Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis.

Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.

Mussels and Local Conditions Interact to Influence Microbial Communities in Mussel Beds.

Microbiomes are increasingly recognized as widespread regulators of function from individual organism to ecosystem scales. However, the manner in which animals influence the structure and function of environmental microbiomes has received considerably less attention. Using a comparative field study, we investigated the relationship between freshwater mussel microbiomes and environmental microbiomes. We used two focal species of unionid mussels, Amblema plicata and Actinonaias ligamentina, with distinct behavioral and physiological characteristics. Mussel microbiomes, those of the shell and biodeposits, were less diverse than both surface and subsurface sediment microbiomes. Mussel abundance was a significant predictor of sediment microbial community composition, but mussel species richness was not. Our data suggest that local habitat conditions which change dynamically along streams, such as discharge, water turnover, and canopy cover, work in tandem to influence environmental microbial community assemblages at discreet rather than landscape scales. Further, mussel burrowing activity and mussel shells may provide habitat for microbial communities critical to nutrient cycling in these systems.