Inflammatory bowel disease (IBD) is a chronic life-long inflammatory disease affecting almost 2 million Americans. Although new biologic therapies have been developed, the standard medical treatment fails to selectively control the dysregulated immune pathways involved in chronic colonic inflammation. Further, IBD patients with uncontrolled colonic inflammation are at a higher risk for developing colorectal cancer (CRC). Intestinal microbes can impact many immune functions, and here we asked if they could be used to improve intestinal inflammation. By utilizing an intestinal adherent E. coli that we find increases IL-10 producing macrophages, we were able to limit intestinal inflammation and restrict tumor formation. Macrophage IL-10 along with IL-10 signaling to the intestinal epithelium were required for protection in both inflammation and tumor development. Our work highlights that administration of immune modulating microbes can improve intestinal outcomes by altering tissue inflammation.
While exposure to microbial antigens in peripheral sites causes expansion of antigen-specific T cells, a role for antigen-specific expansion had not been identified during T cell development in the thymus. We recently found that intestinal colonization induced intestinal dendritic cells migration to the thymus, driving thymic expansion of microbiota-specific T cells early in life. In contrast, colonization in adulthood leads to expansion of peripheral but not thymic microbiota-specific T cells. Thymic microbiota-specific T cells developed early in life were undifferentiated and caused intestinal inflammation in immunocompromised hosts upon antigen reencounter. We sought to understand regulation of this developmental window and define if thymic expansion of microbiota-specific T cells could be restarted in adult mice. We found that microbiota manipulation reestablished expansion of microbiota-specific T cells in the thymus of adult mice. We are in the process of characterizing these T cells in adulthood to assess their impact on intestinal inflammation. Our data suggests that intestinal colonization controls the generation of thymic microbiota-specific T cells which has the potential to modulate inflammatory processes.
Inflammatory bowel disease (IBD) patients with poorly controlled intestinal inflammation are at an elevated risk for colorectal cancer (CRC). IBD patients exhibit intestinal dysbiosis with expanded proteobacteria such as E. coli. Here, we find that colonization with an E. coli isolated from the intestine of an IBD patient (E. coli 541-15) prevents tumorigenesis in an inflammation-related model of CRC. Colonization increased tumor infiltration of T helper 1 (Th1) cells, cytotoxic T lymphocytes (CTLs), and type 1 innate lymphoid cells (ILC1s) and decreased myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Prevention of tumorigenesis occurs if colonization takes place before induction of inflammation. Intestinal inflammation in colitis models was ameliorated by E. coli 541-15 and this protection depended on IL-10 production by macrophages and IL-10 signaling to the intestinal epithelium. Colonization with E. coli 541-15 also promotes these IL-10 pathways if colonization occurs after tumorigenesis is established. However, this leads to worse CRC outcome, with increased tumor burden alongside decreased tumor infiltration of Th1 cells, CTLs, and ILC1s and increased MDSCs and Tregs. These results identify activation of an IL-10 signaling loop between immune cells and the intestinal epithelium after E. coli colonization that modulates intestinal inflammation and CRC. Importantly, these pathways can be protective or pathogenic depending on timing of activation. Supported by 2021 Ludwig Center Basic and Translational Research Award
The intestinal epithelial barrier critically separates exogenous microbes from our internal tissues. Signals from commensal microbes are known to support intestinal barrier integrity and repair. However, the role of specific microbes in maintaining the intestinal barrier is not well-defined. We hypothesize that signals from distinct commensal microbes play different roles in regulating the barrier. We find that mice develop severe colitis with decreased ability to repair the intestinal barrier after antibiotic depletion of intestinal microbes. We further isolated a mouse commensal E. coli that protects from increased colitis after antibiotic treatment. This protection depends on the presence of intestinal antigen presenting cells (APCs) that express the chemokine receptor CX3CR1. We screened a panel of human mucosal-associated E. coli and identified a subset that also protect from colitis in a CX3CR1+ APC dependent manner. All protective E. coli induce IL-1β secretion by activation of the non-canonical inflammasome pathway in CX3CR1+ APCs. In vivo protection is lost if IL-1β signaling is blocked with anti-IL-1β antibody. This E. coli induced IL-1β production activates type 3 innate lymphoid cells (ILC3) to produce IL-22 which drives epithelial proliferation and barrier repair. Collectively, we identified a novel mechanism by which a subset of mucosal-associated intestinal E. coli activate IL-1β production by APCs to protect the intestinal barrier from damage.
Microbiota interactions with host tissue support proper intestinal functions. In diseases such as inflammatory bowel disease, microbial shift along with epithelial dysfunctions are found. Understanding how intestinal epithelial functions are regulated by distinct commensal bacteria is key to improving outcomes in such diseases. Here, we identified a mouse commensal E. coli isolate, GDAR2-2, that promotes intestinal barrier repair in mouse colitis models including Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. In mice, protection after GDAR2-2 colonization depends on CX3CR1+ mononuclear phagocytes (MNPs), which induce expansion of IL-22-secreting type 3 innate lymphoid cells. We detect upregulation of markers of transit amplifying cells, proliferation of which is downstream of IL-22 signaling. Protection is lost if IL-22 is blocked, indicating IL-22 driven epithelial regeneration is downstream of GDAR2-2 colonization. By co-culturing bone marrow derived macrophages with live GDAR2-2, we found GDAR2-2 promotes IL-1b production and the in vivo protection was lost after blockade of IL-1b. We further identified a subset of human commensal E. coli isolates that similarly induce CX3CR1+ MNP expansion and IL-1b mediated protection from C. rodentium infection in mice. This study reveals an unexpected role for IL-1b that promotes intestinal barrier repair and is induced by select commensal bacteria. Supported by NIH (AI125264, P30DK056338)
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