Selection strategy of second-line biologic therapies in adult patients with ulcerative colitis following prior biologic treatment failure: Systematic review and meta-analysis.

BACKGROUND: Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential. OBJECTIVE: Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure. METHODS: A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates. RESULTS: Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6-14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52-54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE. CONCLUSION: For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

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.

Vitamin-Microbiota Crosstalk in Intestinal Inflammation and Carcinogenesis.

Inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) are common diseases of the digestive system. Vitamin deficiencies and gut microbiota dysbiosis have a close relationship with the risk, development, and progression of IBD and CAC. There is a strong link between vitamins and the gut microbiome. Vitamins are extremely crucial for maintaining a healthy gut microbiota, promoting growth and development, metabolism, and innate immunity. Gut microbiota can not only influence the transport process of vitamins, but also produce vitamins to compensate for insufficient food intake. Emerging evidence suggests that oral vitamin supplementation can reduce inflammation levels and improve disease prognosis. In addition, improving the diet structure and consuming foods rich in vitamins not only help to improve the vitamin deficiency, but also help to reduce the risk of IBD. Fecal microbiota transplantation (FMT) and the application of vitamin-producing probiotics can better assist in the treatment of intestinal diseases. In this review, we discuss the interaction and therapeutic roles of vitamins and gut microbiota in IBD and CAC. We also summarize the methods of treating IBD and CAC by modulating vitamins. This may highlight strategies to target gut-microbiota-dependent alterations in vitamin metabolism in the context of IBD and CAC therapy.

Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation?

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. It involves the complex interactions between genetic factors, environmental exposure, and gut microbiota. Specific changes in the gut microbiome and metabolome have been described in CRC, supporting the critical role of gut microbiota dysbiosis and microbiota-related metabolites in the tumorigenesis process. Short-chain fatty acids (SCFAs), the principal metabolites generated from the gut microbial fermentation of insoluble dietary fiber, can directly activate G-protein-coupled receptors (GPCRs), inhibit histone deacetylases (HDACs), and serve as energy substrates to connect dietary patterns and gut microbiota, thereby improving the intestinal health. A significantly lower abundance of SCFAs and SCFA-producing bacteria has been demonstrated in CRC, and the supplementation of SCFA-producing probiotics can inhibit intestinal tumor development. SCFAs-guided modulation in both mouse and human CRC models augmented their responses to chemotherapy and immunotherapy. This review briefly summarizes the complex crosstalk between SCFAs and CRC, which might inspire new approaches for the diagnosis, treatment and prevention of CRC on the basis of gut microbiota-derived metabolites SCFAs.

Prediction modeling of geogenic iodine contaminated groundwater throughout China.

Geogenic iodine-contaminated groundwater represents a threat to public health in China. Identifying high-iodine areas is essential to guide the mitigation of this problem. Considering that traditional analytical techniques for iodine testing are generally time-consuming, laborious, and expensive, alternative methods are needed to supplement and enhance existing approaches. Therefore, we developed an artificial neural network (ANN) model and assessed its feasibility in terms of predicting high iodine levels in groundwater in China. A total of 22 indicators (including climate, topography, geology, and soil properties) and 3185 aggregated samples (measured groundwater iodine concentrations) were utilized to develop the ANN model. The results showed that the accuracy and area under the receiver operating characteristic curve of the model on the test dataset are 90.9% and 0.972, respectively, and climate and soil variables are the most effective predictors. Based on the prediction results, a high-resolution (1-km) nationwide prediction map of high-iodine groundwater was produced. The high-risk areas are mainly concentrated in the central provinces of Henan, Shaanxi, and Shanxi, the eastern provinces of Henan, Shandong, and Hebei, and the northeastern provinces of Liaoning, Jilin, and Heilongjiang. The total number of people estimated to potentially be at high-risk areas because they use untreated high-iodine groundwater as drinking water is approximately 30 million. Considering the growing demand for groundwater in China, this work can guide the prioritization of groundwater contamination mitigation efforts based on regional groundwater quality levels to enhance environmental management.

Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study.

