Akkermansia muciniphila and Parabacteroides distasonis synergistically protect from colitis by promoting ILC3 in the gut

Abstract

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract. The etiology of IBD remains elusive, but the disease is suggested to arise from the interaction of environmental and genetic factors that trigger inadequate immune responses and inflammation in the intestine. The gut microbiome majorly contributes to disease as an environmental variable, and although some causative bacteria are identified, little is known about which specific members of the microbiome aid in the intestinal epithelial barrier function to protect from disease. While chemically inducing colitis in mice from two distinct animal facilities, we serendipitously found that mice in one facility showed remarkable resistance to disease development, which was associated with increased markers of epithelial barrier integrity. Importantly, we show that Akkermansia muciniphila and Parabacteroides distasonis were significantly increased in the microbiota of resistant mice. To causally connect these microbes to protection against disease, we colonized susceptible mice with the two bacterial species. Our results demonstrate that A. muciniphila and P . distasonis synergistically drive a protective effect in both acute and chronic models of colitis by boosting the frequency of type 3 innate lymphoid cells in the colon and by improving gut epithelial integrity. Altogether, our work reveals a combined effort of commensal microbes in offering protection against severe intestinal inflammation by shaping gut immunity and by enhancing intestinal epithelial barrier stability. Our study highlights the beneficial role of gut bacteria in dictating intestinal homeostasis, which is an important step toward employing microbiome-driven therapeutic approaches for IBD clinical management. IMPORTANCE The contribution of the gut microbiome to the balance between homeostasis and inflammation is widely known. Nevertheless, the etiology of inflammatory bowel disease, which is known to be influenced by genetics, immune response, and environmental cues, remains unclear. Unlocking novel players involved in the dictation of a protective gut, namely, in the microbiota component, is therefore crucial to develop novel strategies to tackle IBD. Herein, we revealed a synergistic interaction between two commensal bacterial strains, Akkermansia muciniphila and Parabacteroides distasonis , which induce protection against both acute and chronic models of colitis induction, by enhancing epithelial barrier integrity and promoting group 3 innate lymphoid cells in the colonic mucosa. This study provides a novel insight on how commensal bacteria can beneficially act to promote intestinal homeostasis, which may open new avenues toward the use of microbiome-derived strategies to tackle IBD.

Akkermansia muciniphila and Parabacteroides distasonis as prognostic markers for relapse in ulcerative colitis patients

“…Both bacteria have been associated with reports of both beneficial and pathogenic effects on human health ( Ezeji et al., 2021 ; Abbasi et al., 2023 ). Additionally, recently published data from our research group suggests an interaction between these two species associated with a protective phenotype in mouse models of UC ( Gaifem et al., 2024 ). Our findings suggest an inverse correlation between the levels of these species and remission time.…”

“…These changes induce inflammation of the intestinal mucosa, compromising its barrier function, leading to an increased bacterial translocation, and promoting an exacerbated inflammatory response ( Glassner et al., 2020 ). Previous work from our research group revealed a protective effect of Akkermansia muciniphila and Parabacteroides distasonis in murine models of chemically-induced colitis ( Gaifem et al., 2024 ). The anti-inflammatory properties of A. muciniphila have been reported in both murine models and UC patients ( Abbasi et al., 2023 ).…”

The Impact of Parabacteroides distasonis Colonization on Hosts' Microbiome, Metabolome, Immune Responses, and Diabetes Onset

“…Reduction in these immune cells on colonization indicates a noninflammatory phenotype. P. distasonis significantly reduced intestinal inflammation in murine models of acute and chronic colitis 55 induced by dextran sulphate sodium (DSS) in BALB/c mice. This antiinflammatory effect is mediated by a decrease in proinflammatory cytokines and stabilization of the intestinal microbiota 56 .…”