Gut microbiota-IgA interactions may play a critical role in maintaining colonic homeostasis

The gut microbiota’s composition and activity can be modulated by both environmental and host-derived factors. Among them, the homeostatic functions of immunoglobulin A (IgA) on gastrointestinal commensal bacteria has recently been confirmed in humans with IgA deficiency.

A new study, led by Dr. Keiichiro Suzuki from the Graduate School of Medicine at Kyoto University and RIKEN Yokohama Institute (Japan), has found that IgA synergizes with the gut microbiota to maintain colonic homeostasis.

In order to explore the molecular mechanisms behind IgA’s role in gut health homeostasis, the researchers analyzed interactions between highly glycosylated monoclonal IgA and the gut microbiota in mouse models and samples from healthy human colons.

IgA modulated gut microbiota composition through glycan and lipopolysaccharide (LPS) interactions, irrespective of IgA-cognate antigen recognition; specifically, IgA bound to bacterial commensal subsets Bacteroides thetaiotaomicron (B. theta), B. vulgatus, B. fragilis, and Parabacteroides distasonis via glycan-glycan interactions (IgA-glycan and LPS). Furthermore, IgA enhanced the association of bacteria with host mucus and diet-derived polysaccharide in the outer membrane of the colon.

Mucus-associated B. theta was particularly susceptible to coating by IgA. The researchers discovered that the exposure to IgA caused B. theta to up-regulate two undiscovered proteins—called mucus-associated functional factors (MAFF) C and D— that were structurally shared with other gut bacteria and enhanced the metabolic activity of B. theta.

In colonic mucus in mice and humans, B. theta induced MAFF system expression, depending on interaction with Firmicutes members such as Clostridiales. Likewise, B. theta produced metabolites that induced the expansion of Clostridiales members, thus driving a more diverse microbiota. These findings highlight that IgA-driven B. theta MAFF expression is the result of a regulatory network involving not only the gut microbiota composition, but also its genetic structure and potential function within the mucosal niche.

Finally, in a mouse model of chemical-induced colitis, the colon of mice inoculated with wild-type B. theta recovered after 10 days of being treated with dextran sulfate sodium. In contrast, the colon of mice inoculated with a B. theta strain lacking MAFF proteins still showed signs of damage and intestinal inflammation. These results show that a MAFF-induced gut microbiota enhances the proliferation and regeneration of colonic epithelial cells while also increasing the gut microbiota’s diversity.

In conclusion, optimal in vivo metabolic capacity of commensals Bacteroides species depends on IgA-polysaccharide interactions. This study contributes to a better understanding of the role of IgA on gut homeostasis, which depends on interactions between a diverse microbiota and which is modulated by an up-regulated expression of MAFF microbial genes.

Reference:

Nakajima A, Vogelzang A, Maruya M, et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J Exp Med. 2018; 215(8):2019-34. doi: 10.1084/jem.20180427.