Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain associated with changes in stool consistency or bowel movement frequency. It is a highly prevalent chronic relapsing disorder that substantially impairs patients’ quality of life and elevates societal healthcare costs. The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet has emerged as a cornerstone dietary intervention for IBS owing to its demonstrated efficacy in alleviating symptoms. This article systematically reviews the progress in understanding the mechanism of the low FODMAP diet in the treatment of IBS, covering key dimensions such as reduced intestinal gas production, osmotic regulation, gut microbiota balance, abnormal intestinal fermentation, intestinal inflammatory and immune activation, and improvement in the gut-brain axis function. Additionally, this article reviews predictors of treatment response and outlines future research priorities based on recent evidence.

BACKGROUND:Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterised by progressive multiorgan dysfunction. Direct investigation of human pancreatic tissue in SAP has been extremely limited, and effective targeted therapies are currently lacking. OBJECTIVE:We sought to define the cellular and molecular mechanisms of SAP progression to identify actionable therapeutic targets. DESIGN:Using rare pancreatic tissues from critically ill patients with SAP (n = 8), we constructed the first single-cell transcriptomic atlas of human SAP. Cellular compositional changes and intercellular communication were analysed to elucidate disease mechanisms. Findings were integrated with clinical data from a large patient cohort (n = 153) and validated through in vitro and in vivo studies in murine and porcine models. RESULTS:We identified pancreatic microcirculatory failure as a central pathological event in SAP, driven by CD8+ T cell-mediated endothelial injury. Mechanistically, tumour necrosis factor-alpha (TNF-α) upregulates UL16-binding proteins (ULBPs) on endothelial cells, activating the cytotoxic receptor NKG2D on infiltrating CD8+ T cells and creating a feed-forward loop that amplifies microvascular damage. The TNF-α/ULBP/NKG2D axis correlated with clinical disease severity and microcirculatory dysfunction in patients. In preclinical models, inhibition of TNF-α or CD8+ T cells preserved microvascular integrity, reduced tissue damage and improved survival. CONCLUSION:This study provides the comprehensive cellular map of human SAP and uncovers a pathogenic immune-endothelial circuit-orchestrated by the TNF-α/ULBP/NKG2D axis-that drives microcirculatory dysfunction. These findings establish a mechanistic rationale for targeting TNF-α as a potential therapeutic strategy in SAP.

Background:Three-dimensional high-resolution anorectal manometry (3DHRAM) has been developed and introduced to explore pelvic floor disorder. The aim of this study was to evaluate the diagnostic performance of 3DHRAM in identifying descending perineal syndrome (DPS) in patients with obstructed defecation. Methods:All consecutive patients referred in the previous 1 year for investigations of obstructed defecation were eligible. We included only patients who underwent both 3DHRAM and CD. Binary logistic regression was performed to identify independent predictors of DPS. The sensitivity, specificity, Youden index and area under ROC were calculated in order to propose a diagnostic strategy for DPS. Results:Thirty-eight patients (41.3%) presented with DPS on CD. Binary logistic regression analysis confirmed that perineal descent was independently associated with DPS (odds ratio = 1.13, 95% confidence interval 1.03-1.23, P = 0.009). On 3DHRAM, the excessive perineal descent parameter indicated a sensitivity of 0.61, a specificity of 0.76 with a Youden index of 0.37, and derived a cut-off value of 10.5 mm and achieved an area under the curve of 0.72. Perineal descent combined with rectocele, rectal mucosal prolapse, and dyssynergic pattern derived the best Youden Index (0.44) with a specificity of 0.89 and a sensitivity of 0.55. Conclusion:This study suggests that 3DHRAM has potential as a complementary tool for diagnosing DPS at present. Future multi-center, prospective studies with larger, more diverse cohorts are needed to validate our findings and to better define the role of 3DHRAM in diagnosing DPS.

