Over the last two decades, there has been mounting evidence of the role of the gut microbiome (the collection of microorganisms in the GI tract) in metabolic disorder (Fan and Pedersen 2021) and more recently, in psychiatric illness (Morais, Schreiber, and Mazmanian 2021). The maintenance of the equilibrium of commensal bacteria and their proper compartmentalization and stratification in the gut is critical for health.

There are diverse factors regulating microbiota composition (microbiota homeostasis) (Macpherson and McCoy 2013). I am principally interested in the role of antibodies – the idea that antibodies participate in this process is controversial (Kubinak and Round 2016) because of the difficulty of controlling for the multiple confounding environmental variables that influence the microbiome, but there are theories as to how this happens. The process of the shaping of the microbiota by antibodies was dubbed “antibody-mediated immunoselection” (AMIS) by (Kubinak and Round 2016).

Knockout or deficient mice (e.g. RAG-deficient, Ighm^-/- and Aicda (AID knockout)) have shown varying differences in their microbiota from WT, but there are consistent trends for increased growth of known pathobionts like Helicobacter and Burkholderia. Antibodies can interact with microbes and microbe-associated secreted factors in a number of ways (agglutination, opsonization and  neutralization) with a net effect of limiting bacterial dissemination and virulence factor expression (Kubinak and Round 2016). It is not just the overgrowth of species with known virulence that can be problematic: any bacterial overgrowth can result in bloating, malabsorption and other digestive issues simply due to the properties of microbial metabolism (Macpherson and McCoy 2013). This leaves the question: do the gut antibodies just target harmful bacteria to be removed from the gut, or do they also interact with “good” bacteria?

IgA is the dominant immunoglobulin isotype in the gut (IgM and IgG are also known to be secreted, but IgG is secreted by means of a different receptor) and is expressed in its secretory form (sIgA). It is estimated that around 45% of microbes within human faeces are covered in sIgA. Further, it is disproportionately the mucosal microbiome vs. the lumenal microbiome that is sIgA-bound, consistent with evidence that the secretory component of IgA anchors sIgA to the lining of the gut (Kubinak and Round 2016). Multiple studies have shown that when IgA-targeted organisms are reintroduced into a host with disease, that disease is exacerbated – this led to the idea the purpose of sIgA was to bind to and eliminate microbes negatively impacting the health of the gut. (Weis and Round 2021) However, a smaller body of work suggests that sIgA could also keep microbes’ behaviour in check without eradicating them from the population, by causing them to downregulate molecules that could be harmful to the host – e.g., downregulating capsular polysaccharide gene expression (Weis and Round 2021). This means that sIgA can interact with “good” bacteria, too, to make sure it isn’t tempted to go bad.

In conclusion, the role that antibodies play in maintenance of the microbiome is complex – there are experimental considerations that I have not even touched upon and this is all without any consideration of the importance of the longitudinal and transverse sectioning of microbes within the gut (Macpherson and McCoy 2013). However, it is clear that antibodies do play a role in the maintenance of a healthy gut. The gut microbiome is an area of research that I think a lot of people look upon with interest, and it will be hugely interesting to see what further associations are found between adaptive immunity and downstream health conditions that are mediated by the gut.

 Fan, Yong, and Oluf Pedersen. 2021. ‘Gut Microbiota in Human Metabolic Health and Disease’. Nature Reviews Microbiology 19 (1): 55–71. https://doi.org/10.1038/s41579-020-0433-9.

Kubinak, Jason L., and June L. Round. 2016. ‘Do Antibodies Select a Healthy Microbiota?’ Nature Reviews Immunology 16 (12): 767–74. https://doi.org/10.1038/nri.2016.114.

Macpherson, Andrew J., and Kathy D. McCoy. 2013. ‘Stratification and Compartmentalisation of Immunoglobulin Responses to Commensal Intestinal Microbes’. Seminars in Immunology, Microbiota and the immune system, an amazing mutualism forged by co-evolution, 25 (5): 358–63. https://doi.org/10.1016/j.smim.2013.09.004.

Morais, Livia H., Henry L. Schreiber, and Sarkis K. Mazmanian. 2021. ‘The Gut Microbiota–Brain Axis in Behaviour and Brain Disorders’. Nature Reviews Microbiology 19 (4): 241–55. https://doi.org/10.1038/s41579-020-00460-0.

Weis, Allison M., and June L. Round. 2021. ‘Microbiota-Antibody Interactions That Regulate Gut Homeostasis’. Cell Host & Microbe 29 (3): 334–46. https://doi.org/10.1016/j.chom.2021.02.009.