Butyrate promotes visceral hypersensitivity in IBS model via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.

Emerging evidence indicates that gut dysbiosis is involved in the pathogenesis of visceral hypersensitivity (VH). However, how gut microbiota contributes to the development of VH is unknown. Here, we sought to examine the signal transduction pathways from gut to dorsal root ganglion (DRG) responsible for this. Therefore, abdominal withdrawal reflex (AWR) scores, fecal output, fecal water content, and total gastrointestinal transit time (TGITT) were assessed in Con rats, VH rats, rats treated with NaB, and VH rats treated with VSL#3. Fecal microbiota and its metabolite (short-chain fatty acids, SCFAs), mast cell degranulation in colon, lincRNA-01028, miR-143, and protease kinase C (PKC) and TRPV1 expression in DRGs were further detected. VH rats showed an increased fecal water content, a shortened TGITT, an increased abundance of Clostridium sensu stricto 1 and increased butyrate in fecal samples, an increased mast cell degranulation, an increased expression of lincRNA-01028, PKC, and TRPV1, and a decreased expression of miR-143 in DRGs compared with control rats, which could be restored by the application of probiotic VSL#3. The above-mentioned detection in rats treated with butyrate was similar to that of VH rats. We further confirm whether butyrate sensitized DRG neurons by a lincRNA-01028, miR-143, and PKC-dependent mechanism via mast cell in vitro. In co-cultures, MCs treated with butyrate elicited a higher TRPV1 current, a higher expression of lincRNA-01028, PKC, and a lower expression of miR-143 in DRG neurons, which could be inhibited by a lincRNA-01028 inhibitor. These findings indicate that butyrate promotes visceral hypersensitivity via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.IMPORTANCEIrritable bowel syndrome (IBS), characterized by visceral hypersensitivity, is a common gastrointestinal dysfunction syndrome. Although the gut microbiota plays a role in the pathogenesis and treatment of irritable bowel syndrome (IBS), the possible underlying mechanisms are unclear. Therefore, it is of critical importance to determine the signal transduction pathways from gut to DRG responsible for this in vitro and in vivo assay. This study demonstrated that butyrate sensitized TRPV1 in DRG neurons via mast cells in vivo and in vitro by a lincRNA-01028, miR-143, and PKC-dependent mechanism. VH rats similarly showed an increased abundance of Clostridium sensu stricto 1, an increased fecal butyrate, an increased mast cell degranulation, and increased expression of TRPV1 compared with control rats, which could be restored by the application of VSL#3. In conclusion, butyrate produced by the altered intestinal microbiota is associated with increased VH.

An ESIPT + AIE based dual-response fluorescent probe for continuous detection of PhSH and HClO and visualization of PhSH-induced oxidative stress in living cells.

As a valuable industrial chemical, thiophenol (PhSH) is poisonous, which can be easily absorbed by the human body, leading to many serious health issues. In addition, PhSH-triggered oxidative stress is considered to be related with the pathogenesis and toxicity of PhSH. Therefore, efficient methods for monitoring PhSH and ROS production induced by PhSH in living systems are very meaningful and desired. Herein, we reasonably developed a facile dual-response fluorescent probe (HDB-DNP) by incorporating the dinitrophenyl (DNP) group into a novel methylthio-substituted salicylaldehyde azine (HDB) with AIE and ESIPT features. The probe itself was non-fluorescent owing to the strong quenching effect of DNP group. In the presence of PhSH, HDB-DNP gave an intense red fluorescence (610 nm), which can rapidly switch to green fluorescence (510 nm) upon further addition of HClO, allowing the successive detection of PhSH and HClO in two well-separated channels. HDB-DNP proved to be a very promising dual-functional probe for rapid (PhSH: < 17 min; HClO: 10 s) and selective detection of PhSH and HClO in physiological conditions with low detection limit (PhSH: 13.8 nM; HClO: 88.6 nM). Inspired by its excellent recognition properties and low cytotoxicity, HDB-DNP was successfully applied for monitoring PhSH and PhSH-induced HClO generation in living cells with satisfactory results, which may help to better understand the pathogenesis of PhSH-related diseases.

