The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4⁺ T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4⁺ T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. Peptostreptococcus, Clostridium, and Fournierella) and IPA were decreased, while the IPA-consuming microbiota (e.g. Parabacteroides, Erysipelatoclostridium, and Lachnoclostridium) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RB^highCD4⁺ T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation in vivo. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4⁺ T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.

Insulin resistance proxy indicators are significantly associated with cardiovascular disease (CVD) and diabetes. However, the correlations between the estimated glucose disposal rate (eGDR) index and CVD and its subtypes have yet to be thoroughly researched. 10,690 respondents with diabetes and prediabetes from the NHANES 1999–2016 were enrolled in the study. Three machine learning methods (SVM-RFE, XGBoost, and Boruta algorithms) were employed to select the most critical variables. Logistic regression models were established to evaluate the association between eGDR and CVD. We applied ROC curves, C-statistics, NRI, IDI, calibration curves, and DCA curves to assess model performance. Subgroup analyses were conducted to investigate the association among different subgroups. Participants in the higher quartile showed a decreased prevalence of CVD. Multivariate logistic regression models and RCS curves demonstrated that eGDR had an independently negative linear correlation with the likelihood of CVD[Q4 vs. Q1: OR 0.24(0.18,0.32)], CAD[OR 0.81(0.78,0.85)], CHF[OR 0.81(0.76,0.86)], and stroke[0.85(0.80,0.90)]. Model evaluation showed better performance in fully adjusted models than basic models[C-statistics(Model 3 vs. Model 1): CVD(0.683 vs. 0.814), CAD(0.672 vs. 0.807), CHF(0.714 vs. 0.839) and stroke(0.660 vs. 0.790)]. The AUCs of eGDR were significantly higher than the values of other IR surrogates in the unadjusted models, and slightly higher in the fully adjusted models. Subgroup analyses indicated that the results were robust. A lower eGDR was significantly associated with a heightened likelihood of CVD and its subtypes in diabetic and prediabetic populations. And eGDR exhibited better performance in evaluating the associations compared to other IR proxies encompassing TyG, HOMA-IR, QCUIKI, METS-IR, etc.

Background: Inflammatory bowel disease (IBD) imposes a significant economic and social burden in China. We aim to assess the epidemiological trends of IBD in China, and to predict the burden in the near future. Methods: The incidence, mortality, prevalence, and disability-adjusted life year (DALYs) of IBD from 1990 to 2021 were obtained from Global Burden of Disease Study 2021. Estimated annual percentage change (EAPC), average annual percent change, total percent change, and age-period-cohort model were used to access trends. Bayesian age–period–cohort model was utilized to predict the risk of incidence and mortality. Results: In 2021, IBD affected 168,077 people in China, with 24,941 new cases and 5640 deaths. The age-standardized rate (ASR) of incidence and death was 1.4 and 0.3, respectively. The incidence and prevalence in China were lower than the global and high socio-demographic index (SDI) regions, but the ASR of incidence and prevalence (EAPC: 2.93 and 2.54, respectively) had rapidly increased from 1990 to 2021. The ASR of death and DALYs had significantly decreased (EAPC: −3.05 and −2.93, respectively). Middle-aged and elderly populations faced a severe burden of incidence and prevalence, while the elderly population faced a severe mortality burden. It is projected that by 2035, the ASR of incidence will continue to rise, whereas the death rate will continue to decline. Conclusions: The burden of IBD in China is serious and increasingly severe. Establishing a comprehensive disease management system in China will help better control the medical burden of IBD.