Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast ...with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut‐liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host‐microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment‐stratifiers. In this way, gut microbiome‐based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.
Gut microbiota alterations are important in irritable bowel syndrome (IBS). The aim was to investigate the effect of fecal microbiota transplantation (FMT) on gut microbiota and the symptoms in ...patients with IBS.
The study included 13 IBS patients according to Rome III criteria and 13 healthy donors. Freshly donated feces were administered to the descending part of the duodenum via a gastroscope. Feces were collected from donors and patients before FMT, and from the patients at 1, 3 and 12 weeks and donors and patients at 20/28 weeks after FMT. Microbiota analysis was performed using GA-map Dysbiosis test (Genetic Analysis AS, Oslo, Norway). The patients completed the following questionnaires before and at the aforementioned weeks after FMT: IBS Symptom Questionnaire (IBS-SQ), IBS-Symptom Severity Scoring system (IBS-SSS), Short Form of Nepean Dyspepsia Index (SF-NDI), Bristol stool form scale, the Eysenck Personality Questionnaire-Neuroticism and Hospital Anxiety and Depression.
Donors and IBS patients had significantly different bacterial strain signals before FMT (Ruminococcus gnavus, Actinobacteria and Bifidobacteria) that became non-significant after 3 weeks following FMT. The changes in gut microbiota were similar between donors and patients at 20/28 weeks after FMT. Thus, patients' microbiota profiles became more-or-less similar to donors. The scores of all the questionnaires were significantly improved at all time points following FMT. No reported adverse effects.
FMT was associated with a change in gut microbiota and improvement in IBS symptoms and quality of life lasting for up to 28 weeks.
ClinicalTrials.gov ID: NCT03333291.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established ...that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional ...changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).
Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.
Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.
The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease has inspired hypothetical models in which gut bacteria or bacterial products are key players in PSC ...pathogenesis. Several studies using high-throughput sequencing technology to characterize the gut microbiota in PSC have been published over the past years. They all report reduced diversity and significant shifts in the overall composition of the gut microbiota. However, it remains unclear as to whether the observed changes are primary or secondary to PSC development and further studies are needed to assess the biological implications of the findings. In the present article, we review the published data in perspective of similar studies in other diseases. We discuss aspects of methodology and study design that are relevant to interpretation of the data. Furthermore, we propose that interpretation and further assessments of findings are structured into conceptual compartments, and elaborate three such possible concepts relating to immune function (the "immunobiome"), host metabolism (the "endobiome"), and dietary and xenobiotic factors (the "xenobiome") in PSC.
The short-chain fatty acid (SCFA) butyric acid maintains a healthy gut barrier and vascular endothelium. We aimed to investigate the association between fecal butyric acid, carotid atherosclerosis ...and risk factors for ischemic stroke. Patients with severe carotid atherosclerosis (i.e. ≥ 50% stenosis) (n = 43) were compared with healthy controls (n = 38). We analyzed fecal SCFAs by gas chromatography, microbiota composition by 16S rRNA sequencing, markers of gut barrier damage and inflammasome activation by immunoassay, and plasma SCFAs by ultra-high performance liquid chromatography-tandem mass spectroscopy. Patients had higher fecal butyric acid level (p = 0.024), along with increased functional potential of microbial butyric acid production (p = 0.031), compared with controls. Dietary fiber intake was comparable. Patients had higher levels of gut barrier damage markers CCL25 and IFABP, and the inflammasome activation marker IL-18, whereas plasma level of butyric was similar. Increased fecal butyric acid was associated with higher BMI, waist-hip ratio, HbA1c, CRP and leukocyte count. Contrary to our hypothesis, patients with severe carotid atherosclerosis had higher fecal butyric acid level, and increased microbial production, compared with controls. Gut barrier damage in patients might indicate decreased absorption of butyric acid and hence contribute to the higher fecal level.
•In this cross-sectional study, we found decreased serum levels of primary bile acids and increased levels of specific secondary bile acids, resulting in increased ratios of secondary to primary bile ...acids, in patients with chronic heart failure.•The ratio of secondary to primary bile acids was associated with reduced overall survival in univariate analysis, but not in multivariate analyses.•Although the production of secondary bile acids depends on the gut microbiota, several factors affecting the production, regulation, and elimination of bile acids could contribute to these findings.•Future studies should assess the potential role of bile acid composition in patients with heart failure and investigate whether manipulation of factors influencing bile acid metabolism, including the intestinal microbial community, could alter clinical outcome.
Bile acids (BAs) are now recognized as signaling molecules and emerging evidence suggests that BAs affect cardiovascular function. The gut microbiota has recently been linked to the severity of heart failure (HF), and microbial metabolism has a major impact on BA homeostasis. We aimed to investigate the pattern of BAs, and particularly microbiota-transformed (secondary) BAs, in patients with chronic HF.
This was a prospective, observational, single-center study including 142 patients with chronic HF and 20 age- and sex-matched healthy control subjects. We measured plasma levels of primary, secondary, and total BAs, and explored their associations with clinical characteristics and survival. Plasma levels of primary BAs were lower (P < .01) and the ratios of secondary to primary BAs higher (P < .001) in patients with HF compared with control subjects. Approximately 40% of patients in the upper tertile of the ratio of secondary to primary BAs died during 5.6 years of follow-up (unadjusted Cox regression: hazard ratio 1.93, 95% confidence interval 1.01–3.68, compared with the lower tertiles). However, this association was attenuated and no longer significant in multivariate analyses.
Levels of primary BAs were reduced and specific secondary BAs increased in patients with chronic HF. This pattern was associated with reduced overall survival in univariate analysis, but not in multivariate analyses. Future studies should assess the regulation and potential role of BA metabolism in HF.
Metabolic and inflammatory disturbances may play a role in the development and progression of chronic heart failure (HF), but the mechanisms are not completely understood. The potential role of the ...gut microbiota in HF remains elusive, and only small studies with diverse methods and results have been reported so far (1-3).
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