The impact of vedolizumab therapy on extraintestinal manifestations in patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Extraintestinal manifestations (EIMs) pose a significant threat in inflammatory bowel disease (IBD) patients. Vedolizumab (VDZ) primarily affects the gastrointestinal tract. However, its impact on EIMs remains uncertain. Therefore, we conducted this meta-analysis to examine the effects of VDZ on EIMs during treatment. METHODS: Relevant studies were identified by conducting thorough searches across electronic databases, including PubMed, Ovid Embase, Medline, and Cochrane CENTRAL. Primary outcomes focused on the proportion of patients with resolution for pre-existing EIMs in IBD patients receiving VDZ. Secondary outcomes included the proportion of patients with EIM exacerbations and new onset EIMs during VDZ treatment. RESULTS: Our meta-analysis encompassed 21 studies. The proportion of patients with resolution of pre-existing EIMs in VDZ-treated IBD patients was 39% (150/386; 95% confidence interval [CI] 0.31-0.48). The proportion of patients with EIM exacerbations occurred at a rate of 28% (113/376; 95% CI 0.05-0.50), while new onset EIMs had a rate of 15% (397/2541; 95% CI 0.10-0.20). Subgroup analysis revealed a 40% (136/337) proportion of patients with resolution for articular-related EIMs and a 50% (9/18) rate for erythema nodosum. Exacerbation rates for arthritis/arthralgia, erythema nodosum/pyoderma gangrenosum, and aphthous stomatitis during VDZ use were 28% (102/328), 18% (7/38), and 11% (3/28), respectively. The incidence rate of newly developed EIMs during treatment was 11% (564/4839) for articular-related EIMs, with other EIMs below 2%. CONCLUSION: VDZ demonstrates efficacy in skin-related EIMs like erythema nodosum and joint-related EIMs including arthritis, arthralgia, spondyloarthritis, and peripheral joint diseases. Some joint and skin-related EIMs may experience exacerbation during VDZ therapy.

Fecal microbiota transplantation for irritable bowel syndrome: Current evidence and perspectives.

In this editorial we comment on the article published in the recent issue of the World journal of Gastroenterology. We focus specifically on the mechanisms un-derlying the effects of fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS), the factors which affect the outcomes of FMT in IBS patients, and challenges. FMT has emerged as a efficacious intervention for clostridium difficile infection and holds promise as a therapeutic modality for IBS. The utilization of FMT in the treatment of IBS has undergone scrutiny in numerous randomized controlled trials, yielding divergent outcomes. The current frontier in this field seeks to elucidate these variations, underscore the existing knowledge gaps that necessitate exploration, and provide a guideline for successful FMT imple-mentation in IBS patients. At the same time, the application of FMT as a treatment for IBS confronts several challenges.

The impact of triglyceride glucose-body mass index on all-cause and cardiovascular mortality in elderly patients with diabetes mellitus: evidence from NHANES 2007-2016.

