Based on data-independent acquisition (DIA) proteomics technology, to analyze the proteomic characteristics of colorectal tubular adenoma and explore the expression changes of SLC30A10 and their potential association with the cGAS-STING pathway. A self-controlled design was adopted, collecting colorectal tubular adenoma (TA) and paired normal mucosa (NM) from 15 patients with TA. Differentially expressed proteins were screened by DIA proteomics, followed by GO and KEGG enrichment analyses. Immunohistochemistry was performed to detect the expression of SLC30A10, cGAS, STING, p-IRF3, ISG15, and β-catenin; immunofluorescence double staining was used to observe the co-localization of p-IRF3 and β-catenin; inductively coupled plasma mass spectrometry (ICP-MS) was employed to determine tissue manganese content. DIA analysis showed that SLC30A10 protein expression was significantly downregulated in TA tissues. Functional enrichment analysis indicated abnormalities in signal transduction, metabolic reprogramming, and nitrogen metabolism in TA tissues. IHC results demonstrated that, compared with NM, TA tissues exhibited reduced expression of SLC30A10, while the expression of cGAS, STING, p-IRF3, ISG15, and β-catenin was upregulated. Manganese content in TA tissues was also significantly increased. Immunofluorescence revealed enhanced nuclear signals of p-IRF3 in TA cells, with co-localization of p-IRF3 and β-catenin observed in the nucleus. Downregulation of SLC30A10 in colorectal tubular adenoma is associated with manganese accumulation and alterations in the cGAS-STING pathway, suggesting its potential role in the development and progression of adenoma, a finding with promising research implications.

INTRODUCTION:Epidemiological studies link helminth infections to reduced obesity prevalence, but the mechanisms remain incompletely understood. OBJECTIVES:To determine whether and how Heligomosomoides polygyrus (H. polygyrus) infection impairs dietary fat absorption in fat mice. METHODS:H. polygyrus- infected wild-type (WT) and STAT6 knockout (KO) mice were used to assess the role of STAT6 in helminth-induced lipid metabolism changes. Complementary in vitro experiments were performed using cytokine-treated Caco-2 cells, and single-cell RNA sequencing (scRNA-seq) was conducted on intestinal epithelial cells (IECs) to further explore underlying molecular mechanisms. RESULTS:We demonstrated that H. polygyrus infection impaired dietary fat absorption in mice via STAT6-dependent suppression of microsomal triglyceride transfer protein (MTTP), a key mediator of chylomicron assembly. WT mice infected with H. polygyrus exhibited increased fecal lipid excretion, reduced serum triglycerides, and enterocyte lipid retention, phenotypes absent in STAT6 KO mice. In vitro, IL4/IL13 treatment of polarized Caco-2 cells suppressed MTTP expression and lipid export, mirroring in vivo findings. Single-cell RNA sequencing of IECs revealed STAT6-dependent downregulation of lipid metabolism pathways and upregulation of immune responses. CONCLUSION:These results identify a metabolic-immune trade-off in which helminth-induced Type 2 cytokines prioritize host defense over nutrient absorption, attenuating obesity, highlighting MTTP as a novel therapeutic target for metabolic disorders and underscores the role of helminth immunomodulation in systemic energy homeostasis.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory intestinal disorder characterized by gut dysbiosis, but effective strategies are currently limited. Here, we demonstrated that Agrimoniae Herba Polysaccharides (AHP), the key active components of a herb widely used for intestinal inflammation in East Asia countries, significantly reversed colitis-related phenotypes in a gut microbiota dependent, as antibiotic treatment abolished its therapeutic effect, while gut microbes from AHP-treated mice reproduced the anti-inflammatory effect. Bacterial 16S rRNA sequencing analysis showed AHP greatly reshaped the overall structure of microbiota, especially boosting colonization of Faecalibaculum rodentium (F. rodentium), which led to a significant alleviation of intestinal inflammation, accompanied by the promotion of CD4+ T cell differentiation toward Treg. Additionally, we identified quinic acid as a key metabolite of F. rodentium enriched by AHP treatment, and found that it induced the differentiation of naïve CD4+T cells sorted from UC patients into Treg cells in vitro, which correlated with the enhancement of TAZ/Foxp3 acetylation axis. Collectively, our results show that AHP exerts the beneficial effects in the treatment of UC by acting as a prebiotic to enrich the commensal bacterium F. rodentium, and offer a novel microbiota-dependent strategy for inflammatory bowel disease.

