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.

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.

Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.

PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

Bile acid-gut microbiota crosstalk in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.

Lactobacillus rhamnosus GG supernatant promotes intestinal mucin production through regulating 5-HT4R and gut microbiota.

Lactobacillus rhamnosus GG (LGG) is a well-known probiotic widely used in foods and drugs. It has been reported that LGG can improve bowel dysfunction in gastrointestinal motility disorders, such as constipation; however, the specific mechanisms remain unclear. The colonic mucus layer is mainly composed of mucin secreted by goblet cells, which plays important roles in lubricating colonic contents and maintaining normal defecation function. It has been reported that increased mucin production is beneficial for relieving constipation symptoms. In this study, we aimed to investigate the role of LGG in regulating intestinal mucin production and the associated mechanisms. Six-week-old C57BL/6J mice were randomized into 3 groups, and were treated with De-Man Rogosa and Sharpe broth (MRS group), tegaserod maleate (tegaserod group) and LGG supernatant (LGGs group) by gavage, respectively. After treatments, defecation parameters, intestinal mucin-2 (MUC2) and serotonin 4 receptor (5-HT4R), goblet cells, and microbiota composition of the mice in each group were assessed. In comparison with the MRS group, higher fecal water content and increased fecal pellet number were found in the tegaserod group and LGGs group. Moreover, LGGs increased the number of goblet cells and upregulated the expression of 5-HT4R and MUC2 in the mouse colon. In addition, Alcian Blue Periodic acid Schiff staining showed that activated 5-HT4R enhanced intestinal MUC2 secretion. Further exploration of the mechanism discovered that LGGs upregulated intestinal S100A10, which was found to be involved in regulating 5-HT4R expression. Furthermore, gut microbiota analysis showed the higher abundance of Alistipes, Allobaculum, Desulfovibrio, and Clostridium XlVa in the LGGs group, which have been reported to be involved in regulating gut motility and the intestinal barrier, and alleviating bowel dysfunction. Interestingly, gut dysbiosis was present in the tegaserod group. It is noteworthy that the fecal microbiota transplanted from LGGs-treated mice significantly improved the gut dysmotility in a constipation mouse model. Our results suggested that LGGs could upregulate 5-HT4R to promote MUC2 production, as well as modulate the gut microbiota, thus improving the defecation function in mice. This finding might provide evidence for the application of diet supplementary LGG in relieving gastrointestinal motility disorders.

Saccharomyces boulardii, a yeast probiotic, inhibits gut motility through upregulating intestinal serotonin transporter and modulating gut microbiota.

Saccharomyces boulardii (Sb) is a widely used fungal probiotic in treating various digestive diseases, including irritable bowel syndrome (IBS). However, the specific mechanisms of Sb relieving IBS remain unclear. The abnormal serotonin transporter (SERT) / 5-hydroxytryptamine (5-HT) system could cause disordered gastrointestinal sensation and motility, which closely related to IBS pathogenesis. The aim of this study was to explore the effects and mechanisms of Sb on regulating gut motility. Sb supernatant (SbS) was administered to intestinal epithelial cells and mice. SbS upregulated SERT expression via enhancing heparin-binding epidermal growth factor (HB-EGF) release to activate epidermal growth factor receptor (EGFR). EGFR kinase inhibitor treatment or HB-EGF siRNA transfection in cells blocked SbS upregulating SERT. Consistently, SbS-treated mice presented inhibited gut motility, and EGFR activation and SERT upregulation were found. Moreover, 16 S rDNA sequence presented an evident decrease in Firmicutes / Bacteroidetes ratio in SbS group. In genus level, SbS reduced Escherichia_Shigella, Alistipes, Clostridium XlVa, and Saccharibacteria_genera_incertae_sedis, meanwhile, increased Parasutterella. The abundance of Saccharibacteria_genera_incertae_sedis positively correlated with defecation parameters and intestinal 5-HT content. Fecal microbiota transplantation showed that SbS could modulate gut microbiota to influence gut motility. Interestingly, elimination of gut microbiota with antibiotic cocktail did not entirely block SbS regulating gut motility. Furthermore, SbS administration to IBS-D mice significantly upregulated SERT and inhibited gut motility. In conclusion, SbS could upregulate SERT by EGFR activation, and modulate gut microbiota to inhibit gut motility. This finding would provide more evidence for the application of this yeast probiotic in IBS and other diarrheal disorders.