ETHNOPHARMACOLOGICAL RELEVANCE:Jieduquyuziyin prescription (JP) is an empirical prescription approved for application to treat systemic lupus erythematosus (SLE) in hospital within China. Despite the prominent treatment effect of JP clinically, further investigation is imperative to explore its underlying mechanisms. AIM OF THE STUDY:We aim to investigate the impact of JP on DN T cell apoptosis in the treatment of SLE and the specific regulation mechanisms. MATERIALS AND METHODS:Firstly, female MRL/lpr mice were treated with JP and the therapeutic efficacy of JP was evaluated via skin lesions, lymphoid organ enlargement, accumulation of autoantibodies and renal function. Then, flow cytometer analysis was performed to evaluate the proportions and the apoptosis of T cell subpopulations. Based on the above results, double-negative (DN) T cells were subjected to proteomic with subsequent differential screening. The expression of Ube2m and Bim was further validated using real-time PCR and Western blot. Subsequently, DN T cells were incubated with JP-contained serum in vitro, and cell apoptosis was quantified using flow cytometry. Additionally, the expression levels of Ube2m, Bim and other associated proteins were also assessed through western blotting. To further clarify whether Ube2m serves as the key target of JP in regulating DN T cell apoptosis, the mice that Ube2m was specific deleted in T cells with spontaneous lupus (Ube2m-/-lpr) were utilized. JP was administered to WTlpr or Ube2m-/-lpr mice, followed by assessment of the lupus condition and DN T cell apoptosis. RESULTS:JP administration effectively ameliorated the lupus phenotype. Then flow cytometry assay showed that JP treatment enhanced DN T cell apoptosis to reduce their accumulation and restored the immune homeostasis. Proteomic analysis revealed a significant inhibition of Ube2m for JP treatment, which is essential for maintaining homeostasis of DN T cells. Further experiments confirmed that JP treatment effectively downregulated the expression of Ube2m and subsequently upregulated the level of pro-apoptotic protein Bim with decreased Bim degradation. In vitro experiments also confirmed that JP-contained serum significantly facilitated DN T cell apoptosis and reduced DN T cell accumulation by inhibiting Ube2m expression. Furthermore, Ube2m-/-lpr mice were utilized and the impact of JP treatment on the apoptosis of DN T cells was found to be minimal in the absence of Ube2m. Mechanistic investigation reveals that JP exerts its effects by suppressing the expression of Ube2m, subsequently inhibiting CRL-dependent degradation of Bim, and ultimately promoting Bim-induced apoptosis in DN T cells. Furthermore, the blockade of Ube2m in T cells effectively prevents JP-induced apoptosis in DN T cells, underscoring Ube2m as one crucial therapeutic target of JP in mediating DN T cell apoptosis and managing SLE. CONCLUSIONS:Our findings indicate that JP treatment effectively restores the homeostasis of DN T cells in SLE by inhibiting Ube2m expression, thereby reducing Bim ubiquitination degradation. This ultimately enhanced DN T cell apoptosis and alleviated lupus phenotype.

Background:Irritable bowel syndrome (IBS) is a condition with undetermined pathophysiology. Dysregulation of the gut-brain axis has been implicated in its development. This study aimed to investigate the association between gut microbial dysbiosis and brain N-methyl-D-aspartate receptor (NMDAR) hyperfunction in a mouse model of post-infectious IBS (PI-IBS) with visceral hypersensitivity. Methods:Four-week-old mice were divided into four groups: control mice, PI-IBS mice, PI-IBS mice co-housing with normal mice, and PI-IBS mice administrated with a cocktail of antibiotics. The PI-IBS mouse model was established by using Trichinella spiralis infection. Visceral sensitivity was measured by using the abdominal withdrawal reflex in response to colorectal distension. c-FOS and NMDAR expression in the insula, hippocampus, and hypothalamus were evaluated by using immunostaining and Western blot, respectively. Additionally, NMDAR-mediated evoked excitatory postsynaptic currents (eEPSCs) in these brain regions were recorded by using patch clamp techniques. Results:Visceral hypersensitivity was observed in PI-IBS mice compared with control mice. Increased c-FOS expressions were observed in the insula and hippocampus of PI-IBS mice. Although no changes in the NMDAR subtypes expression were observed, enhanced NMDAR-mediated eEPSCs were detected in the insula and hippocampus of PI-IBS mice compared with control mice. Co-housing and antibiotics treatment effectively reduced NMDAR-mediated eEPSCs and alleviated visceral hypersensitivity. Conclusion:Gut microbiota dysbiosis may serve as an initiating factor for NMDAR hyperfunction in PI-IBS with visceral hypersensitivity.

