Dynamic alterations in metabolomics and transcriptomics associated with intestinal fibrosis in a 2,4,6-trinitrobenzene sulfonic acid-induced murine model.

BACKGROUND & AIMS: Intestinal fibrosis is a common and severe complication of inflammatory bowel disease without clear pathogenesis. Abnormal expression of host genes and metabolic perturbations might associate with the onset of intestinal fibrosis. In this study, we aimed to investigate the relationship between the development of intestinal fibrosis and the dynamic alterations in both fecal metabolites and host gene expression. METHODS: We induced intestinal fibrosis in a murine model using 2,4,6-trinitrobenzene sulfonic acid (TNBS). TNBS-treated or control mice were sacrificed after 4 and 6 weeks of intervention; alterations in colonic genes and fecal metabolites were determined by transcriptomics and metabolomics, respectively. Differential, tendency, enrichment, and correlation analyses were performed to assess the relationship between host genes and fecal metabolites. RESULTS: RNA-sequencing analysis revealed that 679 differential genes with enduring changes were mainly enriched in immune response-related signaling pathways and metabolism-related biological processes. Among them, 15 lipid metabolism-related genes were closely related to the development of intestinal fibrosis. Moreover, the fecal metabolic profile was significantly altered during intestinal fibrosis development, especially the lipid metabolites. Particularly, dynamic perturbations in lipids were strongly associated with alterations in lipid metabolism-related genes expression. Additionally, six dynamically altered metabolites might serve as biomarkers to identify colitis-related intestinal fibrosis in the murine model. CONCLUSIONS: Intestinal fibrosis in colitis mice might be related to dynamic changes in gene expression and metabolites. These findings could provide new insights into the pathogenesis of intestinal fibrosis.

Alterations in short-chain fatty acids and serotonin in irritable bowel syndrome: a systematic review and meta-analysis.

BACKGROUND: Short-chain fatty acids (SCFAs) and serotonin (5-hydroxytryptamine, 5-HT) may be associated with the pathogenesis of irritable bowel syndrome (IBS). There are some reports of alterations in SCFAs and 5-HT in IBS, but their results are inconsistent. We aimed to perform a meta-analysis to assess alterations in SCFAs and 5-HT in IBS patients and their potential role in the abnormal brain-gut-microbiota (BGM) axis. METHODS: Case-control studies detecting SCFAs and 5-HT in IBS patients were identified from PubMed, Web of Science, Cochrane Library, and Scopus databases to identify relevant articles up to September 2018. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) of SCFAs and 5-HT were calculated by REVIEW MANAGER 5.3 to evaluate the alterations of 5-HT and SCFAs in IBS. RESULTS: Five studies on SCFAs and 5 on 5-HT in IBS patients were included. As compared to healthy controls (HCs), the SMDs of 5-HT in IBS patients was 2.35 (95% CI 0.46-4.24) and the SMDs of total SCFAs, acetic acid, propionic acid, and butyric acid in IBS patients were - 0.01 (95% CI - 0.57-0.55), - 0.04 (95% CI - 0.55-0.47), 0.07 (95% CI - 0.45-0.60), and - 0.00 (95% CI - 0.49-0.49), respectively. CONCLUSIONS: There was an increase in 5-HT in blood of IBS patients, indicating the increased 5-HT in blood may be involved in IBS pathogenesis. However, there were no significant differences in SCFAs in feces between IBS patients and HCs. But the study did not differentiate between subgroups of IBS. These findings might provide insight for future studies of the BGM axis in the pathogenesis of IBS. Mei Luo and Xiaojun Zhuang contributed equally to the writing of this article.

DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. METHODS: DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. RESULTS: DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn's disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. CONCLUSIONS: During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.

