone, MG, de Simone, C, Delgado, S, Vila, J, Panés, J, Donskey, C, Fernández-Checa, JC, Fiocchi, C & Sans, M 2011, 'Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase', PLoS One, vol. 6, no. 3, e16953. https://doi.org/10.1371/journal.pone.0016953
Angulo, Sandra ; Morales, Albert ; Danese, Silvio ; Llacuna, Laura ; Masamunt, Maria Carme ; Pultz, Nicole ; Cifone, Maria Grazia ; de Simone, Claudio ; Delgado, Salvadora ; Vila, Jordi ; Panés, Julián ; Donskey, Curtis ; Fernández-Checa, Jose C. ; Fiocchi, Claudio ; Sans, Miquel. / Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase. In: PLoS One. 2011 ; Vol. 6, No. 3.
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AU - Angulo, Sandra

AU - Morales, Albert

AU - Danese, Silvio

AU - Llacuna, Laura

AU - Masamunt, Maria Carme

AU - Pultz, Nicole

AU - Cifone, Maria Grazia

AU - de Simone, Claudio

AU - Delgado, Salvadora

AU - Vila, Jordi

AU - Panés, Julián

AU - Donskey, Curtis

AU - Fernández-Checa, Jose C.

AU - Fiocchi, Claudio

AU - Sans, Miquel

PY - 2011

Y1 - 2011

N2 - Background: Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect. Methodology/Principal Findings: Neutral sphingomyelinase (NSMase) activity was measured in sonicates of the probiotic L. brevis (LB) and S. thermophilus (ST) and the non-probiotic E. coli (EC) and E. faecalis (EF). Lamina propria mononuclear cells (LPMC) were obtained from patients with Crohn's disease (CD) and Ulcerative Colitis (UC), and peripheral blood mononuclear cells (PBMC) from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS) generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB-induced apoptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase. Conclusions: These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics, and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics.

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