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UC is a chronic inflammatory disease of the colonic mucosa and lacks effective treatments because of unclear pathogenesis. Excessive apoptosis of IECs damages the intestinal epithelial barrier and is involved in the progression of UC, but the mechanism is unknown. HSPs are important in maintaining homeostasis and regulate apoptosis through the mitochondrial pathway. In our previous studies, HSF2, an important regulator of HSPs, was highly expressed in UC patients and negatively correlated with inflammation in mice and IECs. Therefore, we hypothesized that HSF2 may protect against intestinal mucositis by regulating the apoptosis of IECs. In this study, a DSS-induced colitis model of hsf2−/− mice was used to explore the relationship between HSF2 and apoptosis in IECs for the first time. The expression of HSF2 increased in the WT + DSS group compared with that in the WT + H2O group. Moreover, the extent of apoptosis was more severe in the KO + DSS group than in the WT + DSS group. The results showed that HSF2 was negatively correlated with apoptosis in vivo. The expression of HSF2 in Caco-2 cells was changed by lentiviral transfection, and the expression of Bax, cytoplasmic Cyto-C, Cleaved Caspase-9 and Cleaved Caspase-3 were negatively correlated with the different levels of HSF2. These results suggest that HSF2 negatively regulates apoptosis of IECs through the mitochondrial pathway. This may be one of the potential mechanisms to explain the protective role of HSF2 in UC.

Bacterial DNA (bacDNA) is frequently found in serum of patient with ulcerative colitis (UC) and Crohns disease, even blood bacterial culture is negative. How bacDNA evades immune elimination and is translocated into blood remain unclear. Here, we showed that bacDNA avoids elimination and disables bacteria-killing function of antimicrobial peptide LL-37 (Cramp in mice) by forming complex with LL-37, which is inducible after culture with bacteria or bacterial products. Elevated LL-37-bacDNA complex was found in plasma and lesions of patients with UC. LL-37-bacDNA promoted inflammation by inducing Th1, Th2 and Th17 differentiation and activating toll-like receptor-9 (TLR9). The complex also increased paracellular permeability, which possibly combines its inflammatory effects to promote local damage and bacDNA translocation into blood. Cramp-bacDNA aggravated mouse colitis severity while interference with the complex ameliorated the disease. The study identifies that inflammatogenic bacDNA utilizes LL-37 as a vehicle for blood translocation and to evade immune elimination. Additionally, bacteria may make a milieu by releasing bacDNA to utilize and resist host antimicrobial peptides as a trojan horse.

Background & Aims Beyond bacteria, the human gastrointestinal tract is host to a vast diversity of fungi, collectively known as the gut mycobiome. Little is known of the impact of geography, ethnicity, and urbanization on the gut mycobiome at a large population level. We aim to delineate the variation of human gut mycobiome and its association with host factors, environmental factors, and diets. Methods Using shotgun metagenomic sequencing, we profiled and compared the fecal mycobiome of 942 healthy individuals across different geographic regions in China (Hong Kong and Yunnan), spanning 6 ethnicities: Han, Zang, Bai, Hani, Dai, and Miao (including both urban and rural residents of each ethnicity). In parallel to fecal sampling, we collected participant metadata (environmental exposure, bowel habits, anthropometrics, and medication), diet, and clinical blood measurement results (a total of 118 variables) and investigated their impact on the gut mycobiome variation in humans. Results The human gut mycobiome was highly variable across populations. Urbanization-related factors had the strongest impact on gut mycobiome variation, followed by geography, dietary habit, and ethnicity. The Hong Kong population (highly urbanized) had a significantly lower fungal richness compared with Yunnan population. Saccharomyces cerevisiae was highly enriched in urban compared with rural populations and showed significant inverse correlations with liver pathology–associated blood parameters, including aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, and direct bilirubin. Candida dubliniensis, which was decreased in urban relative to rural populations, showed correlations with host metabolism-related parameters in blood, including a positive correlation with fasting high-density lipoprotein cholesterol levels and a negative correlation with fasting glucose levels. The fungal-blood parameter correlations were highly geography- and ethnicity-specific. Food choices had differential influences on gut mycobiome and bacterial microbiome, where taxa from the same genus tended to be coregulated by food and thereby cobloom. Ethnicity-specific fungal signatures were associated with distinct habitual foods in each ethnic group. Conclusions Our data highlight, for the first time to our knowledge, that geography, urbanization, ethnicity, and habitual diet play an important role in shaping the gut mycobiome composition. Gut fungal configurations in combination with population characteristics (such as residing region, ethnicity, diet, lifestyle) influence host metabolism and health.

Butyrate-induced autophagy and anti-inflammatory effects of IECs plays an important role in UC. HSP has been proved to be associated with autophagy. HSF2, as an important regulator of HSP, has been determined to be highly expressed in UC. This study was designed to elucidate the relationship between HSF2, butyrate and epithelial autophagy and the potential mechanism of HSF2-related autophagy in UC. The autophagy levels and HSF2 expression in intestinal mucosa were increased in UC patients compared to controls. In DSS colitis models, hsf2-/- mice exhibited more severe intestinal inflammation and lower autophagy levels than wild-type mice. HSF2 expression could be induced by sodium butyrate and LPS as a dose-response relationship in HT-29 cells, epigenetically via increasing histone acetylation levels at the promoter region by sodium butyrate. Autophagy induced by sodium butyrate was promoted by overexpression HSF2 in HT-29 cells. Moreover, overexpression HSF2 decreased the expression and phosphorylation levels of PI3K, Akt and mTOR induced by sodium butyrate. HSF2 might induced by sodium butyrate and inflammation and played protective roles in UC by enhancing autophagy of IECs. This indicated that HSF2 may be a critical target for autophagy modulation and a new potential therapeutic target in UC.