Short-course Rifaximin therapy efficacy and lactulose hydrogen breath test in Chinese patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Gut microbiota alterations including small intestinal bacterial overgrowth (SIBO) might play a role in pathogenesis of irritable bowel syndrome (IBS). Rifaximin could effectively and safely improve IBS symptoms. The aim of this study was to investigate the effect of rifaximin on Gastrointestinal (GI) symptoms, quality of life (QOL) and SIBO eradication in Chinese IBS-D patients. METHODS: This study included 78 IBS-D patients defined by the Rome IV criteria. Patients received 400 mg rifaximin twice daily for 2 weeks and 10-week follow-up. GI symptoms were assessed at week 0, 2, 4, 8 and 12. QOL and lactulose hydrogen breath test (LHBT) results were estimated at week 0 and 4. RESULTS: All participants showed significant improvements in GI symptom subdomains after rifaximin treatment (all P < 0.05), which could maintain at least 10 weeks of follow-up. Additionally, QOL scores were increased with concomitant improvement of clinical symptoms (all P < 0.05). The 45 rifaximin-responsive patients (57.7%) achieved significantly greater GI-symptom improvement than non-responders (all P < 0.05). No GI symptoms were associated with SIBO (all P > 0.05). SIBO normalization after rifaximin treatment measured by LHBT was found in 44.4% (20/45) of patients with SIBO before treatment. CONCLUSION: A short course (2 weeks) of rifaximin improved GI symptoms and QOL in Chinese IBS-D patients whether they had SIBO or not. However, the efficacy of rifaximin could not be explained by the successful eradication of SIBO. Further studies on the therapeutic mechanisms of rifaximin in IBS are urgently needed.

The propionic acid and butyric acid in serum but not in feces are increased in patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Short-chain fatty acids (SCFAs) alteration have been reported in irritable bowel syndrome (IBS), but the results are conflicting. Our study aims to explore the alteration of SCFAs in patients with diarrhea-predominant IBS (IBS-D) and their potential role in the occurrence and development of IBS. METHODS: We recruited patients with IBS-D defined by Rome IV criteria and age-and-gender matched healthy controls (HCs). A headspace solid-phase microextraction gas chromatography-mass spectrometric (HS-SPME-GC-MS) method was developed for the analysis of acetic, propionic and butyric acid in feces and serum. RESULTS: Compared with HCs, the levels of the serum propionate (2.957 ± 0.157 vs 2.843 ± 0.098 mmol/L, P = 0.012) and butyrate (2.798 ± 0.126 vs 2.697 ± 0.077 mmol/L, P = 0.012) were significantly higher in IBS-D group. No significant differences were found among two groups with regard to the concentration of fecal acetate (4.953 ± 1.065 vs 4.774 ± 1.465 mg/g, P = 0.679), propionate (6.342 ± 1.005 vs 6.282 ± 1.077 mg/g, P = 0.868) and butyrate (2.984 ± 0.512 vs 3.071 ± 0.447 mg/g, P = 0.607). CONCLUSIONS: Metabolites of gut microbiota, the propionic and butyric acid, are increased in patients with IBS-D in serum but not in feces. It suggests that propionic and butyric acid might be associated with the occurrence and development of IBS.

Development and Validation of Prognostic Nomograms Based on Lymph Node Ratio for Young Patients with Gastric Cancer: A SEER-Based Study.

PURPOSE: To investigate the role of lymph node ratio (LNR) in young patients with gastric cancer (GC) and develop nomograms to predict the survival of young GC patients. METHODS: This retrospective study enrolled stage I-III GC patients before the age of 40 between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models were used to determine the prognosticators and create the nomograms incorporating LNR to predict overall survival (OS) and cancer-specific survival (CSS). The discriminating superiority of the nomograms was examined using calibration curves, C-index, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and integrated discrimination improvement (IDI) by comparing with the TNM staging. The performance of the nomograms for risk stratification was analyzed by the Kaplan-Meier method. RESULTS: Based on the significant prognosticators identified in multivariate survival analysis, the nomograms were established and showed LNR as the third strongest predictor. The C-index of the nomograms for OS and CSS were higher than those of the TNM staging (OS: 0.773 vs 0.665; CSS: 0.769 vs 0.666). The ROC curves for the nomograms to predict survival exhibited superior sensitivity and specificity when compared with the TNM staging. The calibration plots, DCA curves, and IDI values of the nomograms also demonstrated adequate fit and ideal net benefit in prediction and clinical utility. The Kaplan-Meier analysis observed remarkable differences in patients divided into different risk subgroups (P < .001). CONCLUSIONS: These results found the clinical outperformance of the LNR-based nomograms for predicting survival in young stage I-III GC patients. Our nomograms may improve accuracy of survival risk prediction and facilitate individualized care of young stage I-III GC patients.

Gut Microbiome-Generated Phenylacetylglutamine from Dietary Protein is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Model Possibly via Platelet Activation.

OBJECTIVES: Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite. DESIGN: We collected faecal and serum samples from a CD cohort [n = 136] and healthy controls [n = 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [n = 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD. RESULTS: PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients. CONCLUSION: Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.

Food Additives Associated with Gut Microbiota Alterations in Inflammatory Bowel Disease: Friends or Enemies?