Gut Microbiota-Derived Metabolites in Colorectal Cancer: The Bad and the Challenges.

Accumulating evidence from studies in humans and animal models has elucidated that gut microbiota, acting as a complex ecosystem, contributes critically to colorectal cancer (CRC). The potential mechanisms often reported emphasize the vital role of carcinogenic activities of specific pathogens, but in fact, a series of metabolites produced from exogenous dietary substrates or endogenous host compounds occupy a decisive position similarly. Detrimental gut microbiota-derived metabolites such as trimethylamine-N-oxide, secondary bile acids, hydrogen sulfide and N-nitroso compounds could reconstruct the ecological composition and metabolic activity of intestinal microorganisms and formulate a microenvironment that opens susceptibility to carcinogenic stimuli. They are implicated in the occurrence, progression and metastasis of CRC through different mechanisms, including inducing inflammation and DNA damage, activating tumorigenic signaling pathways and regulating tumor immunity. In this review, we mainly summarized the intimate relationship between detrimental gut microbiota-derived metabolites and CRC, and updated the current knowledge about detrimental metabolites in CRC pathogenesis. Then, multiple interventions targeting these metabolites for CRC management were critically reviewed, including diet modulation, probiotics/prebiotics, fecal microbiota transplantation, as well as more precise measures such as engineered bacteria, phage therapy and chemopreventive drugs. A better understanding of the interplay between detrimental microbial metabolites and CRC would hold great promise against CRC.

Gut mycobiome: A promising target for colorectal cancer.

The human gut is mainly habited by a staggering amount and abundance of bacteria as well as fungi. Gut dysbiosis is believed as a pivotal factor in colorectal cancer (CRC) development. Lately increasing evidence from animal or clinical studies suggested that fungal disturbance also contributed to CRC development. This review summarized the current status of fungal dysbiosis in CRC and highlighted the potential tumorigenic mechanisms of fungi. Then the fungal markers and some therapeutic strategies for CRC were discussed. It would provide a better understanding of the correlation of mycobiota and CRC, and modulating fungal community would be a promising target against CRC.

Diagnostic Value of Gd-EOB-DTPA-Enhanced MRI for the Expression of Ki67 and Microvascular Density in Hepatocellular Carcinoma.

CONTRACT GRANT SPONSOR: National Natural Science Foundation of China; Contract grant number: 81260214. BACKGROUND: Recent studies have highlighted the diagnostic value of Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI in small hepatocellular carcinoma (HCC). Ki67 and CD34 are histologic markers that reflect the proliferation of tumor cells and the microvascular density (MVD). PURPOSE: To explore the diagnostic value of Gd-EOB-DTPA-enhanced MRI for Ki67 expression and MVD in HCC. STUDY TYPE: Retrospective. SUBJECTS: In all, 180 patients with HCC. FIELD STRENGTH/SEQUENCE: 3.0T, Gd-EOB-DTPA-enhanced T1 WI volumetric interpolated breath-hold examination (VIBE) axial fat suppression plain, and enhanced scanning. ASSESSMENT: The T1 relaxation time (T1 rt) and signal intensity (SI) of the lesion were measured. The Ki67 expressions and MVD were evaluated by immunohistochemistry. STATISTICAL TEST: Receiver operating characteristic (ROC) curves were used to analyze the diagnostic efficacy of T1 rt for high Ki67 expression (≥50%) and high MVD (≥100). RESULTS: The T1 rt-20min, rrT1 rt-20min, and SI-hepatobiliary phase (SI-HBP) were strongly correlated with Ki67, the r values were 0.846, -0.765, and -0.760 (P < 0.05), respectively. There were moderate correlations with CD34, with r values -0.444, 0.336, and -0.463 (P < 0.05), respectively. The T1 rt-Pre, T1 rt-20min, SI-Pre, and SI-HBP were significantly different both between the high and low ki67 expression groups (P < 0.05) and between the high MVD and low MVD groups (P < 0.05). In the two groups the T1 rt-20min and SI-HBP was 800.06 ± 128.91 vs. 530.06 ± 139.29 (P < 0.05) and 122.29 ± 39.39 vs. 173.49 ± 46.15 (P < 0.05); T1 rt-20min was found to have high diagnostic efficiency for high ki67 expression (area under the curve [AUC], 0.937; P < 0.05) T1 rt-20min had moderate diagnostic value for high MVD (AUC, 0.716; P < 0.05). DATA CONCLUSION: The T1 rt and SI of Gd-EOB-DTPA-enhanced MRI were correlated with Ki67 expression and MVD. T1 rt-20min has a high diagnostic value for high ki67 expression and high MVD in HCC tissues. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1755-1763.

