Microbiota-antibody interactions that regulate gut homeostasis

Abstract

Immunoglobulin A (IgA) is the most abundant antibody at mucosal surfaces and has been the subject of many investigations involving microbiota research in the last decade. Although the classic functions of IgA include neutralization of harmful toxins, more recent investigations have highlighted an important role for IgA in regulating the composition and function of the commensal microbiota. Multiple reviews have comprehensively covered the literature that describes recent, novel mechanisms of action of IgA and development of the IgA response within the intestine. Here we focus on how the interaction between IgA and the microbiota promotes homeostasis with the host to prevent disease.

Keywords: IgA; intestine; microbiota.

Figure 1:. Depiction of cross-species reactive IgA, species-specific IgA and strain-specific IgA responses against bacteria in the intestinal mucosa.

The left column shows known examples of cross-species reactive SIgA (in blue) binding many different species of commensal bacteria within the gut to various known and unknown antigens. This can be F_ab -dependent or independent. Center column depicts species-specific SIgA binding to just one species within a genera, for example B. theta among other Bacteroides. Right column shown a strain specific SIgA binding to one strain of bacteria among other strains of the same species, for example a B. theta strain among other B. theta strains with specificity for one surface molecule such as a capsular polysaccharide.

Figure 2:. Mechanisms by which SIgA affects bacteria

Mechanisms by which SIgA influence gut microbes. The current mechanisms by which SIgA can affect microbes can either be divided into ways in which SIgA causes Elimination or Neutralization of bacteria or ways in which SIgA can alter gene expression patterns or functions of microbes that might actually aid in their colonization. (A) SIgA eliminates toxins and/or neutralizes microbial molecules by direct binding. This binding prevents binding of the microbial molecule/toxin to the host target receptor so that it will eventually be cleared by peristalsis. (B) by directly binding to the pathogen and by limiting motility and likely invasion. For instance, SIgA can bind to flagella and prevent organisms from accessing the epithelia. These organisms are likely to be eliminated by peristalsis. (C) Aggregation of rapidly dividing bacteria by enchained growth prevents over-population by proliferation while also limiting access to the epithelia. These organisms are likely eliminated by peristalsis. (D) Biofilms are often mechanisms by which microbes can adhere to surfaces and allow colonization. SIgA can prevent biofilm formation which would be predicted to prevent some organisms from colonizing surfaces. It is also possible that that this mechanism could prevent the expression of genes required for biofilm formation. Therefore, this could be a mechanism for both Elimination and Sculpting. (E) SIgA can preferentially bind to surface microbial molecules that anchor the microbe to the epithelial surface. In this way, SIgA might positively select for organisms that express these molecules. (F) Microbes are known for the ability to sense environmental cues and respond by changing their gene expression patterns. SIgA binding of specific molecules on microbes might be sensed by the microbe such that binding results in down-regulation of that surface molecule. In this way, SIgA could fine-tune microbial gene expression to prevent the production of proteins that may be harmful to the host.

Figure 3:. Potential therapeutic strategies based on sIgA

Therapeutic strategies include A) cross-species antibody responses against flagella, LPS, murine lipoprotein, and other outer membrane structures where a commensal can prime against a pathogen B) Blocking invasion and stimulating immune responses to assist in anti-bacterial clearance, for example, blocking SFB invasion while also increasing Th17 responses. Induction of an SIgA response blocking bacteriophages may weaken bacteria fitness and protect against IBD (C). Therapeutic strategies could include utilizing SIgA to facilitate seeding of the gut with beneficial microbes, such as B. fragilis (D). Vaccinations using lyophilized bacteria could be useful for inducing SIgA responses that can be passed through breastmilk to protect neonates (E).