During the 21st century, the incidence and prevalence of inflammatory bowel disease (IBD) is rising globally. Despite the pathogenesis of IBD remaining largely unclear, the interactions between environmental exposure, host genetics and immune response contribute to the occurrence and development of this disease. Growing evidence implicates that food additives might be closely related to IBD, but the involved molecular mechanisms are still poorly understood. Food additives may be categorized as distinct types in accordance with their function and property, including artificial sweeteners, preservatives, food colorant, emulsifiers, stabilizers, thickeners and so on. Various kinds of food additives play a role in modifying the interaction between gut microbiota and intestinal inflammation. Therefore, this review comprehensively synthesizes the current evidence on the interplay between different food additives and gut microbiome alterations, and further elucidates the potential mechanisms of food additives-associated microbiota changes involved in IBD.

Systematic review with meta-analysis: environmental and dietary differences of inflammatory bowel disease in Eastern and Western populations.

BACKGROUND: While the incidence of inflammatory bowel disease (IBD) has stabilised in the West, it is still increasing in several newly industrialised countries. AIMS: To investigate whether the environmental and dietary risk factors for IBD differ between Eastern and Western populations METHODS: We systematically searched PubMed, Embase, and Web of Science for studies published from inception through June 30, 2020. Data were pooled using a random effects model. RESULTS: Overall, 255 studies were assessed. We identified 25 risk factors for IBD, seven of which were noted in both Eastern and Western populations: family history of Crohn's disease [CD] or ulcerative colitis [UC], former smoking (CD/UC), smoking (CD), appendicectomy (CD), tonsillectomy (CD), meat and meat products (CD), and vitamin D deficiency (UC). The remaining factors, including urban living, current smoking, antibiotics, oral contraceptives, caesarean section, isotretinoin, total energy, fat, cholesterol, fatty acids and their sub-classifications, eggs, and soft drinks, were associated with an increased risk of IBD in Western or Eastern populations only. We identified 21 protective factors for IBD, among which eight were common in the East and West: farm animals (CD/UC), Helicobacter pylori infection (CD/UC), multiple births (CD), physical activity (CD), history of breastfeeding (CD), pets (UC), current smoking (UC), and coffee intake (UC). Ten factors conferred protection against IBD in Western populations only, whereas eight factors conferred protection against IBD in Eastern populations only. CONCLUSIONS: Numerous environmental and dietary factors influenced the development of IBD in both Western and Eastern populations, whereas certain factors influenced IBD risk differently in these populations.

Anti-TNF-α agents for refractory intestinal Behçet's disease: case series and meta-analysis.

Background: Behçet's disease (BD) is a relapsing systemic immune disorder, and intestinal BD is a significant cause of mortality in patients with BD. Conventional therapeutic strategies for intestinal BD showed unsatisfactory outcomes, especially in those patients with refractory subtypes. In recent years, biologic agents have exhibited promising results in this field. While the sample sizes of existing studies were limited, the results were heterogeneous. Objectives: This study aimed to observe the efficacy of different biologics in clinical symptomatic improvement and intestinal mucosal healing. Design: This is a study including the report of case series and meta-analysis. Data sources and methods: This meta-analysis was conducted following the PRISMA guidelines. Free-text words and subject terms, including 'Behcet's Syndrome', 'Biologics', 'Tumor Necrosis Factor Antagonist', were used to systematically research the relevant studies in the electronic databases (PubMed, Web of Science, Embase, and Cochrane Library). All retrieved articles were from inception to July 2021, and the data from our institution were also included in this meta-analysis. A double arcsine transformation was performed to stabilize the variance of the original ratio. Heterogeneity was evaluated via Q-test and I 2 statistics. Random-effects or fixed-effects model was used to calculate the pooled parameters, and the results were presented as forest plots with 95% confidence intervals. Results: Twelve studies were included, but only antitumor necrosis factor alpha (anti-TNF-α) agents were prescribed as biologicals for refractory intestinal BD. The symptom improvement rates at our institution ranged from 57.1 to 81.8%, and the mucosal healing rates were from 20 to 60% in different therapeutic periods. A total of 514 patients were enrolled in the meta-analysis, and the synthesized ratios showed that 59.8% (n = 377) and 73.7% (n = 317) of patients who received maintenance therapy with anti-TNF-α agents could achieve clinical symptomatic improvement during short-term (10-14 weeks) and long-term (48-54 weeks) periods, respectively. Furthermore, 77.8% (n = 229) of patients with intestinal BD maintained therapeutic efficacy for a longer time (100 weeks). In addition, 60.9% (n = 120) of the patients achieved sustained intestinal mucosal healing during a long-term follow-up (24-52 weeks). Conclusion: Anti-TNF-α treatment is effective in treating refractory intestinal BD but more studies are required to evaluate the effects of new biologics for intestinal BD in the near future. Registration: This study has been registered on PROSPERO, the ID is CRD42022329211. Plain language summary: Anti-TNF-α agents are effective and safe in patients with intestinal Behçet's disease Behçet's disease (BD) is a disease affecting several organs including the gastrointestinal tract. Nowadays, the efficacy of existing therapy strategies is still unsatisfactory and some patients are suffering from repeated attacks of the disease. We noticed that a new kind of medicine, called antitumor necrosis factor alpha (anti-TNF-α) agents, was applied to these patients recently. The therapeutic efficacy is not convincing enough to evaluate since the number of patients receiving this new medicine was small in every individual study. Regarding this, we conducted a research to learn about the efficacy of this medicine at our own institution. Besides, we composed the results of other studies in an appropriate way. Then, we drew a conclusion on the exact efficacy of anti-TNF-α agents after the data analysis. We unveiled that the anti-TNF-α agents appeared both effective and safe in the management of intestinal BD patients when the classical therapy failed. More than half of the patients could achieve discomfort remission when they got the therapy of the new medicine at our institution. We also found that intestinal ulcers in most patients improved after they received the treatment. All in all, it offered another foothold for getting relief in these patients who were caught in this mire.

