Scientists have shown that altered patterns of gut microbiome colonization early in life could drive immune-related disorders later in life. While previous animal and population-based studies have suggested that antibiotic use during early life may act as a trigger for IBD, especially in genetically prone offspring, mechanistic studies exploring the involvement of key gut bacteria species are lacking.
To demonstrate the causative role of gut microbiome in IBD, first, potentially important members associated with IBD phenotype should be identified. However, to subsequently demonstrate the involvement of specific gut bacteria as causative of disease phenotypes is a challenge due to the complexity and huge diversity of the gut microbiome. Alternatively, one may aim to identify species relevant to conferring immune tolerance.
New proof-of-concept findings in mice led by Vanessa Leone and Eugene B. Chang from the University of Chicago Knapp Center for Biomedical Discovery in Chicago, Illinois, are the first to demonstrate the relevance of a lack of specific keystone species in the development of colitis.
The authors used interleukin-10 deficient mice—a well-studied mice model in experimental colitis that resembles features of human IBD—to explore whether the risk of colitis can be reversed through microbial restitution. An alternative would be to demonstrate that eliminating a single species would severely alter the composition of the gut microbiome. The tools for showing that, however, are not yet available.
The ecological concept for exploring the involvement of the gut microbiome in the pathogenesis of colitis is based on the authors’ previous findings, which showed that maternal antibiotic-induced changes in the gut microbiome that are vertically transmitted to offspring increase experimental colitis in mice.
First, the researchers isolated a key gut commensal Bacteroides strain from murine feces, which was associated with colitis outcomes through the shaping of host immune responses involving CD4+ T cells and dendritic cells.
Then, when the strain was engrafted into germ-free interleukin-10 deficient mice conventionalized with cefoperazone-associated gut microbiome, it was able to restore immune development and reduce the risk of spontaneous colitis development. The treatment of mice with a cocktail of antibiotics later in life eradicated the phylum Bacteroidetes and the genus Bacteroides with overall changes in gut microbiota diversity, but did not eliminate the protective effects of initial strain engraftment in reducing the risk of colitis.
The results clearly show that early life exposure to the Bacteroides strain, rather than its persistent engraftment, is enough to reduce the risk of spontaneous colitis in genetically prone offspring.
Finally, it is interesting to note that late-life engraftment of the Bacteroides strain into antibiotic-associated altered gut microbiome did not lower the risk of spontaneous colitis in IL10-mice. The findings therefore support the idea that the window of immunological development in early life is important for preventing immune-related diseases later on. As such, both the ecological context and the time period matter in gut microbiome-targeted strategies for impacting health outcomes and diseases.
In conclusion, early-life events can alter gut microbiome development and have long-lasting detrimental effects. This study is the first to clearly demonstrate the concept of keystone species in the context of reducing IBD risk through early-life interventions in genetically prone offspring. It reinforces the idea that early-life events may play a role in the development of IBDs, with commensal bacteria being a potential target for decreasing the risk of these conditions later in life in genetically susceptible hosts.
Reference:
Miyoshi J, Miyoshi S, Delmont TO, et al. Early-life microbial restitution reduces colitis risk promoted by antibiotic-induced gut dysbiosis in interleukin 10-/- mice. Gastroenterology. 2021; 161(3):940-952. doi: 10.1053/j.gastro.2021.05.054.
