Abstract: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract, affecting several millions of people around the globe, but more prevalent in western countries. Patients suffering with IBD are at risk of developing colorectal cancer (CRC). Although precise etiologies of these gastrointestinal disorders are unknown, genetic defects, immune dysregulation, gut microbiome, and diet are considered key players of IBD and CRC pathogenesis. My research is focused on understanding the complex interplay between innate immune sensors, diet, and gut microbiome in the pathogenesis of IBD and CRC. In this regard, I will present two separate studies that I conducted during my postdoctoral training at UT Southwestern Medical Center.

A western diet, which is rich in high fat and high sugar, is considered a risk factor for many inflammatory disorders including colitis. However, the impact of dietary sugars, such as glucose, fructose, and sucrose, on colitis remains poorly understood. We, therefore, investigated the role of dietary simple sugars in colitis using dextran sulfate sodium (DSS) and Il10-/- mice models. We fed WT mice with high sugar in drinking water or diet, followed by administration of 2.5% DSS plus high-sugar diet. Sugar-fed wild-type mice showed extreme sensitivity to DSS-induced colitis. To understand the underlying mechanism of the detrimental effect of dietary sugar on colitis, we measured pathophysiological changes in the healthy gut. Interestingly, while there was no induction of cell death, inflammatory mediators, and activation of inflammatory pathways, gut microbiota composition was significantly altered in sugar-fed healthy mice. Notably, the abundance of mucus degrading bacteria Akkermansia muciniphila and Bacteroides fragilis was increased. Consistently, bacteria-derived mucolytic enzymes were enriched and the colonic mucus layers were eroded in sugar-fed mice. Furthermore, germ-free mice colonized with microbiota from sugar-treated mice showed higher abundance of mucus degrading bacteria and increased colitis susceptibility. Overall, our data suggest that high-sugar diet predisposes colitis and enhances colitis pathogenesis by promoting the growth of mucolytic bacteria in the gut.

In a separate study, I investigated the role of NLRP12, an innate immune sensor and member of the NOD-like receptor family, in CAC. We observed that mice deficient in Nlrp12 are highly susceptible to azoxymethane plus dextran sodium sulfate induced CRC. RNA-seq analysis revealed that tumors of Nlrp12-deficient mice express higher levels of protooncogenes, matrix metalloproteinases, and epithelial to mesenchymal transition markers compared to wild-type tumors. Consistently, there was higher activation of the Wnt/β-catenin pathway in Nlrp12- deficient tumors, suggesting a role for NLRP12 in the suppression of the Wnt/β -catenin pathway. With in vitro studies using HEK293T, HCT116 and HT29 cells we confirmed that NLRP12 negatively regulates β-catenin activation and expression of Wnt target genes. Further biochemical and proteomic analysis revealed that NLRP12 interacts with STK38 to inhibit the phosphorylation of GSK3β, leading to the degradation of β-catenin. In agreement, human and mouse colorectal tumors showed reduced expression of NLRP12 along with increased activation of β-catenin and GSK3β phosphorylation. Altogether, these data suggest that NLRP12 is a potent negative regulator of the Wnt/β-catenin pathway in colorectal tumor cells, and the NLRP12/STK38/GSK3β signaling axis could be a novel target for CRC treatment.

Meeting ID: 931 7953 9911
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