Gut microbiota and metabolites as predictors of biologics response in inflammatory bowel disease: A comprehensive systematic review.

Nonresponse to biologic agents in patients with inflammatory bowel disease (IBD) poses a significant public health burden, and the prediction of response to biologics offers valuable insights for IBD management. Given the pivotal role of gut microbiota and their endogenous metabolites in IBD, we conducted a systematic review to investigate the potential of fecal microbiota and mucosal microbiota and endogenous metabolomic markers as predictors for biotherapy response in IBD patients. A total of 38 studies were included in the review. Following anti-TNF-α treatment, the bacterial community characteristics of IBD patients exhibited a tendency to resemble those observed in healthy controls, indicating an improved clinical response. The levels of endogenous metabolites butyrate and deoxycholic acid were significantly associated with clinical remission following anti-TNF-α therapy. IBD patients who responded well to vedolizumab treatment had higher levels of specific bacteria that produce butyrate, along with increased levels of metabolites such as butyrate, branched-chain amino acids and acetamide following vedolizumab treatment. Crohn's disease patients who responded positively to ustekinumab treatment showed higher levels of Faecalibacterium and lower levels of Escherichia/Shigella. In conclusion, fecal microbiota and mucosal microbiota as well as their endogenous metabolites could provide a predictive tool for assessing the response of IBD patients to various biological agents and serve as a valuable reference for precise drug selection in clinical IBD patients.

Efficacy and safety of the Chinese herbal medicine Xiao Yao San for treating anxiety: a systematic review with meta-analysis and trial sequential analysis.

Introduction: The effectiveness and safety of the Chinese herbal medicine (CHM) Xiao Yao San (XYS) used for treating anxiety disorders are still unknown. Thus, we conducted this systematic review with meta-analysis and trial sequential analysis (TSA) to determine its safety and efficacy. Methods: We searched 12 databases for relevant studies from the inception of each database till 10 August 2023. We selected randomized controlled trials to compare the efficacy and safety of XYS (including XYS only and XYS + anxiolytics) to those of anxiolytics in patients with anxiety. Results: We found 14 trials with 1,256 patients in total that met the requirements for inclusion. We assessed the majority of studies (8 out of 14) as being at high risk of bias; 6 were assessed as having a moderate risk of bias. Three trials compared oral XYS to anxiolytic medication, and 11 trials compared oral XYS plus anxiolytics to anxiolytic treatment alone. The pooled results showed that the efficacy of treatment in the XYS + anxiolytics groups was significantly higher than that of the anxiolytics alone group (RR = 1.19; 95% CI: [1.13, 1.26]; p < 0.00001; I2 = 0) and the adverse event rates in the XYS + anxiolytics groups were significantly lower than those in the anxiolytics alone group (RR = 0.44; 95% CI: [0.28, 0.82]; p = 0.001 < 0.05; I2 = 13). The efficacy of treatment in the XYS alone groups was also significantly higher than that of the anxiolytics alone groups (RR = 5.41; 95% CI: [2.23, 13.11]; p < 0.0001; I2 = 0). However, there was no statistical difference between the adverse events of the XYS alone group and the anxiolytics alone group, although the incidence of adverse events in the XYS alone group was lower than that in the anxiolytics alone group. The results of the TSA confirmed the above findings. Conclusion: The use of XYS combined with anxiolytics for treating anxiety was found to be safe and effective. However, although XYS alone is effective in the treatment of anxiety disorder, more large-scale research is needed to investigate adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=350358, identifier CRD42022350358.

Targeting Desulfovibrio vulgaris flagellin-induced NAIP/NLRC4 inflammasome activation in macrophages attenuates ulcerative colitis.