Acute pancreatitis (AP) is currently among the most prevalent digestive diseases. The pathogenesis of AP remains elusive, and there is no specific treatment. Therefore, identifying novel therapeutic targets is imperative for effective management and prevention of AP. In this study, we conducted a comprehensive transcriptomic analysis of peripheral blood from patients with AP and the pancreatic tissue from a mouse model of AP. Our analyses revealed that mouse model of AP exhibited a higher enrichment of mitogen-activated protein kinase signaling, endocytosis, apoptosis and tight junction pathways than the control. Subsequent weighted gene co-expression network analysis identified 15 gene modules, containing between 50 and 1000 genes each, which demonstrated significant correlations within samples from patients with AP. Further screening identified four genes (ACSL4, GALNT3, WSB1, and IL1R1) that were significantly upregulated in severe acute pancreatitis (SAP) in both human and mouse samples. In mouse models of SAP, ACSL4 was significantly upregulated in the pancreas, whereas GALNT3, WSB1, and IL1R1 were not. Lastly, we found that a commercially available ACSL4 inhibitor, PRGL493, markedly reduced IL-6 and TNFα expression, alleviated pancreatic edema and necrosis, and diminished the infiltration of inflammatory cells. In conclusion, this study comprehensively depicts the key genes and signaling pathways implicated in AP and suggests the potential of ACSL4 as a novel therapeutic target for SAP. These findings provide valuable insights for further exploration of therapeutic strategies for SAP.

INTRODUCTION:Long-term studies characterizing the natural history of functional bowel disorder (FBD) from community-based settings and exploring association with psychological factors are sparse. We aimed to evaluate the evolution of symptoms, health outcomes, and association of FBD with psychological disorders in Chinese population. METHODS:Individuals identified from random sampling of residents of Hangzhou, China, participated in a baseline survey in January 2010. Follow-up phone survey was conducted in December 2018. FBD was diagnosed based on Rome III criteria. RESULTS:Among 452 individuals (mean age 44.6 ± 15.3 years, 174 [38%] male) who completed the study, the prevalence of FBD was 36.3% (95% confidence interval [CI] 32.6-40.0%) at enrollment and 36.1% (95% CI 32.3-39.8%) at follow-up survey ( P = 0.94). However, 214 individuals (47%) had interval change in diagnosis. Although no difference in incidence of organic disease or death was observed, a higher proportion of patients with FBD (16/164, 9.8% vs 9/288, 3.1%; P = 0.003) compared with those without FBD received non-cancer-related abdominal and/or pelvic surgery during follow-up. FBD was associated with anxiety and/or depression at initial (adjusted odds ratio [AOR] = 1.7, 95% CI 1.7-2.7, P = 0.02) and follow-up (AOR = 8.0, 95% CI 3.2-20.0, P < 0.001) surveys. Diagnosis of FBD at baseline was associated with new-onset anxiety and/or depression at follow-up (AOR = 3.2, 95% CI 1.2-8.3, P = 0.01). DISCUSSION:Although the prevalence of FBD remained stable, transformation of symptoms was common over time. Patients with FBD may have increased risk of receiving non-cancer-related abdominal and/or pelvic surgery. FBD symptoms at baseline increased the risk of new-onset anxiety and/or depression by 3.2-fold over the next 9 years.

Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells is considered as a crucial commander during SLE. Neddylation, a significant type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE is still unknown. Here, we reported that neddylation inactivation with MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells in lupus mice. Then double knockout (KO) lupus-prone mice ( Ube2m -/- Bim -/- lpr ) were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression. Clinically, we also found that in SLE patients, the proportion of DN T cells was raised and their apoptosis was reduced. Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Altogether, our findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therapeutic approach for this disease.