Dietary inflammatory potential mediated gut microbiota and metabolite alterations in Crohn's disease: A fire-new perspective.

BACKGROUND & AIMS: Pro-inflammatory diet interacting with gut microbiome might trigger for Crohn's disease (CD). We aimed to investigate the relationship between dietary inflammatory potential and microflora/metabolites change and their link with CD. METHODS: The dietary inflammatory potential was assessed using a dietary inflammatory index (DII) based on the Food Frequency Questionnaire from 150 new-onset CD patients and 285 healthy controls (HCs). We selected 41 CD patients and 89 HCs who had not received medication for metagenomic and targeted metabolomic sequencing to profile their gut microbial composition as well as fecal and serum metabolites. DII scores were classified into quartiles to investigate associations among different variables. RESULTS: DII scores of CD patients were significantly higher than HCs (0.56 ± 1.20 vs 0.23 ± 1.02, p = 0.017). With adjustment for confounders, a higher DII score was significantly associated with higher risk of CD (OR: 1.420; 95% CI: 1.049, 1.923, p = 0.023). DII score also was positively correlated with disease activity (p = 0.001). Morganella morganii and Veillonella parvula were increased while Coprococcus eutactus was decreased in the pro-inflammatory diets group, as well as in CD. DII-related bacteria were associated with disease activity and inflammatory markers in CD patients. Among the metabolic change, pro-inflammatory diet induced metabolites change were largely involved in amino acid metabolic pathways that were also observed in CD. CONCLUSIONS: Pro-inflammatory diet might be associated with increased risk and disease activity of CD. Diet with high DII potentially involves in CD by mediating alterations in gut microbiota and metabolites.

Alterations in Bile Acid Metabolism Associated With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder closely related to gut dysbiosis, which is associated with alterations in an important bacterial metabolite, bile acids (BAs). Although certain findings pertinent to BA changes in IBD vary among studies owing to the differences in sample type, quantitated BA species, study methodology, and patient characteristics, a specific trend concerning variations of BAs in IBD has been identified. In elaborating on this observation, it was noted that primary BAs and conjugated BAs are augmented in fecal samples but there is a reduction in secondary BAs in fecal samples. It is not entirely clear why patients with IBD manifest these changes and what role these changes play in the onset and development of IBD. Previous studies have shown that IBD-associated BA changes may be caused by alterations in BA absorption, synthesis, and bacterial modification. The complex relationship between bacteria and BAs may provide additional and deeper insight into host-gut microbiota interactions in the pathogenesis of IBD. The characteristic BA changes may generate profound effects in patients with IBD by shaping the gut microbiota community, affecting inflammatory processes, causing BA malabsorption associated with diarrhea, and even leading to intestinal dysplasia and cancer. Thus, therapeutic strategies correcting the alterations in the composition of BAs, including the elimination of excess BAs and the supplementation of deficient BAs, may prove promising in IBD.