[This corrects the article DOI: 10.3892/etm.2017.5076.].

Objective:To investigate the anti-inflammatory mechanisms of Hudi enteric-coated capsule (HDEC) and its major bioactive constituent, polydatin, in ulcerative colitis (UC). Methods:Mouse models of colitis were established by transplantation adoptive transfer of CD45RBhighCD4+ T cells and treated with or without HDEC/polydatin. Therapeutic efficacy was evaluated by assessing disease activity, colon length, and histopathological damage. The differentiation of Th1, Th17, and Treg cells was analyzed using quantitative real-time polymerase chain reaction and flow cytometry. In vitro cultures of mouse and human CD4+ T cells were utilized to assess the immunomodulatory activity. RNA sequencing, Western blotting, and immunofluorescence were used to explore the underlying mechanism. Molecular docking, molecular dynamics, and surface plasmon resonance (SPR) assays were employed to confirm the interaction between polydatin and KEAP1. Results:Treatment with HDEC and polydatin significantly ameliorated murine colitis and mucosal damage. Mechanistically, polydatin directly binds to KEAP1 to promote NFE2L2 nuclear translocation. This NFE2L2 activation reduces intracellular oxidative stress, thereby inhibiting pathogenic Th1/Th17 differentiation and enhancing Treg generation. Importantly, these effects were consistently validated in human CD4+ T cells and UC mucosal tissues. Conclusion:HDEC and polydatin alleviate UC by targeting the KEAP1-NFE2L2 axis to reduce oxidative stress, thereby restoring the Th1/Th17/Treg balance. This highlights polydatin as a promising KEAP1-targeting agent with strong translational potential.

Nonalcoholic fatty liver disease (NAFLD) is a growing health burden worldwide. The association between blood selenium (Se) and NAFLD in naturally menopausal women remains unclear. This study aimed to evaluate the association of blood Se levels with the prevalence of NAFLD, hepatic steatosis, and liver fibrosis in the US naturally menopausal women population. This study analyzed the dataset from the 2017 to 2018 National Health and Nutrition Examination Survey, including 595 naturally menopausal women. Weighted logistic regression models were used to evaluate the cross-sectional association between blood Se levels and the prevalence of NAFLD. Linear regression and ordinal logistic regression were used to evaluate the association between blood Se levels and liver steatosis and fibrosis. All analyses were conducted using the R survey package. There were no significant associations of blood Se levels with NAFLD in 3 adjusted models (odds ratio [OR] = 0.52, 95% confidence interval [CI], 0.04-7.11; OR = 0.66, 95% CI, 0.04-9.82; OR = 0.79, 95% CI, 0.08-8.08). However, in the fully adjusted model, blood Se levels showed a negative association with liver fibrosis (β = -2.32, 95% CI, -4.21, -0.43). Participants were divided into quartiles (Q1-Q4) based on the distribution of blood Se concentrations within the study cohort. The specific cutoff points were Q1 group (<173.67 μg/L), Q2 group (173.67 to <189.15 μg/L), Q3 group (189.15 to <204.35 μg/L), and Q4 group (≥204.35 μg/L). Compared with the reference group (Q1 group, <173.67 μg/L), significant inverse associations were also found for the higher Se groups (Q3 group: OR = 0.23, 95% CI, 0.1-0.53; Q4 group: OR = 0.28, 95% CI, 0.12-0.66). Our results showed that blood Se levels were not significantly associated with the prevalence of NAFLD in a US population of naturally menopausal women, but higher blood Se levels were negatively associated with liver fibrosis. Further research is needed to assess the causal relationship between exposure and disease risk.

Ethnopharmacological relevance The Hewei Jiangni Prescription (HP) is a traditional Chinese prescription, which has shown clinical benefits for many years in non-erosive reflux disease (NERD)-associated esophageal hypersensitivity. However, its mechanism of effects remains unclear. Aim of the study To investigate the mechanism of HP in treating NERD-associated esophageal hypersensitivity and identify its pharmacologically active components. Materials and methods NERD-associated esophageal hypersensitivity model mice were treated with HP. Proteomics and protein interaction networks were employed to identify differentially regulated targets. Effects on key targets were validated in cell models and model mice using enzyme-linked immunosorbent assay, western blotting, reverse transcription‒quantitative polymerase chain reaction, and immunofluorescence. Bio-layer interference technology was used to identify HP components binding to targets, followed by liquid chromatography‒mass spectrometry identification and functional validation in cell models. Results HP mitigated esophageal pathology and visceral hypersensitivity in NERD-associated esophageal hypersensitivity model mice. Additionally, HP may attenuate neuroimmune dysregulation in the experimental model by downregulating MrgprX2/B2 overexpression in mast cells and dorsal root ganglion (DRG) neurons, lowering intracellular Ca2+ levels, and decreasing the release of mast cell tryptase and calcitonin gene-related peptide. Vitexin was identified as one of the bioactive components of HP, reproducing its core pharmacological effects in vitro and exhibiting high affinity for the MRGX2 target. Conclusions This study suggests that HP may attenuate neuroimmune dysregulation between mast cells and DRG neurons by regulating MrgprX2/B2, thereby mitigating NERD-associated esophageal hypersensitivity. Additionally, the study findings suggest that vitexin may be one of the bioactive components of HP.