INTRODUCTION: The perturbations of gut microbiota could interact with excessively activated immune responses and play key roles in the etiopathogenesis of ulcerative colitis (UC). Desulfovibrio, the most predominant sulfate reducing bacteria (SRB) resided in the human gut, was observed to overgrow in patients with UC. The interactions between specific gut microbiota and drugs and their impacts on UC treatment have not been demonstrated well. OBJECTIVES: This study aimed to elucidate whether Desulfovibrio vulgaris (D. vulgaris, DSV) and its flagellin could activate nucleotide-binding oligomerization domain-like receptors (NLR) family of apoptosis inhibitory proteins (NAIP) / NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4) inflammasome and promote colitis, and further evaluate the efficacy of eugeniin targeting the interaction interface of D. vulgaris flagellin (DVF) and NAIP to attenuate UC. METHODS: The abundance of DSV and the occurrence of macrophage pyroptosis in human UC tissues were investigated. Colitis in mice was established by dextran sulfate sodium (DSS) and gavaged with DSV or its purified flagellin. NAIP/NLRC4 inflammasome activation and macrophage pyroptosis were evaluated in vivo and in vitro. The effects of eugeniin on blocking the interaction of DVF and NAIP/NLRC4 and relieving colitis were also assessed. RESULTS: The abundance of DSV increased in the feces of patients with UC and was found to be associated with disease activity. DSV and its flagellin facilitated DSS-induced colitis in mice. Mechanistically, RNA sequencing showed that gene expression associated with inflammasome complex and pyroptosis was upregulated after DVF treatment in macrophages. DVF was further demonstrated to induce significant macrophage pyroptosis in vitro, depending on NAIP/NLRC4 inflammasome activation. Furthermore, eugeniin was screened as an inhibitor of the interface between DVF and NAIP and successfully alleviated the proinflammatory effect of DVF in colitis. CONCLUSION: Targeting DVF-induced NAIP/NLRC4 inflammasome activation and macrophage pyroptosis ameliorates UC. This finding is of great significance for exploring the gut microbiota-host interactions in UC development and providing new insights for precise treatment.

Clostridium butyricum inhibits epithelial-mesenchymal transition of intestinal carcinogenesis through downregulating METTL3.

Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrate-producing bacteria reduction. Our previous study suggested that administration of Clostridium butyricum, a butyrate-producing bacterium, exerts a crucial effect against CRC, however the potential mechanism is not clear. We first found that methyltransferase-like 3 (METTL3) showed a positive correlation with proliferation, epithelial-mesenchymal transition (EMT), DNA repair, metastasis, and invasion in a database analysis. The expression of METTL3 gradually increased from human normal colon tissue, to adenoma, and carcinoma, and was positively correlated with E-cadherin and CD34 levels. Overexpression of METTL3 promoted the proliferation, migration, and invasion of CRC cells and induced vasculogenic mimicry (VM) formation. Clostridium butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Clostridium butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. The anti-EMT effect on METTL3 reduction of C. butyricum could be blunted by knocking down G-protein coupled receptor 43. Moreover, C. butyricum prevented EMT and VM and inhibited tumor metastasis in nude mice. Accordingly, C. butyricum could inhibit EMT and VM formation of intestinal carcinogenesis through downregulating METTL3. These findings broaden our understanding of probiotics supplement in CRC prevention and treatment.

Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: a novel therapeutic strategy?

Tumor immune microenvironment (TIME), a tumor-derived immune component, is proven to be closely related to the development, metastasis, and recurrence of tumors. Gut microbiota and its fermented-metabolites short-chain fatty acids (SCFAs) play a critical role in maintaining the immune homeostasis of gastrointestinal tumors. Consisting mainly of acetate, propionate, and butyrate, SCFAs can interact with G protein-coupled receptors 43 of T helper 1 cell or restrain histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. Studies have shed light on SCFAs can mediate the differentiation and function of regulatory T cells, as well as cytokine production in TIME. Additionally, SCFAs can alter epigenetic modification of CD8+ T cells by inhibiting HDACs to participate in the immune response process. In gastrointestinal tumors, the abundance of SCFAs and their producing bacteria is significantly reduced. Direct supplementation of dietary fiber and probiotics, or fecal microbiota transplantation to change the structure of gut microbiota can both increase the level of SCFAs and inhibit tumor development. The mechanism by which SCFAs modulate the progression of gastrointestinal tumors has been elucidated in this review, aiming to provide prospects for the development of novel immunotherapeutic strategies.

"Jing-Ning Granules" Can Alleviate Attention Deficit Hyperactivity Disorder in Rats by Modulating Dopaminergic D2/D1-Like Receptor-Mediated Signaling Pathways.

