The human intestines harbor trillions of microscopic organisms collectively referred to as the microbiota. This mutually beneficial co-existence is dynamically regulated by multiple factors including a single cell epithelial layer overlayed with mucus and an arsenal of immune cells interspersed between and underlying the epithelial cells. In most people, these mechanisms successfully prevent inflammatory responses to our microbiota, thereby maintaining a healthy state that is sometimes referred to as intestinal immune homeostasis. However, in some individuals, including those with certain genetic predispositions, disruption of this peaceful relationship with our microbiota can ultimately lead to the diseases collectively referred to as inflammatory bowel disease (IBD), the major forms of which are Crohn’s disease and ulcerative colitis.
Mechanisms regulating the activity and functions of gut mucus-associated (MA) microbes.
Bacteria belonging to the Lachnospiraceae and Ruminococcaceae families inhabit the mucus layer of the large intestine. The abundance of Lachnospiraceae is negatively correlated with Crohn’s disease activity. These organisms encode varying numbers of flagellins, the basic monomeric units of flagellar filaments that are necessary for their characteristic motility. Antibodies that recognize Lachnospiraceae flagellins are readily detected in the circulation of Crohn’s disease patients but not in healthy individuals. However, there is also tremendous inter- and intra-species variability among the Lachnospiraceae and other MA families, which likely dictates how they interact with the mammalian host. Thus, we are currently exploring whether and how this genomic diversity impacts the functions of specific mucus-associated organisms in health and under inflammatory conditions.
Anti-commensal antibodies in host-microbiota mutualism
MA organisms can often utilize similar mechanisms as pathogens and likely elicit similar immune responses that, instead of promoting inflammation, aid in tolerance of these organisms. We previously showed that in the mice unable to generate T-dependent antibodies, there is impaired recognition of MA bacterial antigens particularly by anti-commensal antibodies, and increased susceptibility to colitis, especially when the IL-10 pathway is also transiently disrupted. Thus, we are interested in exploring (1) the importance of T-dependent antibodies for the regulation of gut immune homeostasis, and (2) the synergy that exists between these antibodies and other immune pathways to continually promote immune homeostasis and prevent deleterious responses to benign commensal organisms.
Mucus-dependent regulation of susceptibility to inflammation and colorectal cancer
Risk factors for colorectal cancer (CRC) include conditions associated with severe or low-grade colonic inflammation including ulcerative colitis, obesity, alcoholism, and aging. All these conditions challenge the epithelial repair machinery to constantly restore the physical barriers that limit infiltration of opportunistic symbionts. As a first-line defense against microbial invasion, the gut mucus layer and key proteins that maintain its structural integrity, help to restore this host-microbiota separation following injury. This reduces the likelihood of chronic inflammation and lowers the risk of tumorigenesis. Ongoing work in the lab is exploring how components of the colon mucus layer (1) interface with the mucus-associated microbiota in health and disease, (2) impact barrier restitution following an inflammatory insult, and (3) prevent chronic activation of the epithelium to limit epithelial hyperproliferation .