Anti -TNFα agents in preventing the postoperative recurrence of Crohn's disease: Do they still play a role in the biological era?

BACKGROUND: Approximately half of patients with Crohn's disease (CD) may inevitably receive surgical intervention as the disease progress. However, about 75% of CD patients will experience postoperative recurrence (POR). Biologics are appealing alternatives for the prevention of POR; however, it is still unclear which biological agents are more efficient. This meta-analysis aimed to investigate the efficacy of biologics for POR prevention and to compare the superiority of different biologics. METHODS: We conducted a thorough search of online databases and screened for studies on the efficacy of biologics in preventing POR (clinical, endoscopic, or histological) that were published until January 2021. The results were presented as forest plots and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We included 26 studies with 2,136 participants. Overall, biologics were more efficient over non-biological treatments in preventing endoscopic, severe endoscopic, and clinical POR without increasing the frequency of adverse events. Among the various types of biologics, anti-TNFα agents were better than vedolizumab in preventing endoscopic POR. Moreover, infliximab had a similar curative effect to adalimumab in preventing endoscopic, severe endoscopic, and clinical recurrence. CONCLUSION: Biologics, especially anti-TNFα agents, still play a vital role in preventing POR in the biological era.

Gut Microbiota Profile in Pediatric Patients With Inflammatory Bowel Disease: A Systematic Review.

Background and Aim: Accumulating evidence have implicated gut microbiota alterations in pediatric and adult patients with inflammatory bowel disease (IBD); however, the results of different studies are often inconsistent and even contradictory. It is believed that early changes in new-onset and treatment-naïve pediatric patients are more informative. We performed a systematic review to investigate the gut microbiota profiles in pediatric IBD and identify specific microbiota biomarkers associated with this disorder. Methods: Electronic databases were searched from inception to 31 July 2020 for studies that observed gut microbiota alterations in pediatric patients with IBD. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 41 original studies investigating gut microbiota profiles in pediatric patients with IBD were included in this review. Several studies have reported a decrease in α-diversity and an overall difference in ß-diversity. Although no specific gut microbiota alterations were consistently reported, a gain in Enterococcus and a significant decrease in Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Roseburia, Ruminococcus, and Lachnospira were found in the majority of the included articles. Moreover, there is insufficient data to show specific microbiota bacteria associated with disease activity, location, and behavior in pediatric IBD. Conclusions: This systematic review identified evidence for differences in the abundance of some bacteria in pediatric patients with IBD when compared to patients without IBD; however, no clear overall conclusion could be drawn from the included studies due to inconsistent results and heterogeneous methodologies. Further studies with large samples that follow more rigorous and standardized methodologies are needed.

Index-Based Dietary Patterns and Inflammatory Bowel Disease: A Systematic Review of Observational Studies.

Diet is one of the most critical factors for inflammatory bowel disease (IBD). A whole dietary pattern should be considered when doing nutrient-based research to preserve the potential for synergism between nutrients. Dietary indices are important tools to evaluate diet quality, and we investigated the associations of it with IBD. Fourteen studies on the relation between index-based dietary patterns and IBD were included. 6 studies showed the relation between index-based dietary patterns and IBD risk, 7 studies explored the dietary indices and progression of IBD, and 1 study investigated the relationship between index and all-cause mortality in IBD patients. These results implied that a high score on the Mediterranean diet was negatively associated with risk and progression of IBD. However, a diet with high inflammatory potential could increase risk and aggravate disease activity in IBD. Dietary scores have the potential to evaluate the association between overall diet quality and risk and progression of IBD. Future randomized controlled trials are required to confirm the effect of the change in dietary score. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42020220926.

Gut Microbiota Profiles and Microbial-Based Therapies in Post-operative Crohn's Disease: A Systematic Review.