To investigate the potential link between gut microbiota and functional dyspepsia (FD). Genome-wide association studies (GWAS) of gut microbiota and FD were used in Mendelian randomization (MR) research. Using the GWAS of 18,340 people, instrumental variables related to gut microbiota as an exposure factor were identified. In a GWAS investigation, 189,695 control individuals and 4376 FD patients were included as outcome variables. The primary analysis technique was inverse variance weighted analysis. The reliability of MR analysis results is tested using sensitivity analysis. Two-sample Mendelian randomization analysis revealed the presence of 7 gut microbiota associated to FD. In the inverse variance weighted analysis method, Order Erysipelotrichales (odds ratio (OR): 1.301; 95% confidence interval (CI): 1.016, 1.665; P = .037), Family Erysipelotrichales (OR: 1.301; 95% CI: 1.016, 1.665; P = .037), Genus Haemophilus (OR: 1.236; 95% CI 1.059, 1.442; P = .007), Genus Ruminiclostridium 9 (OR: 1.422; 95% CI: 1.078, 1.877; P = .013), Genus Lachnospiraceae NK4A 136 group (OR: 1.297; 95% CI: 1.059, 1.589; P = .012) was positively associated with FD. Class Gammaproteobacteria (OR: 0.705; 95% CI: 0.522, 0.952; P = .022) and Genus Erysipelatoclostridium (OR: 0.747; 95% CI: 0.628, 0.888; P = .001) were found to be inversely related to FD. There was no evidence of pleiotropy or heterogeneity in the sensitivity analysis. Our research provides evidence for a possible link between FD and a number of gut microbiota. The role that gut microbiota plays in the development of FD requires more investigation.

Background and study aims Functional dyspepsia (FD) is a common disease with an unclear pathology. Autophagy is associated with inflammation and has been proposed to play a role in the development of FD. This study aimed to evaluate expression of the autophagy proteins beclin1 and p62/SQSTM1 in patients with FD. Patients and methods Duodenal mucosal tissues were collected from 10 patients with FD and 10 asymptomatic controls. The extent of autophagy was determined by examining expression levels of beclin1 and p62/SQSTM1 using quantitative polymerase chain reaction and immunohistochemistry techniques. Results Lower expression levels of beclin1 protein were detected in the duodenal bulb (D1) and the second portion of the duodenum (D2) in patients with FD compared with asymptomatic controls. Higher levels of p62 protein were expressed in D1 in patients with FD than in controls. No differences in mRNA expression of beclin1 and p62 were observed between patients with FD and controls. Conclusion Abnormal autophagy was involved in FD, which may be associated with the pathogenesis of FD.

Background: Although indications for evaluation and treatment of Helicobacter pylori infection are broadening to include primary prevention for gastric adenocarcinoma, potential adverse effects on gut microbiota have been raised. We performed a systematic review and meta-analysis to evaluate the effects of H. pylori therapy on gut microbiota. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science (to 4/2021) were searched for studies quantitatively evaluating microbiota before and after H. pylori therapy. Meta-analysis was performed to assess early (<1 year) and long-term (≥1 year) effects on gut microbiota after H. pylori treatment. Subgroup analysis evaluating the effects of H. pylori therapy with addition of probiotics on gut microbiota was also performed. Results: Thirty studies (N = 1,218) met the criteria. Early after H. pylori therapy, intestinal microbial diversity was reduced in nearly all studies. At the genus level, reduction in the abundance of Enterococcus, while increase in Lactobacillus, Bifidobacterium, and Bacteroides counts were observed. However, Enterococcus, Lactobacillus, Bifidobacterium, and Bacteroides counts remained stable in patients who received probiotics with H. pylori therapy. At the phylum level, the relative abundance of Actinobacteria and Firmicutes increased after treatment. At ≥1 year, intestinal microbial diversity normalized in six of seven studies. No differences in the relative abundance of Actinobacteria, Firmicute, Bacteroidetes, and Proteobacteria were observed ≥1 year after therapy. Conclusion: The impact of H. pylori therapy on gut microbiota appears transient with early changes largely resolving after 1 year. Probiotics may reduce the early impact of H. pylori therapy on gut microbiota.

