Microbial Dynamics During Gut Inflammation And Infection

Abstract

The gastrointestinal (GI) tract is colonized with complex microbial communities, known as the microbiota, that contribute to the health of the host. The intestinal microbiota plays an important role in determining susceptibility to enteric infection and therapeutic response to cancer treatment. The composition of the microbiota is known to influence the efficacy of a range of cancer therapies. We found that differences in the microbiota’s composition affects patients’ risk of developing inflammatory complications of immunotherapy. Increased representation of the Bacteroidetes phylum as well as B vitamin biosynthesis pathways are correlated with resistance to checkpoint-blockade-induced colitis. The microbiota’s composition is also known to impact the colonization density of antibiotic-resistant pathogens, an important cause of bacteremia in cancer patients receiving allogeneic hematopoietic stem cell transplants. We found that obligate anaerobes provide colonization resistance to Klebsiella pneumoniae, which is inhibited by short-chain fatty acids. Once colonized, enteric pathogens can evolve in the GI tract. This evolution can be tracked by the accumulation of single nucleotide polymorphisms (SNP) over time. In a mouse model of Enterococcus faecium colonization, SNPs were acquired at a rapid and regular rate, enabling us to study its diversification in real-time. Our work indicates that E. faecium can rapidly adapt in the gut by acquiring mutations in the pencillin-binding protein 5 while exposed to long-term ampicillin treatment.