BACKGROUND:Traditional Chinese medicines, as a burgeoning field of medication, significantly alleviate ulcerative colitis (UC) by improving intestinal microbiota-metabolism. Our previous studies demonstrated the significant efficacy of Hudi Enteric-coated capsules (HDEC), Qingchang Wenzhong decoction (QCWZ), and Modified Wumei pill (MWMP) using a mouse model of colitis. However, the mechanism of these therapies through the modulation of microbiota-metabolism remains uncertain. OBJECTIVE:Three multicenter randomized controlled trials were designed to explore the effects of three therapies on the microbiota-metabolism of UC patients with different severity. METHODS:A total of 143 patients with different severities of UC were recruited from 10 hospitals. The clinical efficacy of HDEC for mild UC, QCWZ for moderate UC, and MWMP for severe UC (SUCs) was evaluated by colorectal Mayo scores and systemic inflammatory indicators. The 16S rRNA sequencing and metabolomics were used to analyze intestinal microbiota and metabolite profiles. RESULTS:Three therapies used alone or combined with mesalazine (MS) were comparable to MS alone in improving Mayo scores and hematic inflammatory parameters. Microbial diversities and architectures of SUCs showed the greatest response to MWMP+MS than other medications, as reflected by the enriched Ruminococcus and Anaerostipes together with the reduced Enterococcus, Streptococcus, and Streptococcus anginosus. Furthermore, MWMP+MS boosted the production of the microbiota-derived short-chain fatty acids (SCFAs) of SUCs. These differential microbes and metabolites further displayed significant statistical relationships with clinical parameters. CONCLUSION:Herbal therapies, especially MWMP+MS, effectively improve microbiota composition and SCFA metabolism, which correlates with the improvements of serum inflammatory markers and endoscopic findings in patients.

Inflammatory bowel disease (IBD) is a chronic recurrent IBD, whose cause involves the interaction between genetic and environmental factors. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial. This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional 2-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between 5 circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including ulcerative colitis (UC) and Crohn disease (CD) was analyzed. Horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results. Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR) = 1.0017; 95% confidence interval (CI) = 1.0004–1.003; P = .009] and UC [OR = 2.465; 95% CI = 1.236–4.916; P = .01]. In addition, we also found that IBD [OR: 12.07; 95% CI = 1.909–76.316; P = .008] and CD [OR = 1.014; 95% CI = 1.004–1.023; P = .005] were significantly associated with higher circulating neutrophils count in reverse MR. This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Background:Consumption of red and processed meats has been classified as probably carcinogenic and carcinogenic to humans, respectively. However, the association between their consumption and the incidence or recurrence of ulcerative colitis (UC) remains unclear. This study aims to systematically evaluate the dose-response relationship between red or processed meat consumption and UC. Methods:Databases including PubMed, Cochrane Library, Web of Science, Embase, CNKI, VIP, Wanfang, SinoMed, Yiigle, and ICTRP were searched from inception through July 2024. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were estimated using random-effects or fixed-effects models based on heterogeneity. A dose-response meta-analysis was conducted using R 4.4.2. Results:Eighteen studies comprising 1,384,024 participants were included, all rated as moderate to high quality. Red meat consumption was significantly associated with an increased risk of UC development [RR = 1.21, 95% CI (1.03, 1.42), p = 0.020]. Processed meat consumption showed a tendency toward increased UC risk, although not statistically significant [RR = 1.54, 95% CI (0.99, 2.42), p = 0.058]. Neither red nor processed meat consumption was significantly associated with UC recurrence. Dose-response analysis indicated that each additional 100 g/day of red meat intake increased UC incidence risk by 65% [RR = 1.65, 95% CI (1.30, 2.09)]. Conclusion:Based on very low-certainty evidence, increased red meat intake may be associated with a potential risk of developing UC. However, there is currently insufficient evidence to support an association between red or processed meat consumption and the recurrence of UC. Future studies with long-term follow-up and rigorous design are warranted to verify these findings and explore underlying mechanisms. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/view/CRD42024573557, identifier (CRD42024573557).