Objective:To preliminary explore the potential application value of ultrasound shear wave elastography (SWE) in assessing functional defecation disorders compared with anorectal manometry and X-ray defecography.Methods:From July 2022 to December 2022, the results of SWE, anorectal manometry and X-ray defecography of 39 patients with functional defecation disorders visited Sir Run Run Shaw Hospital, School of Medicine of Zhejiang University were retrospectively analyzed. Non-parametric tests were used to analyze the changes in elastic modulus values of anorectal muscle groups at different phase.Chi-square test and Bland-Altman plots were used to assess the consistency between SWE, X-ray defecography and anorectal manometry in evaluating spastic pelvic floor syndrome, as well as the changes in the anorectal angle measured by SWE and X-ray defecography (from resting phase to contraction phase, resting phase to strain phase (Valsalval maneuver).Results:The elastic modulus values measured by SWE of the puborectalis muscle, internal anal sphincter, and external anal sphincter of patients with functional defecation disorders during strain phase were 32.4 kPa (19.1 kPa, 60.3 kPa), 25.3 kPa (17.0 kPa, 53.8 kPa), and 28.6 kPa (21.3 kPa, 55.1 kPa), respectively, which had no statistically significant differences compared to elastic modulus values in resting phase (33.5 kPa (22.1 kPa, 44.9 kPa), 28.9 kPa (22.4 kPa, 45.1 kPa), and 32.4 kPa (23.1 kPa, 49.4 kPa), all P>0.05). The consistency between SWE and X-ray defecography in the diagnosis of spastic pelvic floor syndrome was poor (Kappa=0.190). The consistency between SWE and anorectal manometry in the diagnosis of dyssynergic defecation was poor (Kappa=0.160). The differences in the changes of anorectal angle detected by SWE and X-ray defecography were within the 95% consistency limit ( P=0.429 and 0.582). Conclusion:SWE is sensitive in evaluating changes in anorectal angle, and it shows good consistency with defecography in assessing angle changes.

INTRODUCTION: Slow colon transit and visceral hypersensitivity are recognized as major pathophysiological mechanisms in irritable bowel syndrome with constipation (IBS-C). However, there is a lack of therapies targeting both abdominal pain and colonic motility. This study was designed to investigate the long-term effects and possible mechanisms of transcutaneous electrical acustimulation (TEA) in patients with IBS-C. METHODS: Fifty-two patients with IBS-C were randomized into 2 groups: daily TEA for 4 weeks (n = 26) and daily sham-TEA for 4 weeks (n = 26). The number of complete spontaneous bowel movements per week (CSBMs/week, primary outcome), Irritable Bowel Syndrome Severity Scoring System, Patient Assessment of Constipation Quality of Life, visual analog scale (VAS) pain score, colonic transit time, and anorectal physiology were evaluated before treatment and at the end of the treatment. Colonic transit was assessed with radiopaque markers. Electrocardiograms were recorded for assessing autonomic functions. RESULTS: (i) TEA improved constipation and abdominal pain. After the treatment, the number of CSBMs/week during the last week in the TEA group was higher than that in the sham-TEA group (3.5 ± 1.6 vs 2.3 ± 0.6, P = 0.002). Similar effects were also noted in the visual analog scale pain score (P = 0.002) and Irritable Bowel Syndrome Severity Scoring System score (P = 0.025). In addition, there was a significant improvement in the quality of life of patients with constipation. The Patient Assessment of Constipation Quality of Life total score was significantly decreased in the TEA group (P = 0.004). (ii) Compared with sham-TEA, TEA improved colon transit (P = 0.002) and increased the threshold of rectal sensation (desire to defecate, P = 0.004; maximum tolerability, P < 0.001). (iii) TEA increased vagal activity, compared with sham-TEA (P < 0.05); at the end of the treatment, the vagal activity was significantly correlated with colon transit and the CSBMs/week. DISCUSSION: TEA improves constipation and symptoms of IBS by accelerating colon transit and reducing rectal sensation, possibly mediated by using the autonomic mechanisms.

