Towards a More Detailed Understanding of How the Immune System Gardens the Gut Microbiome

The gut microbiome consists of a broad range of microbial populations locked into in a constant, dynamic state of competitive population growth and decline. The balance of benign versus harmful microbial species is important to health and the progression of aging. Benign species produce useful metabolites, while harmful microbes provoke systemic chronic inflammation, an important contribution to many of the dysfunctions of aging and age-related disease. There is a bidirectional relationship between the immune system and the gut microbiome. The immune system gardens the microbiome by destroying selected cells, particularly those capable of producing inflammation, while the microbiome can influence the immune system into inflammatory behavior.

With age, the immune system declines in effectiveness, and the balance of populations in the gut microbiome shifts. Beneficial populations decline while harmful, inflammatory populations increase in number. Some of these shifts occur surprisingly early in adult life, in the mid-30s. Restoring a youthful gut microbiome via fecal microbiota transplantation from young animals to old animals has been shown to improve health, reduce inflammation, and extend life span. Other approaches shown to improve the microbiome may be similarly beneficial to long-term health, to various degrees, such as icariin supplementation or flagellin innoculation. It remains to be assessed as to how much of an effect on late life health and mortality these interventions can produce in humans.

Immune system keeps the intestinal flora in balance

The bacteria living in the intestine consist of some 500 to 1000 different species. They make up what is known as the intestinal flora, which plays a key role in digestion and prevents infections. Unlike pathogens that invade from the outside, they are harmless and tolerated by the immune system. The way in which the human immune system manages to maintain this delicate balance in the intestine largely remains unknown. It is known that type A immunoglobulins, referred to as IgA antibodies, play an important role. These natural defense substances are part of the immune system, and recognize an exogenous pathogen very specifically.

A group of researchers have recently been able to show in a mouse model that IgA antibodies specifically limit the fitness of benign bacteria at several levels. This enables the immune system to fine-tune the microbial balance in the intestine. The researchers succeeded in tracking the in-vitro and in-vivo effect in the intestines of germ-free mice with pinpoint accuracy. The antibodies were found to affect the fitness of the bacteria in several ways. The mobility of bacteria was restricted, for example, or they hindered the uptake of sugar building blocks for the metabolism of the bacteria. The effect depended on the surface component that was specifically recognized. "This means that the immune system is apparently able to influence the benign intestinal bacteria through different approaches on a simultaneous basis. Understanding exactly how and where antibodies recognize microorganisms in the intestine will also allow us to develop vaccines against pathogenic organisms on a more targeted basis."

Parallelism of intestinal secretory IgA shapes functional microbial fitness

Dimeric IgA secreted across mucous membranes in response to nonpathogenic taxa of the microbiota accounts for most antibody production in mammals. Diverse binding specificities can be detected within the polyclonal mucosal IgA antibody response, but limited monoclonal hybridomas have been studied to relate antigen specificity or polyreactive binding to functional effects on microbial physiology in vivo. Here we use recombinant dimeric monoclonal IgAs (mIgAs) to finely map the intestinal plasma cell response to microbial colonization with a single microorganism in mice. We identify a range of antigen-specific mIgA molecules targeting defined surface and nonsurface membrane antigens.

Secretion of individual dimeric mIgAs targeting different antigens in vivo showed distinct alterations in the function and metabolism of intestinal bacteria, largely through specific binding. Even in cases in which the same microbial antigen is targeted, microbial metabolic alterations differed depending on IgA epitope specificity. By contrast, bacterial surface coating generally reduced motility and limited bile acid toxicity. The overall intestinal IgA response to a single microbe therefore contains parallel components with distinct effects on microbial carbon-source uptake, bacteriophage susceptibility, motility, and membrane integrity.

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