Background and Aims: Gut microbiota recolonization after intestinal resection had been reported to be associated with post-operative recurrence in Crohn's disease (CD). However, the results of different studies are inconsistent and even contradictory. In addition, knowledge on the efficacy of microbial-based therapies in preventing post-operative recurrence of CD is limited. Therefore, the aim of this review was to investigate gut microbiota profiles in patients with CD before and after surgery and evaluate microbial-based therapies in preventing post-operative recurrence. Methods: Electronic databases were searched from inception to 31 June 2020 using predefined terms. Studies that investigated gut microbiota pre- and post-intestinal resection, and microbial-based therapies in preventing post-operative recurrence, were eligible. Study quality was assessed using either the Newcastle-Ottawa scale or Jadad scoring system. Results: Twelve studies investigating gut microbiota of CD patients suffering from operation, and other 12 studies evaluating the efficacy of antibiotics and probiotics, were included in our review. The mucosa-associated microbiota in surgical biopsy of CD patients is significantly distinct from that in normal mucosa from healthy subjects. Gut microbiota recolonization following surgery might be associated with post-operative recurrence in CD patients. Furthermore, CD patients with post-operative recurrence presented a gain in pro-inflammatory pathogenic bacteria and a loss in short-chain fatty acid-producing bacteria before and after surgery. However, no consistent bacteria or metabolites were found to predict the post-operative recurrence of CD. Additionally, microbial-based therapies are deficient and present restricted widespread clinical utility due to several deficiencies. Conclusion: Recurrence-associated bacteria observed pre- and post- operation might be promising in preventing the post-operative recurrence of CD. Furthermore, potential microbe biomarkers for predicting subsequent disease recurrence should be validated with larger sample sizes using more rigorous and standardized methodologies.

Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn's Disease.

BACKGROUND: Gut microbiota dysbiosis is associated with the occurrence and development of Crohn disease (CD). Currently, infliximab (IFX) is used more and more to treat CD; however, gut microbiota alterations during IFX therapy are variable and sometimes even contradictory. We longitudinally identified microbial changes during IFX therapy associated with the clinical and endoscopic response to IFX treatment in CD. METHODS: Fecal-associated microbiota was analyzed using 16S sequencing in 49 patients with active CD who were prospectively recruited at baseline, week 6, and week 30, respectively. Moreover, a model trained on the gut microbiota alterations at week 6 was developed to investigate their potential to predict clinical and endoscopic responses to IFX therapy at weeks 14 and 30. RESULTS: Characteristics of fecal microbiota composition in patients with CD after IFX treatment displayed an increased diversity and richness, a significant gain in short-chain fatty acid -producing bacteria, and a loss of pathogenic bacteria. Furthermore, certain functional profiles of Kyoto Encyclopedia of Genes and Genomes pathways were predictably altered during the treatment period. Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30. CONCLUSIONS: We found that IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function. Specifically, increased Lachnospiraceae and Blautia at week 6 are associated with the clinical and endoscopic response to IFX, providing potentially predictive biomarkers for IFX treatment decision-making.

Fecal Microbiota Alterations Associated With Diarrhea-Predominant Irritable Bowel Syndrome.

Altered gut microbiota are assumed to be involved in the pathogenesis of irritable bowel syndrome (IBS). However, gut microbiota alterations reported in different studies are divergent and sometimes even contradictory. To better elucidate the relationship between altered gut microbiota and IBS, we characterized fecal microbiota of diarrhea-predominant IBS (IBS-D) patients and further explored the effect of rifaximin on gut microbiota using bacterial 16S rRNA gene-targeted pyrosequencing. In our study, IBS-D patients defined by Rome III criteria and age-and-gender matched healthy controls (HC) were enrolled to investigate the fecal microbiota alterations. These IBS-D patients were then treated with rifaximin for 2 weeks and followed up for 10 weeks. Fecal microbiota alterations, small intestine bacterial overgrowth (SIBO) and gastrointestinal (GI) symptoms of IBS-D patients were analyzed before and after treatment. Our results showed fecal microbiota richness but not diversity was decreased in IBS-D patients as compared to HC and there were alterations of fecal microbiota at different taxonomy levels. The abundant phyla Firmicutes was significantly decreased and Bacteroidetes was increased in IBS-D patients. Moreover, the alterations of predominant fermenting bacteria such as Bacteroidales and Clostridiales might be involved in the pathophysiology of IBS-D. In addition, rifaximin was effective in terms of SIBO eradication and even GI symptoms of IBS-D patients achieved at least 10-week improvement after treatment. Furthermore, rifaximin induced alterations of some special bacteria rather than affected the overall composition of microbiota in IBS-D patients. Meanwhile, a potential decrease in propanoate and butanoate metabolism was found in these IBS-D patients after rifaximin treatment. Taken together, there were alterations of gut microbiota in IBS-D patients as compared to HC. Rifaximin could relieve GI symptoms, modify gut microbiota in IBS-D patients and eradicate SIBO in those patients with SIBO, suggesting an additional therapeutic mechanism of rifaximin in the treatment of IBS-D. Our findings of compositional gut microbiota alterations in IBS-D and the effect of rifaximin on the gut microbiota implied that altered gut microbiota were associated with the pathogenesis of IBS.