BACKGROUND: The relationship between triglyceride glucose-body mass index (TyG-BMI) index and mortality in elderly patients with diabetes mellitus (DM) are still unclear. This study aimed to investigate the association between TyG-BMI with all-cause and cardiovascular mortality among elderly DM patients in the United States (US). METHODS: Patients aged over 60 years with DM from the National Health and Nutrition Examination Survey (2007-2016) were included in this study. The study endpoints were all-cause and cardiovascular mortality and the morality data were extracted from the National Death Index (NDI) which records up to December 31, 2019. Multivariate Cox proportional hazards regression model was used to explore the association between TyG-BMI index with mortality. Restricted cubic spline was used to model nonlinear relationships. RESULTS: A total of 1363 elderly diabetic patients were included, and were categorized into four quartiles. The mean age was 70.0 ± 6.8 years, and 48.6% of them were female. Overall, there were 429 all-cause deaths and 123 cardiovascular deaths were recorded during a median follow-up of 77.3 months. Multivariate Cox regression analyses indicated that compared to the 1st quartile (used as the reference), the 3rd quartile demonstrated a significant association with all-cause mortality (model 2: HR = 0.64, 95% CI 0.46-0.89, P = 0.009; model 3: HR = 0.65, 95% CI 0.43-0.96, P = 0.030). Additionally, the 4th quartile was significantly associated with cardiovascular mortality (model 2: HR = 1.83, 95% CI 1.01-3.30, P = 0.047; model 3: HR = 2.45, 95% CI 1.07-5.57, P = 0.033). The restricted cubic spline revealed a U-shaped association between TyG-BMI index with all-cause mortality and a linear association with cardiovascular mortality, after adjustment for possible confounding factors. CONCLUSIONS: A U-shaped association was observed between the TyG-BMI index with all-cause mortality and a linear association was observed between the TyG-BMI index with cardiovascular mortality in elderly patients with DM in the US population.

The prognostic value of the stress hyperglycemia ratio for all-cause and cardiovascular mortality in patients with diabetes or prediabetes: insights from NHANES 2005-2018.

BACKGROUND: The Stress hyperglycemia ratio (SHR) is a novel marker reflecting the true acute hyperglycemia status and is associated with clinical adverse events. The relationship between SHR and mortality in patients with diabetes or prediabetes is still unclear. This study aimed to investigate the predictive value of the SHR for all-cause and cardiovascular mortality in patients with diabetes or prediabetes. METHODS: This study included 11,160 patients diagnosed with diabetes or prediabetes from the National Health and Nutrition Examination Survey (2005-2018). The study endpoints were all-cause and cardiovascular mortality, and morality data were extracted from the National Death Index (NDI) up to December 31, 2019. Patients were divided into SHR quartiles. Cox proportion hazards regression was applied to determine the prognostic value of SHR. Model 1 was not adjusted for any covariates. Model 2 was adjusted for age, sex, and race. Model 3 was adjusted for age, sex, race, BMI, smoking status, alcohol use, hypertension, CHD, CKD, anemia, and TG. RESULTS: During a mean follow-up of 84.9 months, a total of 1538 all-cause deaths and 410 cardiovascular deaths were recorded. Kaplan-Meier survival analysis showed the lowest all-cause mortality incidence was in quartile 3 (P < 0.001). Multivariate Cox regression analyses indicated that, compared to the 1st quartile, the 4th quartile was associated with higher all-cause mortality (model 1: HR = 0.89, 95% CI 0.74-10.7, P = 0.226; model 2: HR = 1.24, 95% CI 1.03-1.49, P = 0.026; model 3: HR = 1.30, 95% CI 1.08-1.57, P = 0.006). The 3rd quartile was associated with lower cardiovascular mortality than quartile 1 (model 1: HR = 0.47, 95% CI 0.32-0.69, P < 0.001; model 2: HR = 0.66, 95% CI 0.45-0.96, P = 0.032; model 3: HR = 0.68, 95% CI 0.46-0.99, P = 0.049). There was a U-shaped association between SHR and all-cause mortality and an L-shaped association between SHR and cardiovascular mortality, with inflection points of SHR for poor prognosis of 0.87 and 0.93, respectively. CONCLUSION: SHR is related to all-cause and cardiovascular mortality in patients with diabetes or prediabetes. SHR may have predictive value in those patients.

Development and validation of a nomogram to predict non-response to 5-aminosalicylic acid in patients with ulcerative colitis.