Background:Mesalazine preparations serve as first-line therapy for active mild-to-moderate ulcerative colitis(UC),however,not all patients respond to mesalazine.Patients with mesalazine-refractory UC often switch to corticosteroids,immunological therapy,and biological agents,but their use is limited owing to their well-characterised side effects(e.g.osteoporosis and cushingoid feature).Therefore,there is an unmet medical need for novel treatments with a manageable safety profile for patients with mesalazine-refractory UC.New Wumei Pill is a novel and effective herbal prescription for the treatment of UC,and our preliminary study suggested that New Wumei Pill has a significant effect on patients with mesalazine-refractory UC.However,its effectiveness and safety has not been evaluated convincingly. Objectives:This trail aims to evaluate efficacy,safety and mechanisms of New Wumei Pill in the treatment of patients with mesalazine-refractory UC. Methods:This is a prospective,randomized,double-blind control trial,in which 72 patients with mesalazine-refractory mild-to-moderate UC will be randomized in a 1:1 ratio in the treatment and control group.Patients will be screened for eligibility at the outpatient and ward of the Department of Gastroenterology in Dongfang Hospital,Beijing University of Chinese Medicine.72 participants will undergo strict screening to meet the diagnostic criteria of mildly to moderately active UC,with modified Mayo score of 3-10 points.All patients will be administered by mesalazine enteric-coated tablets for 8 weeks,at the same time,the patients in treatment group will receive New Wumei Pill,while patients from control group will be administered by dummy New Wumei Pill. Results:The primary outcomes are clinical efficacy rate and clinical remission rate according to the modified Mayo score.The secondary outcomes are individual symptom score,TCM syndrome score,endoscopic response rate,mucosal healing rate,and quality of life scale score.Finally,biological samples from participants will be preserved to reveal the mechanisms of New Wumei Pill on UC. Conclusions:We hypothesize that the patients with mesalazine-refractory mild-to-moderate UC will benefit from New Wumei Pill.If successful,this trial will provide evidence of traditional Chinese medicine in the treatment of UC,and hold promises for novel options UC patients and policymakers.

Tissue-resident memory T (TRM) cells are a type of tissue-restricted memory T cells with terminal differentiation and a memory function. They exist in mucosal tissues for a long period. In the absence of disease, TRM cells promote essential inflammation, which reinforces the intestinal barrier and prevents bacterial translocation. However, in inflammatory or autoimmune environments, TRM cells are hyperactivated. This heightened activity causes the host to release excessive pro-inflammatory cytokines, resulting in local immune imbalances and damage to the barrier, ultimately leading to tissue lesions. Numbers of studies have shown that TRM cells play a crucial role in the development and progression of inflammatory bowel disease (IBD), suggesting that targeted regulation of TRM cells homeostasis may be an important strategy for treating IBD. Here, we compiled the existing understanding of the role of TRM cells in IBD, with particular emphasis on the associated mechanisms and approaches for targeting TRM cells in IBD treatment. This review will serve as a foundation for a better understanding of IBD development and enhancing the effectiveness of clinical treatments for IBD.

