BackgroundAlthough the unconjugated secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood. We hypothesize that the cytotoxic bile acids may promote stemness in colonic epithelial cells leading to generation of cancer stem cells (CSCs) that play a role in the development and progression of colon cancer.MethodsNormal human colonic epithelial cells (HCoEpiC) were used to study bile acid DCA/LCA-mediated induction of CSCs. The expression of CSC markers was measured by real-time qPCR. Flow cytometry was used to isolate CSCs. T-cell factor/lymphoid-enhancing factor (TCF/LEF) luciferase assay was employed to examine the transcriptional activity of β-catenin. Downregulation of muscarinic 3 receptor (M3R) was achieved through transfection of corresponding siRNA.ResultsWe found DCA/LCA to induce CSCs in normal human colonic epithelial cells, as evidenced by the increased proportion of CSCs, elevated levels of several CSC markers, as well as a number of epithelial–mesenchymal transition markers together with increased colonosphere formation, drug exclusion, ABCB1 and ABCG2 expression, and induction of M3R, p-EGFR, matrix metallopeptidases, and c-Myc. Inhibition of M3R signaling greatly suppressed DCA/LCA induction of the CSC marker ALDHA1 and also c-Myc mRNA expression as well as transcriptional activation of TCF/LEF.ConclusionsOur results suggest that bile acids, specifically DCA and LCA, induce cancer stemness in colonic epithelial cells by modulating M3R and Wnt/β-catenin signaling and thus could be considered promoters of colon cancer.

AIMTo determine whether and to what extent the gut microbiome is involved in regulating racial disparity in colorectal cancer (CRC).METHODSAll patients were recruited and experiments were performed in accordance with the relevant guidelines and regulations by the Institutional Review Boards (IRB), committees of the John D. Dingell VAMC and Wayne State University guidelines. African American (AA) and Caucasian American (CA) patients were scheduled for an outpatient screening for colonoscopy, and no active malignancy volunteer patients were doubly consented, initially by the gastroenterologist and later by the study coordinator, for participation in the study. The gut microbial communities in colonic effluents from AAs and CAs were examined using 16sRNA profiling, and bacterial identifications were validated by performing SYBR-based Real Time PCR. For metagenomic analysis to characterize the microbial communities, multiple software/tools were used, including Metastats and R statistical software.RESULTSIt is generally accepted that the incidence and mortality of CRC is higher in AAs than in CAs. However, the reason for this disparity is not well understood. We hypothesize that the gut microbiome plays a role in regulating this disparity. Indeed, we found significant differences in species richness and diversity between AAs and CAs. Bacteroidetes was more abundant in AAs than in CAs. In particular, the pro-inflammatory bacteria Fusobacterium nucleatum and Enterobacter species were significantly higher in AAs, whereas probiotic Akkermansia muciniphila and Bifidobacterium were higher in CAs. The polyphyletic Clostridia class showed a divergent pattern, with Clostridium XI elevated in AAs, and Clostridium IV, known for its beneficial function, higher in CAs. Lastly, the AA group had decreased microbial diversity overall in comparison to the CA group. In summary, there were significant differences in pro-inflammatory bacteria and microbial diversity between AA and CA, which may help explain the CRC disparity between groups.CONCLUSIONOur current investigation, for the first time, demonstrates microbial dysbiosis between AAs and CAs, which could contribute to the racial disparity of CRC.

Background As the World Health Organization seeks to eliminate trachoma by 2020, countries are beginning to control the transmission of trachomatous inflammation–follicular (TF) and discontinue mass drug administration (MDA) with oral azithromycin. We evaluated the effect of MDA discontinuation on TF1–9 prevalence at the district level. Methods We extracted from the available data districts with an impact survey at the end of their program cycle that initiated discontinuation of MDA (TF1–9 prevalence <5%), followed by a surveillance survey conducted to determine whether TF1–9 prevalence remained below the 5% threshold, warranting discontinuation of MDA. Two independent analyses were performed, 1 regression based and 1 simulation based, that assessed the change in TF1–9 from the impact survey to the surveillance survey. Results Of the 220 districts included, TF1–9 prevalence increased to >5% from impact to surveillance survey in 9% of districts. Regression analysis indicated that impact survey TF1–9 prevalence was a significant predictor of surveillance survey TF1–9 prevalence. The proportion of simulations with >5% TF1–9 prevalence in the surveillance survey was 2%, assuming the survey was conducted 4 years after MDA. Conclusion An increase in TF1–9 prevalence may represent disease resurgence but could also be due to measurement error. Improved diagnostic tests are crucial to elimination of TF1–9 as a public health problem.

The World Health Organization (WHO) recommends continuing azithromycin mass drug administration (MDA) for trachoma until endemic regions drop below 5% prevalence of active trachoma in children aged 1–9 years. Azithromycin targets the ocular strains of Chlamydia trachomatis that cause trachoma. Regions with low prevalence of active trachoma may have little if any ocular chlamydia, and, thus, may not benefit from azithromycin treatment. Understanding what happens to active trachoma and ocular chlamydia prevalence after stopping azithromycin MDA may improve future treatment decisions. We systematically reviewed published evidence for community prevalence of both active trachoma and ocular chlamydia after cessation of azithromycin distribution. We searched electronic databases for all peer-reviewed studies published before May 2020 that included at least 2 post-MDA surveillance surveys of ocular chlamydia and/or the active trachoma marker, trachomatous inflammation–follicular (TF) prevalence. We assessed trends in the prevalence of both indicators over time after stopping azithromycin MDA. Of 140 identified studies, 21 met inclusion criteria and were used for qualitative synthesis. Post-MDA, we found a gradual increase in ocular chlamydia infection prevalence over time, while TF prevalence generally gradually declined. Ocular chlamydia infection may be a better measurement tool compared to TF for detecting trachoma recrudescence in communities after stopping azithromycin MDA. These findings may guide future trachoma treatment and surveillance efforts.