N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are excitatory neurotransmission receptors of the central nervous system and play vital roles in synaptic plasticity. Although not fully elucidated, visceral hypersensitivity is one of the most well-characterized pathophysiologic abnormalities of functional gastrointestinal diseases and appears to be associated with increased synaptic plasticity. In this study, we review the updated findings on the physiology of NMDARs and AMPARs and their relation to visceral hypersensitivity, which propose directions for future research in this field with evolving importance.

Background Due to complex pathophysiology of functional dyspepsia, medications to treat functional dyspepsia are not effective for all patients. Transcutaneous electrical acustimulation (TEA) is an potentially effective therapy for functional dyspepsia without proofs of definite mechanisms. Aims We aimed to investigate the therapeutic impacts of TEA on postprandial distress syndrome (PDS) and explore potential neuroimmune mechanisms. Methods We conducted a double-blinded, randomized, controlled trial in 30 PDS patients randomized for 4-week TEA or sham-TEA. Dyspeptic symptoms, gastric accommodation, gastric emptying and heart rate variability (HRV) were assessed. Duodenal mucosal inflammation was also evaluated. Results The dyspeptic symptoms were improved with TEA compared with sham-TEA (P = 0.03). The initial satiety volume and the maximum tolerable volume (MTV) were both improved after the TEA treatment, compared with the sham-TEA group (P all < 0.05). The gastric emptying time (T1/2) was not altered with TEA or sham-TEA. The TEA treatment increased vagal activity and decreased sympathovagal ratio assessed by HRV (P all < 0.01). The IL-6 expression in bulb mucosa was downregulated by the TEA treatment compared to the baseline (P < 0.05). Conclusions Noninvasive TEA improves gastric accommodation and dyspeptic symptoms, possibly by downregulating the IL-6 expression in duodenal bulb mucosa via the vagal efferent pathway.

Hebbian-type synaptic plasticity which includes long term potentiation (LTP) and long term depression (LTD), is the main cellular mechanism underlying learning and memory. Effective activity and synaptic content of tyrosine phosphatase SHP2 are required for AMPA receptor trafficking during LTP. However, the role of SHP2 in LTD has not been fully elucidated. This study shows that the phosphorylation level of SHP2 at Y542 decreased after LTD induction either in hippocampal cultures or acute CA1 mini slices. This change occurred at least 10 min after LTD induction and was alleviated by administration of NMDA receptor antagonist, APV. Furthermore, the SHP2 mutant (D61G), found in Noonan syndrome patients, prevented the removal of surface AMPA receptors during chemical-induced LTD on cultured hippocampal neurons. The results revealed a molecular basis of regulatory role of SHP2 in long term depression, thus expands our understanding of the SHP2 function in learning and memory.

ObjectiveIrritable bowel syndrome (IBS) is a common functional bowel disorder characterized with visceral hypersensitivity. Previous studies indicated gut microbiota alteration associated short-chain fatty acids (SCFAs) dysregulation is associated with IBS development. The aim of the study is to explore the potential role of microbiota dysbiosis mediated visceral hypersensitivity in postinfectious-IBS (PI-IBS) mouse model.MethodsFour-week-old NIH mice were randomly allocated into four groups: control mice, PI-IBS mice, PI-IBS mice co-housing with normal mice, and PI-IBS mice were administrated with a cocktail of antibiotics. Trichinella spiralis infection established PI-IBS mouse model. Microbiota in cecal contents and feces were analyzed by 16S rDNA sequencing. SCFAs were detected by gas chromatography. 5-hydroxytryptamine (5-HT) was evaluated by ELISA, and N-methyl-D-aspartate receptors (NMDARs) were examined by western blot. Visceral sensitivity was determined by abdominal withdrawal reflex in response to colorectal distention.ResultsIncreased SCFAs were observed in cecal contents and feces in PI-IBS mice accompanied with higher 5-HT and NMDAR subunits expressions in ileum and colon. Visceral hypersensitivity was observed in PI-IBS mice compared to control mice. When administrated with antibiotics cocktails and co-housing with normal mice, PI-IBS mice showed decreased SCFAs, 5-HT, NMDAR subunits expressions, and improved visceral hypersensitivity.ConclusionGut microbiota alteration induced increased SCFAs, 5-HT and NMDAR subunits expressions were associated with visceral hypersensitivity in PI-IBS mice. The critical role of gut microbiota in improving visceral hypersensitivity was further identified by treatment of antibiotics cocktail and co-housing.

