The microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Besides this, it has recently become relevant that alterations of intestinal microbial communities may be involved in the immune dysregulation that leads to autoimmune disorders such as type 1 diabetes and multiple sclerosis. But little is known regarding the immunomodulatory effects of specific human gut microbes.
A recent study, led by Prof. Dennis Kasper from the Department of Microbiology and Immunobiology at Harvard Medical School (Boston, USA), has found specialized and complementary immunomodulatory effects for gut microbes that are not related to their phylogeny.
The researchers performed a system-wide analysis of microbial influence on a broad range of immune cells and genes expressed in the gut, which offers a precise understanding of the interplay between individual gut microbes and the host. Briefly, 53 individual bacterial species selected from the Human Microbiome Project to represent all five of the major phyla were collected and inoculated into sterile mouse guts, one kind of microbe at a time (monocolonized mice). Two weeks later, each microbe’s effects on the composition and activation of 21 types of immune cells and on intestinal tissue transcriptomes were observed and the results were compared with those of mice whose guts were completely germ-free.
Microbial effects on each immune cell type, genes expressed in the gut, and genes regulating the activity of cytokines varied from no effect at all to a powerful influence. Some of the effects were contrary, whereas others offset each other. According to a Harvard announcement about the research, “These oppositional effects suggest an evolutionary checks-and-balances mechanism to ensure that no single bacterium can over-power the others in its effects on the immune system. Similarly, some bacteria upregulated certain genes, while others downregulated them, indicating that microbes can have balancing effects on intestinal gene expression”.
Bacteria belonging to the same class exhibited several specialized, complementary, and redundant immune effects that were independent of microbial phylogeny. This functional redundancy, previously reported in a review, is thought to ensure the preservation of key immune functions among bacteria. Among immunomodulatory activities that have not been reported previously were the increase of interleukin (IL) 10-producing T cells and the parallel decrease of IL22-producing innate lymphoid cells in the colon by Veillonella, the reduction of plasmacytoid dendritic cell numbers by Lactobacillus rhamnosus, and the strong suppression of naturally secreted antimicrobials and upregulation of genes involved in arachidonic acid metabolism and inflammation by Fusobacterium varium. Plasmacytoid dendritic cells, which affect the function of regulatory T cells and the secretion of interferons, were the most potently affected type of immune cells.
On the whole, this study shows that the human gut microbiota carries out an abundance of immunomodulatory activities. These results provide a blueprint for identifying important microbial influencers of health and disease and can help scientists develop molecules or bacterial strains that can be used as precision-targeted immune treatments. Further research considering the additive effects of several commensal bacterial species at a time will give a clearer picture.
Geva-Zatorsky N, Sefik E, Kua L, et al. Mining the human gut microbiota for immunomodulatory organisms. Cell. 2017; doi: 10.1016/j.cell.2017.01.022.