The potential liver injury induced by metronidazole-provoked disturbance of gut microbiota: modulatory effect of turmeric supplementation.

It has been reported that the gut-liver axis and intestinal microbiome contribute crucially to different liver diseases. So, targeting this hepato-intestinal connection may provide a novel treatment modality for hepatic disorders such as drug-induced liver injury (DILI). The present study thought to investigate the protective effect of turmeric (TUR) on metronidazole (MNZ)-induced liver damage and the possible association of the gut-liver axis and gut microbiota as a suggested underlying mechanism. In the first experiment, a MNZ-induced liver injury rat model was reproduced after 130 mg/kg oral MNZ administration for 30 days. Meanwhile, the treatment group was orally treated with 100 mg/kg turmeric daily. In the second experiment, fecal microbiome transplantation (FMT) was conducted, in which the fecal microbiome of each group in the first experiment was transplanted to a healthy corresponding group in the second experiment. The liver enzymes (aminotransferase (ALT) and aspartate aminotransferase (AST)) and histopathological examination were estimated to assess liver function. Inflammatory cytokines and oxidative markers were evaluated in the liver tissues. Histological analysis, intestinal barrier markers, and expression of tight junction proteins were measured for assessment of the intestinal injury. Changes in the gut microbial community and possible hepatic bacterial transmission were analyzed using 16S rRNA sequencing. MNZ induced intestinal and liver injuries which were significantly improved by turmeric. Increased firmicutes/bacteroidetes ratio and bacterial transmission due to gut barrier disruption were suggested. Moreover, TUR has maintained the gut microbial community by rebalancing and restoring bacterial proportions and abundance, thereby repairing the gut mucosal barrier and suppressing bacterial translocation. TUR protected against MNZ-induced gut barrier disruption. Reshaping of the intestinal bacterial composition and prohibition of the hepatic microbial translocation were suggested turmeric effects, potentially mitigating MNZ-related liver toxicity.

Transplant of microbiota from Crohn's disease patients to germ-free mice results in colitis.

Although the role of the intestinal microbiota in the pathogenesis of inflammatory bowel disease (IBD) is beyond debate, attempts to verify the causative role of IBD-associated dysbiosis have been limited to reports of promoting the disease in genetically susceptible mice or in chemically induced colitis. We aimed to further test the host response to fecal microbiome transplantation (FMT) from Crohn's disease patients on mucosal homeostasis in ex-germ-free (xGF) mice. We characterized and transferred fecal microbiota from healthy patients and patients with defined Crohn's ileocolitis (CD_L3) to germ-free mice and analyzed the resulting microbial and mucosal homeostasis by 16S profiling, shotgun metagenomics, histology, immunofluorescence (IF) and RNAseq analysis. We observed a markedly reduced engraftment of CD_L3 microbiome compared to healthy control microbiota. FMT from CD_L3 patients did not lead to ileitis but resulted in colitis with features consistent with CD: a discontinued pattern of colitis, more proximal colonic localization, enlarged isolated lymphoid follicles and/or tertiary lymphoid organ neogenesis, and a transcriptomic pattern consistent with epithelial reprograming and promotion of the Paneth cell-like signature in the proximal colon and immune dysregulation characteristic of CD. The observed inflammatory response was associated with persistently increased abundance of Ruminococcus gnavus, Erysipelatoclostridium ramosum, Faecalimonas umbilicate, Blautia hominis, Clostridium butyricum, and C. paraputrificum and unexpected growth of toxigenic C. difficile, which was below the detection level in the community used for inoculation. Our study provides the first evidence that the transfer of a dysbiotic community from CD patients can lead to spontaneous inflammatory changes in the colon of xGF mice and identifies a signature microbial community capable of promoting colonization of pathogenic and conditionally pathogenic bacteria.

Common Variable Immunodeficiency Patient Fecal Microbiota Transplant Recapitulates Gut Dysbiosis.