Ethnopharmacological relevance: The Jieduquyuziyin prescription (JP), a traditional Chinese medicine (TCM) formula, has been used as an approved hospital prescription to improve the efficacy of prednisone (Pred) in systemic lupus erythematosus (SLE) and lupus nephritis (LN) treatment. Although the synergistic effect of JP and Pred is prominent, the underlying mechanisms require further investigation. Aim of the study: To explore the key therapeutic targets of JP in improving the role of Pred in the treatment of LN. Materials and methods: Lupus-prone female MRL/lpr mice were administered JP, Pred, or JP combined with Pred. The effect of JP on LN was estimated by evaluating renal function and inflammation levels in the kidneys. On this basis, RNA sequencing of kidney tissues was performed, and the differentially expressed genes were analyzed and summarized. The role of JP in the expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2) in the kidneys was further confirmed by real-time PCR, immunohistochemistry, and western blotting. Results: JP combined with Pred exhibited the most remarkable therapeutic effect compared with JP or Pred alone. Transcriptome analysis indicated that Nrf2, a central mediator of the antioxidative response, was significantly upregulated by JP. Based on these results, we speculated that Nrf2 is a critical factor for JP, improving the efficacy of Pred in treating LN by notably suppressing the oxidative stress level in the kidneys. Furthermore, we found that Nrf2 expression decreased with the exacerbation of LN in MRL/lpr mice. In addition, the downregulated Nrf2 was notably restored after JP treatment, accompanied by suppressed oxidative stress levels in the kidneys. It includes inhibited accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), restored mitochondrial membrane potential (MMP) levels, and increased antioxidant enzyme activity of superoxide dismutase (SOD). Conclusions: Our findings show that JP increases Pred efficacy by increasing Nrf2 expression, implying that Nrf2 may be a promising therapeutic target for the treatment of LN.

INTRODUCTION: The prevalence and shedding of fecal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA indicate coronavirus disease 2019 (COVID-19) infection in the gastrointestinal (GI) tract and likely infectivity. We performed a systemic review and meta-analysis to evaluate the prevalence and the duration of shedding of fecal RNA in patients with COVID-19 infection. METHODS: PubMed, Embase, Web of Science, and Chinese databases Chinese National Knowledge Infrastructure and Wanfang Data up to June 2020 were searched for studies evaluating fecal SARS-CoV-2 RNA, including anal and rectal samples, in patients with confirmed COVID-19 infection. The pooled prevalence of fecal RNA in patients with detectable respiratory RNA was estimated. The days of shedding and days to loss of fecal and respiratory RNA from presentation were compared. RESULTS: Thirty-five studies (N = 1,636) met criteria. The pooled prevalence of fecal RNA in COVID-19 patients was 43% (95% confidence interval [CI] 34%–52%). Higher proportion of patients with GI symptoms (52.4% vs 25.9%, odds ratio = 2.4, 95% CI 1.2–4.7) compared with no GI symptoms, specifically diarrhea (51.6% vs 24.0%, odds ratio = 3.0, 95% CI 1.9–4.8), had detectable fecal RNA. After loss of respiratory RNA, 27% (95% CI 15%–44%) of the patients had persistent shedding of fecal RNA. Days of RNA shedding in the feces were longer than respiratory samples (21.8 vs 14.7 days, mean difference = 7.1 days, 95% CI 1.2–13.0). Furthermore, days to loss of fecal RNA lagged respiratory RNA by a mean of 4.8 days (95% CI 2.2–7.5). DISCUSSION: Fecal SARS-CoV-2 RNA is commonly detected in COVID-19 patients with a 3-fold increased risk with diarrhea. Shedding of fecal RNA lasted more than 3 weeks after presentation and a week after last detectable respiratory RNA.