Background: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attention deficit, hyperactivity, and impulsivity. Jing-Ning Granules (JNG) is a traditional Chinese medicine (TCM) that can alleviate ADHD. Although JNG is commonly used for the effective treatment of ADHD and has obtained the national invention patent, the exact mechanism of action remains unclear. Objective: In this study, we examined the effect and mechanism of JNG in spontaneously hypertensive rats (SHRs). We hypothesized that JNG affects dopaminergic D2/D1-like receptors and related pathways. Materials and Methods: Six rat groups were used in the experiment: Wistar-Kyoto rats (WKY, control group) and five SHR groups, including a model group; atomoxetine (ATX, positive control) group; and low, medium, and high-dose JNG groups. The corresponding treatments were daily administered to each group for 6 weeks. A behavioral test, including a step-down test and open field test (OFT), was carried out at the end of treatment. After the behavioral test, all animals were sacrificed, and the brain tissue was collected and analyzed ex vivo; histopathological analysis was performed to assess the pathological changes of the hippocampus; expression of D1-like and D2-like receptors, sensor protein calmodulin (CaM), protein kinase A (PKA), and calcium/calmodulin-dependent serine/threonine protein kinase (CaMKII) in the striatum and hippocampus was measured by western blot and real-time quantitative PCR (RT-PCR); cyclic adenosine monophosphate (cAMP) levels in the striatum were analyzed using an enzyme-linked immunosorbent assay (ELISA), while the level of Ca2+ in the striatum was analyzed by a calcium kit. Results: Our results showed that ATX or JNG could ameliorate the hyperactive/impulsive behavior and cognitive function of ADHD by promoting neuroprotection. Mechanistically, ATX or JNG could prompt the expressions of Dl-like and D2-like receptors and improve the mRNA and protein levels of cAMP/PKA and Ca2+/CAM/CAMKII signaling pathways. Conclusion: These results indicate that JNG can produce therapeutic effects by regulating the balance of D2/D1-like receptor-mediated cAMP/PKA and Ca2+/CaM/CaMKII signaling pathways.

Dietary Patterns and Gut Microbiota Changes in Inflammatory Bowel Disease: Current Insights and Future Challenges.

Inflammatory bowel disease (IBD) is a result of a complex interplay between genes, host immune response, gut microbiota, and environmental factors. As one of the crucial environmental factors, diet plays a pivotal role in the modulation of gut microbiota community and the development of IBD. In this review, we present an overview of dietary patterns involved in the pathogenesis and management of IBD, and analyze the associated gut microbial alterations. A Westernized diet rich in protein, fats and refined carbohydrates tends to cause dysbiosis and promote IBD progression. Some dietary patterns have been found effective in obtaining IBD clinical remission, including Crohn's Disease Exclusion Diet (CDED), Mediterranean diet (MD), Anti-Inflammatory Diet (AID), the low-"Fermentable Oligo-, Di-, Mono-saccharides and Polyols" (FODMAP) diet, Specific Carbohydrate Diet (SCD), and plant-based diet, etc. Overall, many researchers have reported the role of diet in regulating gut microbiota and the IBD disease course. However, more prospective studies are required to achieve consistent and solid conclusions in the future. This review provides some recommendations for studies exploring novel and potential dietary strategies that prevent IBD.

Carnitine palmitoyltransferase 1 (CPT1) alleviates oxidative stress and apoptosis of hippocampal neuron in response to beta-Amyloid peptide fragment Aß25-35.

CPT1C, which is expressed in hippocampus, influences ceramide level, endogenous cannabinoid and oxidation process, as well as plays an important role in various brain functions such as learning. This study aimed to investigate the role of CPT1C in Alzheimer's disease (AD) and its underlying mechanism. We established a model of Alzheimer's disease in vitro by exposing primary hippocampal neurons to beta-Amyloid peptide fragment 25-35 (Aß25-35). The cell viability, lactate dehydrogenase (LDH) level, expressions of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected using Cell Counting Kit-8 (CCK-8), LDH assay, ROS kits, malondialdehyde (MDA) kits and SOD kits, respectively. Moreover, the expression of oxidative stress-related proteins as well as the expressions of amyloid precursor protein (App), p-Tau andß-site APP-cleaving enzyme1 (Bace-1) were measured using quantitative reverse transcription PCR (RT-qPCR) and western blot. Tunel and western blot were adopted to detect apoptosis as well as its related proteins. After the treatment of peroxisome proliferators-activated receptor alpha (PPARα), CPT1C expression was detected with the application of RT-qPCR and western blot. CPT1C expression was reduced in Aß25-35-induced HT22 cells. Overexpression of CPT1C relieved cell viability and toxic injury as well as attenuated oxidative stress, apoptosis and expression levels of AD marker proteins. Moreover, higher doses of PPARα agonist activate the expression of CPT1C in Aß25-35-induced HT22 cells. In conclusion, CPT1C alleviates Aß25-35-induced oxidative stress, apoptosis and deposition of AD marker proteins in hippocampal neurons, suggesting that CPT1C has favorable effects on alleviating AD and participates in PPARα activation.