BACKGROUND: there are some patients with ulcerative colitis (UC) who have non-response (NR) to 5-aminosalicylic acid (5-ASA). To promote individualized treatment in UC patients, it is crucial to identify valid predictors to estimate NR to 5-ASA. Therefore, this study aimed to identify the predictive value of clinical and biochemical markers and to construct a nomogram model predicting NR to 5-ASA in patients with UC. METHODS: data of patients diagnosed with UC in the First Hospital of China Medical University between January 2012 and December 2020 were retrospectively analyzed. Primary outcome was the proportion of NR to 5-ASA. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. RESULTS: of 284 UC patients who were treatment-naive, 86 (30.3 %) had NR to 5-ASA. Univariate regression analysis showed that disease classification (DC) (p = 0.008), monocytes (MONO) (p = 0.041), platelet distribution width (PDW) (p = 0.027), serum total cholesterol (TC) (p = 0.031) and α1 globulin (p < 0.001) were strongly associated with NR to 5-ASA. Receiver operating characteristics (ROC) analysis indicated the AUC was 0.852, it showed that this model has a good degree of discrimination. The DCA curve showed that the predicted probability is 0.0-96.0 %. CONCLUSION: this study developed a predictive model with good discrimination and calibration, and high clinical validity, which can effectively estimate the risk of NR to 5-ASA. DC, MONO, PDW, TC and α1 globulin can be used as predictors for NR to 5-ASA in UC patients.

The incidence and predisposing factors for irritable bowel syndrome following COVID-19: a systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder. Several studies have analyzed the long-term GI symptoms and IBS following coronavirus disease 2019 (COVID-19). The purpose of this study is to evaluate the incidence and predisposing factors for IBS following COVID-19 by a systematic review and meta-analysis. METHODS: Electronic databases were searched to identify relevant studies. Primary outcomes were the pooled incidence rate of IBS following COVID-19 and the pooled relative risk (RR) for IBS in the COVID-19 group compared to the non-COVID-19 group. Secondary outcomes were the pooled RR and the standardized mean difference (SMD) for predisposing factors in the IBS group compared to the non-IBS group. Heterogeneity was evaluated using Cochran's Q test and I2 statistics. RESULTS: Ten studies were included in this study. The pooled incidence rate of IBS in COVID-19 patients was 12%. The pooled incidence rate of IBS-D, IBS-C and IBS-M was 5%, 2% and 1%. The pooled incidence rate of IBS in 6 and 12 months was 10% and 3%. The pooled RR for IBS in COVID-19 patients was 1.23 [95% confidence interval (CI) = 0.50-3.01] compared to non-COVID-19 patients. The pooled RR or SMD for mild, moderate, and severe disease activity, procalcitonin (PCT), depression or anxiety in IBS patients following COVID-19 was 0.94 (95% CI = 0.74-1.21), 1.19 (95% CI = 0.65-2.21), 1.30 (95% CI = 0.63-2.66), 6.73 (95% CI = 6.08-7.38) and 3.21 (95% CI = 1.79-5.75). CONCLUSION: The incidence of IBS following COVID-19 was 12%. But it was not higher than the general population. We also found some predisposing factors for IBS including depression or anxiety, PCT.

Effectiveness and safety of upadacitinib for inflammatory bowel disease: A systematic review and meta-analysis of RCT and real-world observational studies.