Objective:To investigate the therapeutic efficacy and mechanisms of transcutaneous electrical acupoint stimulation (TEAS) in the treatment of postprandial distress syndrome (PDS) in functional dyspepsia (FD).Methods:A double-blinded, randomized, controlled study was conducted. At Sir Run Run Shaw Hospital, Medical School Zhejiang University 40 patients aged 18-70 years old who met the Rome Ⅳ diagnostic criteria of PDS were prospectively enrolled. After informed consent, the patients were randomly assigned to TEAS group or sham-TEAS group. The patients in the TEAS group received transcutaneous electrical acupoint stimulation at acupoints Zusanli and Neiguan, and those in the sham-TEAS group underwent stimulation at other mimic acupoints for four weeks. The symptoms, gastric accommodation (initial satiety volume (ISV) and maximum tolerable volume (MTV), time of half gastric emptying of solid food ( T1/2) and heart rate variability (high frequency, low frequency and ratio of low frequency to high frequency) were compared between the two groups before and after treatment. The expression levels of inflammatory cytokines in duodenal mucosa were also evaluated by polymerase chain reaction in PDS patients and 24 healthy volunteers. Independent sample t test, Mann-Whitney U test and chi square test were used for statistical analysis. Results:A total of 26 PDS patients were enrolled in the study, 13 cases each in the TEAS group and sham-TEAS group. Between the patients of the two groups, there were no statistically significant differences in gender, age, or score of 36-item short form health survey (SF-36), score of self-rating anxiety scale (SAS), score of self-rating depression scale (SDS), score of dyspeptic symptom severity index (DSSI), ISV, MTV, T1/2 or heart rate variability indexes (high frequency, low frequency and ratio of low frequency to high frequency) before treatment (all P>0.05). After treatment, the DSSI score of TEAS group was lower than that of sham-TEAS group (13.5±5.3 vs. 19.9±9.3), the values of ISV and MTV were both higher than those of sham-TEAS group ((180.0±44.6) mL vs. (121.9±61.0) mL, (480.4±200.7) mL vs. (338.5±108.8) mL), and the differences were all statistically significant ( t=2.18, 2.77 and 2.24, all P<0.05). After treatment there was no statistically significant difference in T1/2 between TEAS group and sham-TEAS group ( P>0.05). There was no statistically significant difference in T1/2 between before and after treatment in patients of TEAS group ( P>0.05). After treatment, the high frequency increased (5.3±1.2 vs. 4.0±0.9) and the ratio of low frequency to high frequency decreased (1.0±0.2 vs. 1.3±0.2), and the differences were statistically significant ( t=-3.31 and 3.73, both P<0.01). The expression levels of interleukin 6 (IL-6) mRNA in mucosa of duodenal bulb and descending duodenum of PDS patients were both higher than that of healthy control group (0.68, 0.11 to 6.74 vs. 0.03, 0.02 to 0.25; 6.46, 1.35 to 12.62 vs. 0.86, 0.32 to 2.90), and the differences were statistically significant ( Z=-2.24 and -2.03, P=0.02 and 0.04). After TEAS treatment for four weeks, the expression of IL-6 mRNA in duodenal bulb mucosa decreased compared with that before treatment in TEAS group (0.04, 0.01 to 0.06 vs. 0.23, 0.09 to 3.66) and the difference was statistically significant ( Z=-2.07, P=0.04). Conclusions:TEAS can improve the gastric accommodation and dyspeptic symptoms in PDS patients. The mechanism may be related with the vagal pathway mediating and regnlating the expression of inflammatory cytokine IL-6 in duodenal bulb mucosa.