Purpose: Patients with non-infectious complications have worse clinical outcomes in common variable immunodeficiency (CVID) than those with infections-only. Non-infectious complications are associated with gut microbiome aberrations, but there are no reductionist animal models that emulate CVID. Our aim in this study was to uncover potential microbiome roles in the development of non-infectious complications in CVID. Methods: We examined fecal whole genome shotgun sequencing from patients CVID, and non-infectious complications, infections-only, and their household controls. We also performed Fecal Microbiota transplant from CVID patients to Germ-Free Mice. Results: We found potentially pathogenic microbes Streptococcus parasanguinis and Erysipelatoclostridium ramosum were enriched in gut microbiomes of CVID patients with non-infectious complications. In contrast, Fusicatenibacter saccharivorans and Anaerostipes hadrus, known to suppress inflammation and promote healthy metabolism, were enriched in gut microbiomes of infections-only CVID patients. Fecal microbiota transplant from non-infectious complications, infections-only, and their household controls into germ-free mice revealed gut dysbiosis patterns in recipients from CVID patients with non-infectious complications, but not infections-only CVID, or household controls recipients. Conclusion: Our findings provide a proof of concept that fecal microbiota transplant from CVID patients with non-infectious complications to Germ-Free mice recapitulates microbiome alterations observed in the donors.

Impact of Fecal Microbiota Transplantation on Gut Bacterial Bile Acid Metabolism in Humans.

Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included Desulfovibrio fairfieldensis and Clostridium hylemonae. To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. Bacteroides ovatus and Phocaeicola dorei were positively correlated with unconjugated bile acids. Bifidobacterium adolescentis, Collinsella aerofaciens, and Faecalibacterium prausnitzii were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.

Our Microbiome: On the Challenges, Promises, and Hype.

The microbiome field is increasingly raising interest among scientists, clinicians, biopharmaceutical entities, and the general public. Technological advances from the past two decades have enabled the rapid expansion of our ability to characterize the human microbiome in depth, highlighting its previously underappreciated role in contributing to multifactorial diseases including those with unknown etiology. Consequently, there is growing evidence that the microbiome could be utilized in medical diagnosis and patient stratification. Moreover, multiple gut microbes and their metabolic products may be bioactive, thereby serving as future potential microbiome-targeting or -associated therapeutics. Such therapies could include new generation probiotics, prebiotics, fecal microbiota transplantations, postbiotics, and dietary modulators. However, microbiome research has also been associated with significant limitations, technical and conceptual challenges, and, at times, "over-hyped" expectations that microbiome research will produce quick solutions to chronic and mechanistically complex human disorders. Herein, we summarize these challenges and also discuss some of the realistic promises associated with microbiome research and its applicability into clinical application.

Limited engraftment of donor microbiome via one-time fecal microbial transplantation in treated HIV-infected individuals.

Many HIV-infected individuals on antiretroviral therapy (ART) exhibit persistent systemic inflammation, which predicts morbidity and mortality. ART-treated subjects concurrently exhibit marked compositional alterations in the gut bacterial microbiota and the degree of dysbiosis correlates with systemic inflammation. Whether interventions to modulate the microbiome can affect systemic inflammation is unknown. An open-label fecal microbial transplantation (FMT) was delivered by colonoscopy to asymptomatic HIV-infected ART-suppressed individuals without antibiotic pre-treatment. Stool was assessed before and after FMT for engraftment of donor microbes, and peripheral blood was assayed for immune activation biomarkers. Six participants received FMT and 2 participants served as controls. No serious adverse effects occurred during 24 weeks of follow-up. At baseline, HIV-infected individuals exhibited microbiota profiles distinct from uninfected donors. During the 8 weeks post-FMT, recipients demonstrated partial engraftment of the donor microbiome (P < 0.05). Recipient microbiota remained significantly distant from donors, unlike that observed following FMT for treatment of C. difficile infection. Systemic inflammatory markers showed no significant change post-FMT. FMT was well-tolerated in ART-treated, HIV-infected individuals. Engraftment was detectable but modest, and appeared to be limited to specific bacterial taxa. Whether antibiotic conditioning can enhance engraftment and the capacity of microbiota to modulate inflammation remains to be investigated.