BACKGROUND: Upadacitinib, a novel and selective inhibitor of Janus kinase 1, has demonstrated promising efficacy in managing inflammatory bowel disease (IBD). In this systematic review and meta-analysis, our primary aim was to comprehensively assess the therapeutic effectiveness and safety profile of upadacitinib in the treatment of patients with IBD. METHODS: We conducted an extensive literature search across prominent databases, including Medline, Embase, Web of Science, and Cochrane Central, to identify pertinent studies providing insights into the efficacy and safety of upadacitinib in IBD. The primary endpoint was the achievement of clinical remission, while secondary endpoints encompassed clinical response, endoscopic response, endoscopic remission, and the evaluation of adverse events (AEs). RESULTS: In this meta-analysis of nine studies, we categorized results by study type. Clinical remission rates were: RCTs 36 % (95 % CI = 30-42 %), real-world studies 25 % (95 % CI = 1-49 %), retrospective studies 40 % (95 % CI = 24-56 %), cohort studies 55 % (95 % CI = 25-85 %). Clinical response rates were: RCTs 61 % (95 % CI = 55-67 %), real-world studies 42 % (95 % CI = 14-70 %), cohort studies 65 % (95 % CI = 57-73 %). Endoscopic remission rates were: RCTs 19 % (95 % CI = 15-24 %), cohort studies 29 % (95 % CI = 5-52 %). Endoscopic response rates were: RCTs 41 % (95 % CI = 36-47 %), cohort studies 57 % (95 % CI = 31-83 %). Incidence rate for any AEs: IBD 69 % (95 % CI = 63-76 %), UC 65 % (95 % CI = 57-74 %), CD 75 % (95 % CI = 67-82 %). CONCLUSION: Cumulative data from real-world studies and trials confirm the efficacy of upadacitinib in IBD induction and maintenance, with consistent safety. However, further long-term studies are needed to understand its sustained effectiveness and safety.

Infliximab-induced psoriasis in an ulcerative colitis patient successfully treated with guselkumab.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract. Tumor necrosis factor (TNF) inhibitors such as infliximab (IFX) are used to treat UC. But TNF inhibitors can induce psoriasis, which was characterized by IL-17/IL-22 expressing Th17 cells and IFN-γ expressing Th1 cells, with increased expression of Th17 cells correlated with more severe skin lesions and a need for Ustekinumab (UST) therapy1. UST is a monoclonal antibody that binds to the p40 subunit of the interleukin (IL)-12 and IL-23. It has shown remarkable efficacy in psoriasis and UC2. Guselkumab, a subcutaneously administered fully human IgG1 monoclonal antibody that selectively inhibits the p19 subunit of IL-23, is approved for the treatment of patients with moderate-to-severe plaque psoriasis3. It was shown to be efficacious in patients with prior failure of other biologics such as UST and was also observed in the treatment of psoriasis localized in difficult-to-treat body regions including the scalp, palms, soles, and fingernails. We report a case of successful use of guselkumab to treat a UC patient with IFX-induced psoriasis that was refractory to UST therapy.

Development and validation of a nomogram to predict non-response to 5-aminosalicylic acid in patients with ulcerative colitis

Background: there are some patients with ulcerative colitis (UC) who have non-response (NR) to 5-aminosalicylic acid (5-ASA). To promote individualized treatment in UC patients, it is crucial to identify valid predictors to estimate NR to 5-ASA. Therefore, this study aimed to identify the predictive value of clinical and biochemical markers and to construct a nomogram model predicting NR to 5-ASA in patients with UC. Methods: data of patients diagnosed with UC in the First Hospital of China Medical University between January 2012 and December 2020 were retrospectively analyzed. Primary outcome was the proportion of NR to 5-ASA. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. Results: of 284 UC patients who were treatment-naive, 86 (30.3 %) had NR to 5-ASA. Univariate regression analysis showed that disease classification (DC) (p = 0.008), monocytes (MONO) (p = 0.041), platelet distribution width (PDW) (p = 0.027), serum total cholesterol (TC) (p = 0.031) and α1 globulin (p < 0.001) were strongly associated with NR to 5-ASA. Receiver operating characteristics (ROC) analysis indicated the AUC was 0.852, it showed that this model has a good degree of discrimination. The DCA curve showed that the predicted probability is 0.0-96.0 %. Conclusion: this study developed a predictive model with good discrimination and calibration, and high clinical validity, which can effectively estimate the risk of NR to 5-ASA. DC, MONO, PDW, TC and α1 globulin can be used as predictors for NR to 5-ASA in UC patients. (AU)

Infliximab-induced psoriasis in an ulcerative colitis patient successfully treated with guselkumab

