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July 24, 2018

Peaceable Gut Microbiota Express Symbiosis-Promoting Factors in Response to IgA

Ten days after being treated with an intestine-damaging drug, the colons of mice inoculated with wild-type B. theta have largely recovered (top row). But the colons of mice inoculated with a B. theta strain lacking MAFF proteins still show signs of damage and intestinal inflammation (bottom row). [Nakajima et al., 2018]

  • It’s something of a peaceable kingdom, a gut-dwelling microbial community that can, in response to a host antibody, foster cooperation and form a community that protects the body against disease. The host antibody is immunoglobulin A (IgA), and it has been known to enhance the growth of healthy gut bacteria. But our understanding of IgA’s contribution to gut health has been incomplete. No explanatory mechanism was available.

    To rectify this shortcoming, scientists based at the RIKEN Center for Integrative Medical Science in Japan tested whether “bystander” IgA (that is, IgA elicited by antigens other than bacterial antigens) can modulate gut microbiota via glycan–glycan interactions among IgA, bacteria, and mucus. This work allowed the scientists to discover that bystander IgA has the capacity to modulate gene expression and function of members of the gut microbial community, promoting symbiosis between commensal bacterial species required for colonic homeostasis.

    Details of this work appeared July 24 in the Journal of Experimental Medicine, in an article titled, “IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria.”

    “We found that a heavily glycosylated monoclonal IgA recognizing ovalbumin coats Bacteroides thetaiotaomicron (B. theta), a prominent gut symbiont of the phylum Bacteroidetes,” the article’s authors wrote. “In vivo, IgA alters the expression of polysaccharide utilization loci (PUL), including a functionally uncharacterized molecular family provisionally named Mucus-Associated Functional Factor (MAFF).”

    "We knew that IgA contributed in some way to gut health, but it was exciting to discover this new mechanism—the MAFF system—that actually promotes symbiosis among the bacteria that inhabit the mucus membrane of the gut," said Keiichiro Suzuki, a researcher at Kyoto University and the leader of the study. "The MAFF system is also present in humans, so it is an interesting target of research, but there is still much to be investigated.”

    Antibodies usually fight off harmful bacteria by recognizing specific proteins on the bacteria's surface. But Suzuki and colleagues found that even IgAs that recognize a nonbacterial protein can coat the surface of healthy gut bacteria because sugar molecules attached to the tails of IgAs can bind to a molecule called lipopolysaccharide that is found on many different species of bacteria.

    The prominent human gut bacterium B. theta was particularly susceptible to coating by IgA. Suzuki and colleagues discovered that exposure to IgA causes B. theta to up-regulate two proteins that were structurally shared with many other bacterial strains, and the researchers named these molecules MAFFs. These proteins appear to help B. theta grow in the mucous membrane of the intestine and produce metabolites that allow other beneficial bacteria, such as Clostridiales, to thrive as well. Mice inoculated with a strain of B. theta unable to up-regulate MAFFs had an altered gut microbiome and were more susceptible to intestinal inflammation, or colitis.

    An average adult has over a thousand species of bacteria in their intestines that improve the function of the intestines and immune system, significantly impacting human health and disease. Altering gut microbiota’s composition and function, perhaps by activating MAFFs, could promote human health. “We need to identify the MAFF system’s molecular target and find out how its expression is regulated along with neighboring genetic elements,” Suzuki explained, “with the hope that answering these questions could lead to the development of new methods for therapies or prophylaxis of inflammatory bowel disease."

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