From Flare to Repair: Commensal Bacteria's Influence on Inflammation and Wound Healing

Extensive crosstalk between the microbiome and the immune system is well established, and the gut microbiota has been recognized as a critical contributor to various diseases such as inflammatory bowel disease (IBD), cancer, and even extra-intestinal inflammatory manifestations. Disruptions of the microbiome, known as dysbiosis, can affect the host by releasing specific metabolites, stimulating inflammatory responses, and disrupting homeostasis. However, it remains unclear how bacterial dysbiosis drives inflammation beyond the gut, how the microbiota influences the central nervous system (CNS) where microbes are absent, and if there are specific commensals that may attenuate inflammation. To that end, Chapter 3 demonstrates that IL-10 deficiency leads to both lung and gut inflammation, which was dependent on commensal bacteria. Two candidate bacteria, Delftia acidovorans and Rhodococcus erythropolis were sufficient to initiate the lung inflammation in the IL-10 deficient mice. Transplantation of human fecal microbiota also induced gut inflammation followed by lung inflammation in the IL-10 deficient mice. In Chapter 4 we demonstrate that gut commensal CD4+ T cells specific for an ileum-colonizing microbe, segmented filamentous bacteria (SFB), drive neuroinflammation in the absence of regulatory T cell control. These T cells become dysregulated in the gut, gain a license to cross the blood brain barrier, and are re-stimulated by host proteins in the CNS to cause neuroinflammation. Chapter 5 explores the microbiota’s capacity to promote epithelial repair and protect against inflammation. We show that antibiotic treatment can enrich for commensals that activate group 3 innate lymphoid cells (ILC3s) to produce the epithelial regenerating cytokine IL-22. From this enriched microbial community, we isolated Klebsiella oxytoca, which alone, significantly enhanced survival in a model of lethal chemically induced colitis through IL-1R1 and IL-23R dependent mechanisms. Taken together these data highlight the ability of the microbiota to stimulate extra-intestinal inflammatory manifestations and offer new insights into microbial candidates that can be harnessed to mitigate intestinal inflammation.