BACKGROUND: Chemoprevention of colorectal adenoma and colorectal cancer remains an important public health goal. The present study aimed to investigate the clinical potential and safety of berberine for prevention of colorectal adenoma recurrence. METHODS: This double-blind, randomised, placebo-controlled trial was done in seven hospital centres across six provinces in China. Individuals aged 18-75 years who had at least one but no more than six histologically confirmed colorectal adenomas that had undergone complete polypectomy within the 6 months before recruitment were recruited and randomly assigned (1:1) to receive berberine (0·3 g twice daily) or placebo tablets via block randomisation (block size of six). Participants were to undergo a first follow-up colonoscopy 1 year after enrolment, and if no colorectal adenomas were detected, a second follow-up colonoscopy at 2 years was planned. The study continued until the last enrolled participant reached the 2-year follow-up point. All participants, investigators, endoscopists, and pathologists were blinded to treatment assignment. The primary efficacy endpoint was the recurrence of adenomas at any follow-up colonoscopy. Analysis was based on modified intention-to-treat, with the full analysis set including all randomised participants who received at least one dose of study medication and who had available efficacy data. The study is registered with ClinicalTrials.gov, number NCT02226185; the trial has ended and this report represents the final analysis. FINDINGS: Between Nov 14, 2014, and Dec 30, 2016, 553 participants were randomly assigned to the berberine group and 555 to the placebo group. The full analysis set consisted of 429 participants in the berberine group and 462 in the placebo group. 155 (36%) participants in the berberine group and 216 (47%) in the placebo group were found to have recurrent adenoma during follow-up (unadjusted relative risk ratio for recurrence 0·77, 95% CI 0·66-0·91; p=0·001). No colorectal cancers were detected during follow-up. The most common adverse event was constipation (six [1%] of 446 patients in the berberine group vs one [<0·5%] of 478 in the placebo group). No serious adverse events were reported. INTERPRETATION: Berberine 0·3 g twice daily was safe and effective in reducing the risk of recurrence of colorectal adenoma and could be an option for chemoprevention after polypectomy. FUNDING: National Natural Science Foundation of China.

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing.

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.

Stress Triggers Flare of Inflammatory Bowel Disease in Children and Adults.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease characterized by chronic and relapsing manifestations. It is noteworthy that the prevalence of IBD is gradually increasing in both children and adults. Currently, the pathogenesis of IBD remains to be completely elucidated. IBD is believed to occur through interactions among genetics, environmental factors, and the gut microbiota. However, the relapsing and remitting course of IBD underlines the importance of other modifiers, such as psychological stress. Growing evidence from clinical and experimental studies suggests that stress acts as a promoting or relapsing factor for IBD. Importantly, recent studies have reported an increasing incidence of anxiety or depression in both children and adults with IBD. In this article, we review the mechanisms by which stress affects IBD, such as via impaired intestinal barrier function, disturbance of the gut microbiota, intestinal dysmotility, and immune and neuroendocrine dysfunction. With regard to both children and adults, we provide recent evidence to describe how stress can affect IBD at various stages. Furthermore, we emphasize the importance of mental healing and discuss the value of approaches targeting stress in clinical management to develop enhanced strategies for the prevention and treatment of IBD.

Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis.

The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)-induced intestinal adenoma-adenocarcinoma sequence. Apc min/+ mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA-treated Apc min/+ mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α-dehydroxylation reaction. The intestinal adenoma-adenocarcinoma sequence was observed in CA-treated Apc min/+ mice and was accompanied by an impaired intestinal barrier function and IL-6/STAT3-related low-grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA-induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.

Diammonium Glycyrrhizinate Protects against Nonalcoholic Fatty Liver Disease in Mice through Modulation of Gut Microbiota and Restoration of Intestinal Barrier.

Nonalcoholic fatty liver disease (NAFLD), as a common chronic liver disorder, is prevalent in the world. Recent evidence demonstrates that the "gut-liver axis" is related well to the progression of NAFLD, which regards gut microbiota and the intestinal barrier as two critical factors correlated with NAFLD. Diammonium glycyrrhizinate (DG), a compound of the natural bioactive pentacyclic triterpenoid glycoside, is the main component of licorice root extracts. The anti-inflammatory and liver protection effects of DG have already been reported, but to date, the mechanism has not been fully elucidated. In this research, we observed that DG reduced body weight, liver steatosis, as well as hepatic inflammation in NAFLD model mice induced by a high-fat diet. Illumina sequencing of the 16S rRNA revealed that DG intervention notably altered the composition of the gut microbiota in NAFLD mice. The richness of gut microbiota was significantly increased by DG. Specifically, DG reduced the Firmicutes-to- Bacteroidetes ratio and the endotoxin-producing bacteria such as Desulfovibrio and elevated the abundance of probiotics such as Proteobacteria and Lactobacillus. DG could augment the levels of short-chain fatty acid (SCFA)-producing bacteria such as Ruminococcaceae and Lachnospiraceae and promote SCFA production. In addition, DG supplementation dramatically alleviated the intestinal low-grade inflammation. Meanwhile, DG improved the expression of tight junction proteins, the goblet cell number, and mucin secretion and sequentially enhanced the function of intestinal barrier. Collectively, the prevention of NAFLD by DG might be mediated by modulating gut microbiota and restoring the intestinal barrier.

