A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. A classifier we trained using the normalized copy numbers of 33 HMI-associated metabolic modules not only distinguished states of health vs IBD, but also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.
Keywords: computational biology; ecology; gut microbiome; inflammatory bowel disease; metabolic reconstruction; microbial metabolism; none; systems biology.
The human gut hosts an array of microbes that form a complex community beginning shortly after birth. These microbes prime the immune system, help extract nutrients from the diet and offer protection against pathogens. Decades of research have shown that individuals who suffer from inflammatory bowel diseases (IBD) or other systemic disorders tend to have far less variety of gut microbes compared to healthy individuals. Yet it remains unclear to what extent the difference in microbial diversity is the cause of the disease or a consequence of it. In 2023, a study suggested that the usual teamwork between different kinds of microbes breaks down during disease. Many microbes depend on each other to provide certain nutrients, while others can survive on their own. It could be that people with IBD lose most of the ‘dependent’ microbes and retain those that are more self-sufficient and thus able to survive in the stressed and deteriorating gut environment. To test this hypothesis, Veseli et al. – who are part of the research group that performed the 2023 study – developed a computer program to quantify self-sufficient gut microbes in large numbers of stool samples collected from healthy individuals and patients with IBD. This revealed that individuals with IBD had higher numbers of self-sufficient microbes, while healthy people also harbored microbes that depended on others for the provision of essential metabolites. External disruptions to the gut homeostasis, such as antibiotics, resulted in a similar selection for independent microbes. These findings support the idea that changes in the gut microbiome are more likely a by-product of disease, rather than its cause and offer important ecological clues for microbial therapies that aim to restore gut health. While this perspective assigns a more neutral role for gut microbial communities in non-transmissible diseases, more research is needed to see if an enrichment of self-sufficient microbes could negatively influence disease progression.
© 2023, Veseli et al.