The Potential Role of Gut Mycobiome in Irritable Bowel Syndrome.

The human gut is inhabited by diverse microorganisms that play crucial roles in health and disease. Gut microbiota dysbiosis is increasingly considered as a vital factor in the etiopathogenesis of irritable bowel syndrome (IBS), which is a common functional gastrointestinal disorder with a high incidence all over the world. However, investigations to date are primarily directed to the bacterial community, and the gut mycobiome, another fundamental part of gut ecosystem, has been underestimated. Intestinal fungi have important effects on maintaining gut homeostasis just as bacterial species. In the present article, we reviewed the potential roles of gut mycobiome in the pathogenesis of IBS and the connections between the fungi and existing mechanisms such as chronic low-grade inflammation, visceral hypersensitivity, and brain-gut interactions. Moreover, possible strategies targeted at the gut mycobiome for managing IBS were also described. This review provides a basis for considering the role of the mycobiome in IBS and offers novel treatment strategies for IBS patients; moreover, it adds new dimensions to researches on microorganism.

Hepatocellular carcinoma grading and recurrence prediction using T1 mapping on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging.

The aim of the present study was to explore the value of T1 mapping on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for grading hepatocellular carcinoma (HCC) and predicting its recurrence rate. A retrospective study was performed that included 75 patients (66 men and 9 women; mean age, 52.89 years; age range, 23-79 years) with HCC who had undergone Gd-EOB-DTPA-enhanced MRI with T1 mapping before surgery. The T1 relaxation time of the 81 lesions and non-tumorous liver parenchyma in 75 patients with HCC were measured before Gd-EOB-DTPA was injected and then at 5, 10 and 20 min after administration, respectively. T1[lesion (L)-hepatic parenchyma (H)]/H (%) was calculated as the increment rate of the T1 value in the lesions relative to the non-tumorous liver parenchyma. One-way analysis of variance and Spearman's correlation analysis was used to compare the differences and relationship of T1 mapping values among the three grades of HCC. A total of 81 lesions were divided into well-differentiated HCC (grades I; n=21), moderately differentiated HCC (grades II; n=40) and poorly differentiated HCC (grades III; n=20) according to the histopathology. The T1(L-H)/H (%) value among grades I, II and III HCC on pre-contrast results and on post-contrast results at the 5-, 10- and 20-min hepatobiliary phase (HBP) were significantly different (P<0.05), and T1(L-H)/H (%) was correlated with the histological grade of HCC at each time point (r=0.637, r=0.554, r=0.499 and r=0.560, respectively, P<0.001). A total of 41 recurrence cases [grade I (n=5), grade II (n=23) and grade III (n=13)] were verified by imaging (CT, MRI or ultrasound) or reoperation. Patients with grade III and grade II HCC had higher recurrence rates compared with that in patients with grade I HCC (P<0.05; median recurrence times were 258 days, 605 days and undefined, respectively). According to the optimal cut-off point for the T1(L-H)/H (%) of the three grades of HCC, patients with HCC in the low T1(L-H)/H (%) value group (≤155.15%) had lower cumulative recurrence rates compared with that in the medium (T1(L-H)/H (%) >155.15% and T1(L-H)/H (%) ≤241.20%) and high (T1(L-H)/H (%) >241.20%) value groups at the 20-min HBP (P<0.05; median recurrence times were undefined, 530 days and 447 days, respectively). These results indicate that the parameters of T1 mapping would be beneficial for predicting the grading and recurrence of HCC.