BACKGROUND:Non-alcoholic steatohepatitis (NASH) is an important clinical issue and a challenge in the field of global public health. However, there are very few clinically approved drugs that can effectively treat NASH. Rhein is a natural organic compound with anti-inflammatory and antioxidant properties, but the specific role and mechanism on NASH remain unexplored. PURPOSE:This study investigated the role and associated mechanism of rhein in NASH mice. METHODS:The effects of rhein on lipid accumulation were evaluated in NASH mice through systemic signs of obesity, biochemical parameters, and histological changes. Network pharmacology was employed to determine the main bioactive compounds and key targets of rhein for the NASH treatment. Additionally, antibiotics treatment and fecal microbiota transplantation (FMT) were performed to investigate the role of microbiota in the treatment of NASH with rhein. Bacterial 16S rRNA amplicon sequencing, LC-MS/MS analysis and flow cytometric were employed to investigate the mechanisms underlying rhein's regulatory effects on gut microbiota, BA metabolism and immune balance. Finally, in vitro cell experiments were conducted to explore the effects of metabolites on Th17 cell differentiation. RESULTS:Our results showed that mice treated with rhein showed a significant alleviating effect from high-fat diet (HFD)-induced liver lipid accumulation and pathological changes compared to those in HFD group. The protective effects of rhein are gut microbiota dependent, as demonstrated by fecal microbiome transplantation and antibiotics treatment. Microbiota transferred from rhein-treated mice displayed a similar role in attenuating hepatic lipid deposition as rhein on NASH in mice, and depletion of the gut microbiota through antibiotics treatments diminished the protective effects of rhein on NASH mice. Moreover, the results from bacterial 16S rRNA sequencing suggested that rhein partially attenuated HFD-induced gut dysbiosis in NASH mice. Network pharmacology analyses was implemented and showed that Th17 cell differentiation might be the potential target in the treatment of rhein against NASH, which was confirmed by flow cytometric analysis showing markedly decrease of the percentage of Th17 cells, corresponded with upregulated Treg cells in rhein-treated NASH mice. Furthermore, targeted bile acid metabolomics analysis showed that supplement with rhein greatly increased the levels of primary bile acids β-MCA and AlloLCA, positively correlated with the relative abundances of Bifidobacterium_choerinum, which may play the key role by which rhein-altered gut microbiota promoted the restoration of Th17/Treg balance in NASH mice. Subsequent in vitro experiments confirmed that AlloLCA directly inhibits Th17 cell differentiation, with suppression of glycolysis potentially serving as the underlying mechanism for the immunomodulatory effects of AlloLCA. CONCLUSIONS:Collectively, our results suggested that orally administrated rhein reduced hepatic lipid deposition through the modulation of dysregulated gut microbiota and bile acids metabolism, thus regulating Th17/Treg immune balance. This study uncovers a novel mechanistic axis in NASH pathogenesis and providing new research directions for microbiota-targeted clinical strategies.

In recent years,the reform of the registration,evaluation,and approval system for traditional Chinese medicine(TCM)has been promoted at the national level,with establishment of an evaluation evidence system for TCM registration that combines TCM theory,human use experience,and clinical trials(known as the"three-combined"evaluation evidence system).This system,which aligns with the characteristics of TCM clinical practice and the laws of TCM research and development,recognizes the unique value of human use experience in medicine and returns to the essence of medicine as an applied science,thus receiving widespread recognition from both academia and industry.However,it meanwhile poses new and higher challenges.This article delves into the value and chal-lenges faced by the"three-combined"evaluation evidence system from three perspectives:registration management,medical institu-tions,and the TCM industry.Furthermore,it discusses how the China Association of Chinese Medicine,leveraging its academic plat-form advantages and leading roles,has made exploratory and practical efforts to facilitate the research and development of new TCM drugs and the implementation of the"three-combined"evaluation evidence system.

Intestinal microbiota plays a key role in ulcerative colitis (UC), and its composition may vary between the disease's acute (AUC) and chronic (CUC) stages. Using dextran sulfate sodium-induced mice models of AUC and CUC, this study characterized their distinct microbial dysbiosis patterns and evaluated the efficacy of a traditional Chinese medicine formula, Bawei Huangqin Enema (BHE). BHE treatment effectively alleviated colonic inflammation in both models. This was achieved by remodeling the gut microbiota in a stage-specific manner and by enhancing intestinal barrier integrity through the upregulation of tight junction proteins Occludin and MUC2. These findings highlight the distinct microbial features of AUC versus CUC and suggest that BHE's therapeutic potential derives from its dual regulation of the microbiome and intestinal barrier, supporting a multi-target approach for managing UC.

The gut microbiota plays a critical role in the occurrence and development of IBS-D, however, IBS-D-associated tongue coating microbiome dysbiosis has not yet been clearly defined. To address this, we analyzed the structure and composition of the tongue coating microbiome in 23 IBS-D patients and 12 healthy controls using 16S rRNA high-throughput sequencing analysis. The 16S rRNA sequencing results revealed that the overall observed OTUs of tongue coating microbiome in IBS-D patients exhibited a significant decrease compared with the healthy controls. Alpha diversity analysis showed that the diversity and community richness were significantly reduced in IBS-D patients, and PCoA revealed a distinct clustering of tongue coating microbiome between the IBS-D patients and healthy controls. Microbial comparisons at the genus level showed that the abundance of Veillonella, Prevotella in IBS-D patients was higher than those in healthy controls, while Streptococcus, Haemophilus, Granulicatella, and Rothia were significantly reduced compared with the healthy volunteers. Functional analysis results showed significant differences in 88 functional metabolic pathways between the IBS-D patients and the healthy controls, including fatty acid biosynthesis. These findings identified the structure, composition, functionality of tongue coating microbiome in IBS-D patients, and hold promise the potential for therapeutic targets during IBS-D management.