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract. Tumor necrosis factor (TNF) inhibitors such as infliximab (IFX) are used to treat UC. But TNF inhibitors can induce psoriasis, which was characterized by IL-17/IL-22 expressing Th17 cells and IFN-γ expressing Th1 cells, with increased expression of Th17 cells correlated with more severe skin lesions and a need for Ustekinumab (UST) therapy1. UST is a monoclonal antibody that binds to the p40 subunit of the interleukin (IL)-12 and IL-23. It has shown remarkable efficacy in psoriasis and UC2. Guselkumab, a subcutaneously administered fully human IgG1 monoclonal antibody that selectively inhibits the p19 subunit of IL-23, is approved for the treatment of patients with moderate-to-severe plaque psoriasis3. It was shown to be efficacious in patients with prior failure of other biologics such as UST and was also observed in the treatment of psoriasis localized in difficult-to-treat body regions including the scalp, palms, soles, and fingernails. We report a case of successful use of guselkumab to treat a UC patient with IFX-induced psoriasis that was refractory to UST therapy. (AU)

Impact of malnutrition and sarcopenia on quality of life in patients with inflammatory bowel disease: A multicentre study.

BACKGROUND: Malnutrition and subsequent alterations in body composition (BC), particularly sarcopenia, are common but not yet elucidated in patients with inflammatory bowel disease (IBD); we aimed to detail the changes in BC and the characteristics of co-occurrence of malnutrition and sarcopenia in IBD patients and to investigate its effect on quality of life. METHODS: This study was a multicentre, prospective, observational study involving four tertiary referral hospitals in China. The following data were collected from consecutive IBD inpatients: demographic information, medical history, recent weight change, handgrip strength (HGS) and BC parameters by bioelectrical impedance analysis (BIA). Nutritional assessments were performed through stepwise screening (Nutritional Risk Screening 2002) and diagnosis (World Health Organization-related body mass index [BMI], subjective global assessment, European Society for Clinical Nutrition and Metabolism 2015 and Global Leadership Initiative on Malnutrition [GLIM] criteria). The quality of life was assessed by the Inflammatory Bowel Disease Questionnaire. IBD patients were compared with 1:1 sex-, age- and BMI-matched healthy controls (MHC). RESULTS: A total of 238 IBD patients (177 Crohn's disease [CD] and 61 ulcerative colitis [UC]), 68.5% male, with a mean age of 38.5 ± 14.0 years and a mean BMI of 19.8 ± 3.5 kg/m2 , were recruited. Compared with MHC (n = 122), IBD patients showed significant deterioration in BC and physical function, characterized by muscle depletion (appendicular skeletal muscle mass index [ASMI], 8.0 ± 1.3 vs. 6.7 ± 1.2 kg/m2 , Δ% -15.0% [-22.0%, -10.0%], P < 0.001) and fat accumulation (visceral fat area, 32.9 ± 22.6 vs. 66.5 ± 35.8, Δ% 110.0% [35.0%, 201.0%], P < 0.001). The prevalence of GLIM-defined malnutrition and sarcopenia in IBD patients was 60.1% and 25.2%, respectively. The nutritional status of patients with CD was worse than that of patients with UC. The activity phase of IBD significantly and negatively affected BC, while the lesion location did not. The co-occurrence of sarcopenia and malnutrition was not optimistic; 16.4-21.8% of patients suffer from sarcopenia and malnutrition based on different criteria at the same time, which was accompanied by a reduction in quality of life. HGS was correlated with various BC parameters (body cell mass, r = 0.76; ASMI, r = 0.70; fat-free mass, r = 0.73, all P < 0.001). CONCLUSIONS: GLIM-defined malnutrition and sarcopenia were prevalent in IBD patients and kept a high rate of co-occurrence, which was accompanied with impaired quality of life. The alteration of BC in IBD patients was characterized by muscle depletion and fat accumulation. The strong correlation between HGS and BIA-derived BC suggested its hopeful evaluation in nutritional status and sarcopenia in IBD patients.