Background: The overgrowth of Desulfovibrio, an inflammation promoting flagellated bacteria, has been found in ulcerative colitis (UC) patients. However, the molecular mechanism in promoting colitis remains unestablished. Methods: The relative abundance Desulfovibrio vulgaris (D. vulgaris) in stool samples of UC patients was detected. Mice were treated with dextran sulfate sodium to induce colitis with or without administration of D. vulgaris or D. vulgaris flagellin (DVF), and the severity of colitis and the leucine-rich repeat containing 19 (LRRC19) signaling were assessed. The interaction between DVF and LRRC19 was identified by surface plasmon resonance and intestinal organoid culture. Lrrc19^−/− and Tlr5^−/− mice were used to investigate the indispensable role of LRRC19. Finally, the blockade of DVF-LRRC19 interaction was selected through virtual screening and the efficacy in colitis was assessed. Results: D. vulgaris was enriched in fecal samples of UC patients and was correlated with the disease severity. D. vulgaris or DVF treatment significantly exacerbated colitis in germ-free mice and conventional mice. Mechanistically, DVF could interact with LRRC19 (rather than TLR5) in colitis mice and organoids, and then induce the production of pro-inflammatory cytokines. Lrrc19 knockdown blunted the severity of colitis. Furthermore, typhaneoside, a blockade of binding interfaces, blocked DVF-LRRC19 interaction and dramatically ameliorated DVF-induced colitis. Conclusions: D. vulgaris could promote colitis through DVF-LRRC19 interaction. Targeting DVF-LRRC19 interaction might be a new therapeutic strategy for UC therapy.

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco‐2 cells were cultured, and H₂O₂ was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p‐AMPK, mTOR and p‐mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p‐AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK‐mTOR signalling pathway, thereby reducing intestinal injury due to UC.

A high‐fat diet (HFD) leads to long‐term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial‐mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD‐treated Apc^min/+ mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apc^min/+ mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT‐116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA‐induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis.

Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan–Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.