Inflammatory diseases,a common category of disorders involving multiple systems and organs,are characterized by their chronic and relapsing nature.These features severely impact patients' quality of life and pose a persistent challenge to the global healthcare system.Through long-term clinical practice,traditional Chinese medicine(TCM),with its multi-target and multi-pathway treatment characteristics,has amassed rich theoretical achievements and practical experiences in the prevention and treatment of inflammatory diseases,forming a comprehensive and effective diagnosis and treatment system.To further promote academic exchanges and the translation of research findings in this field for TCM,and to facilitate the high-quality development of the TCM discipline,we organized a special issue on"Traditional Chinese Medicine in the Treatment of Inflammatory Diseases"in the World Journal of Integrated traditional and western Medicine(WJIM).This special issue aims to gather the wisdom and achievements from the global TCM community and contribute to the cause of human health.

BACKGROUND:Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by recurrent abdominal pain and chronic diarrhea. T lymphocytes, which play a crucial role in gut inflammation and immune responses, may significantly contribute to the pathophysiology of IBS-D. However, the exact mechanisms by which T lymphocytes affect IBS-D remain unclear. The precise pathways and interactions involved in IBS-D are still to be determined. METHODS:We conducted single-cell RNA sequencing on blood samples from 4 IBS-D patients and 4 healthy controls. Following data preprocessing, we conducted subsequence bioinformatics analysis. Additionally, serum and colon tissue samples from IBS-D rat models were analyzed using ELISA and three-parameter fluorescence to further elucidate the T lymphocytes landscape associated with IBS-D. RESULTS:A total of 45,649 cells were classified into four distinct cell types. Among them, T lymphocytes were further subdivided into 20 unique clusters. Novel markers that were highly expressed in T lymphocytes were identified. Dysregulation of HIF-1α pathway, NF-kappa B pathway, and IL-17 signaling pathway, were observed through trajectory analysis. Additionally, single-cell regulatory network inference and clustering analysis revealed the FOS signaling pathway as a potential therapeutic target for IBS-D. Furthermore, we detected abnormally elevated levels of PLK3 and NFKBIZ in the serum and colon tissues of the IBS-D rat model. Our study mapped the communication atlas of T lymphocytes that may influence the pathophysiology of IBS-D. CONCLUSIONS:This study uncovers novel molecular features and identifies potential therapeutic targets of T lymphocytes in IBS-D, thereby advancing our understanding of the disease and expanding treatment options.

Background:Irritable bowel syndrome (IBS), a gastrointestinal motility disorder affecting millions of patients worldwide, has a substantial impact on healthcare economics and patient quality of life. However, fully satisfactory therapeutic options remain lacking. The identification of pathogenic proteins supported by causal genetic evidence enables the exploration of potential therapeutic targets for IBS. Methods:A Mendelian randomization (MR) study was performed to discover potential treatment targets linked to IBS. Summary data for IBS (outcome) were acquired from the two largest independent cohorts: sample sizes of 486,601 (53,400 cases and 433,201 controls) and 101,884 (24,735 cases and 77,149 controls), respectively. Instrumental variables were derived from cis-expression quantitative trait loci (cis-eQTL) data of druggable genes, obtained through the eQTLGen Consortium database. Colocalization analysis was employed to assess whether IBS risk and gene expression were influenced by shared SNPs. An IBS mouse model was additionally utilized to confirm the therapeutic potential of drug targets. Results:Four drug targets (P2RY14, SLC5A6, ATRAID, and IL1RL1) displayed notable MR findings in two separate datasets. Purinergic receptor P2Y14 (P2RY14) and all-trans retinoic acid-induced differentiation factor (ATRAID) exhibited robust evidence of colocalization with IBS. We further showed an abnormal increase in expression of P2RY14 and a significant decrease in ATRAID level in the colon tissue of IBS mice. Conclusion:This study proposes two potential therapeutic targets for IBS: P2RY14 and ATRAID. Drugs aimed at targeting these two genes have a greater chance of success in clinical trials, potentially facilitating the prioritization of IBS drug development and lowering associated costs.