Berberine Inhibits Intestinal Polyps Growth in Apc (min/+) Mice via Regulation of Macrophage Polarization.

Antitumor effect of berberine has been reported in a wide spectrum of cancer, however, the mechanisms of which are not fully understood. The aim of this study was to investigate the hypothesis that berberine suppresses tumorigenesis in the familial adenomatous polyposis (FAP) by regulating the macrophage polarization in Apc (min/+) mouse model. Berberine was given to Apc (min/+) mice for 12 weeks. Primary macrophages were isolated; after berberine treatment, the change in signaling cascade was determined. The total number and size of polyps were reduced remarkably in berberine group, compared with control group. A significant decrease in protein levels of F4/80, mannose receptor (MR), and COX-2 in stroma of intestinal polyps and an increase in the level of iNOS were observed after berberine treatment. The mRNA level of MR and Arg-1 in berberine group was significantly lower than those in IL-10 or IL-4 group, while no significant difference in mRNA levels of iNOS and CXCL10 was observed. The migration and invasiveness assays in vitro showed that berberine could reduce the capability of migration and invasiveness. These findings suggest that berberine attenuates intestinal tumorigenesis by inhibiting the migration and invasion of colorectal tumor cells via regulation of macrophage polarization.

Fecal microbiota transplantation broadening its application beyond intestinal disorders.

Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson's disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.

Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling.

As a traditional anti-inflammatory Chinese herbal medicine, Alkaloid berberine has been recently reported to exhibit anti-tumour effects against a wide spectrum of cancer. However, the mechanism was largely unknown. Gene chip array reveals that with berberine treatment, c-Myc, the target gene of Wnt pathway, was down-regulated 5.3-folds, indicating that berberine might inhibit Wnt signalling. TOPflash analysis revealed that Wnt activity was significantly reduced after berberine treatment, and the mechanism of which might be that berberine disrupted ß-catenin transfer to nucleus through up-regulating the expression of adenomatous polyposis coli (APC) gene and stabilized APC-ß-catenin complex. Berberine administration in ApcMin/+ mice exhibited fewer and smaller polyps in intestine, along with reduction in cyclin D1 and c-Myc expression. In clinical practice, oral administration of berberine also significantly reduced the familial adenomatous polyposis patients' polyp size along with the inhibition of cyclin D1 expression in polyp samples. These observations indicate that berberine inhibits colon tumour formation through inhibition of Wnt/ß-catenin signalling and berberine might be a promising drug for the prevention of colon cancer.

Berberine promotes recovery of colitis and inhibits inflammatory responses in colonic macrophages and epithelial cells in DSS-treated mice.

Inflammatory bowel disease (IBD) results from dysregulation of intestinal mucosal immune responses to microflora in genetically susceptible hosts. A major challenge for IBD research is to develop new strategies for treating this disease. Berberine, an alkaloid derived from plants, is an alternative medicine for treating bacterial diarrhea and intestinal parasite infections. Recent studies suggest that berberine exerts several other beneficial effects, including inducing anti-inflammatory responses. This study determined the effect of berberine on treating dextran sulfate sodium (DSS)-induced intestinal injury and colitis in mice. Berberine was administered through gavage to mice with established DSS-induced intestinal injury and colitis. Clinical parameters, intestinal integrity, proinflammatory cytokine production, and signaling pathways in colonic macrophages and epithelial cells were determined. Berberine ameliorated DSS-induced body weight loss, myeloperoxidase activity, shortening of the colon, injury, and inflammation scores. DSS-upregulated proinflammatory cytokine levels in the colon, including TNF, IFN-γ, KC, and IL-17 were reduced by berberine. Berberine decreased DSS-induced disruption of barrier function and apoptosis in the colon epithelium. Furthermore, berberine inhibited proinflammatory cytokine production in colonic macrophages and epithelial cells in DSS-treated mice and promoted apoptosis of colonic macrophages. Activation of signaling pathways involved in stimulation of proinflammatory cytokine production, including MAPK and NF-κB, in colonic macrophages and epithelial cells from DSS-treated mice was decreased by berberine. In summary, berberine promotes recovery of DSS-induced colitis and exerts inhibitory effects on proinflammatory responses in colonic macrophages and epithelial cells. Thus berberine may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders.