BACKGROUND AND AIMS: Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt-FGF19 axis. APPROACH AND RESULTS: Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7-α-hydroxy-4-cholesten-3-one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up-regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. CONCLUSIONS: CR in patients with IF-TDE restored bile salt-FGF19 signaling and improved gut-liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.
- MeSH
- Anastomosis, Surgical adverse effects MeSH
- Enteral Nutrition methods MeSH
- Enterostomy adverse effects MeSH
- Fibroblast Growth Factors blood metabolism MeSH
- Gastrointestinal Contents * MeSH
- Middle Aged MeSH
- Humans MeSH
- Nutritional Status MeSH
- Prospective Studies MeSH
- Intestinal Failure blood etiology metabolism therapy MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Bile Acids and Salts blood metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. METHODS: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. RESULTS: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. CONCLUSIONS: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.
- MeSH
- Fibroblast Growth Factors * blood MeSH
- Hepatectomy * MeSH
- Liver metabolism surgery MeSH
- Klatskin Tumor * surgery pathology blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Bile Duct Neoplasms * surgery pathology blood MeSH
- Liver Regeneration * physiology MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Bile Acids and Salts * blood metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Immunologically mediated liver diseases belong to the common extraintestinal manifestations of celiac disease. We have reviewed the current literature that addresses the association between celiac disease and liver disorders. We searched relevant articles on MEDLINE/PubMed up to 15 June 2018. The objective of the article is to provide a comprehensive and up-to-date review on the latest hypotheses explaining the pathogenetic relationship between celiac disease and liver injury. Besides the involvement of gut⁻liver axis, tissue transglutaminase antibodies, and impairment of intestinal barrier, we integrate the latest achievements made in elucidation of the role of gut microbiota in celiac disease and liver disorders, that has not yet been sufficiently discussed in the literature in this context. The further objective is to provide a complete clinical overview on the types of liver diseases frequently found in celiac disease. In conclusion, the review highlights the clinical implication, recommend a rational approach for managing elevated transaminases in celiac patients, and underscore the importance of screening for celiac disease in patients with associated liver disease.
- MeSH
- Autoimmunity * MeSH
- Hepatitis, Autoimmune diet therapy epidemiology immunology microbiology MeSH
- Autoantibodies immunology MeSH
- Diet, Gluten-Free MeSH
- Celiac Disease diet therapy epidemiology immunology microbiology MeSH
- Dysbiosis MeSH
- Liver immunology microbiology MeSH
- Humans MeSH
- Non-alcoholic Fatty Liver Disease diet therapy epidemiology immunology microbiology MeSH
- Vitamin D Deficiency epidemiology immunology MeSH
- Permeability MeSH
- Prognosis MeSH
- GTP-Binding Proteins immunology MeSH
- Risk Factors MeSH
- Intestines immunology MeSH
- Gastrointestinal Microbiome MeSH
- Intestinal Mucosa metabolism MeSH
- Transglutaminases immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Modulation of gut microbiome composition seems to be a promising therapeutic strategy for a wide range of pathologic states. However, these microbiota-targeted interventions may affect production of microbial metabolites, circulating factors in the gut-liver axis influencing hepatic drug metabolism with possible clinical relevance. Butyrate, a short-chain fatty acid produced through microbial fermentation of dietary fibers in the colon, has well established anti-inflammatory role in the intestine, while the effect of butyrate on the liver is unknown. In this study, we have evaluated the effect of butyrate on hepatic AhR activity and AhR-regulated gene expression. We have showed that AhR and its target genes were upregulated by butyrate in dose-dependent manner in HepG2-C3 as well as in primary human hepatocytes. The involvement of AhR has been proved using specific AhR antagonists and siRNA-mediated AhR silencing. Experiments with AhR reporter cells have shown that butyrate regulates the expression of AhR target genes by modulating the AhR activity. Our results suggest also epigenetic action by butyrate on AhR and its repressor (AHRR) presumably through mechanisms based on HDAC inhibition in the liver. Our results demonstrate that butyrate may influence the drug-metabolizing ability of liver enzymes e.g., through the interaction with AhR-dependent pathways.
The development of inflammatory bowel disease (IBD) is associated with alterations in the gut microbiota. There is currently no universal treatment for this disease, thus emphasizing the importance of developing innovative therapeutic approaches. Gut microbiome-derived metabolite butyrate with its well-known anti-inflammatory effect in the gut is a promising candidate. Due to increased intestinal permeability during IBD, butyrate may also reach the liver and influence liver physiology, including hepatic drug metabolism. To get an insight into this reason, the aim of this study was set to clarify not only the protective effects of the sodium butyrate (SB) administration on colonic inflammation but also the effects of SB on hepatic drug metabolism in experimental colitis induced by dextran sodium sulfate (DSS) in mice. It has been shown here that the butyrate pre-treatment can alleviate gut inflammation and reduce the leakiness of colonic epithelium by restoration of the assembly of tight-junction protein Zonula occludens-1 (ZO-1) in mice with DSS-induced colitis. In this article, butyrate along with inflammation has also been shown to affect the expression and enzyme activity of selected cytochromes P450 (CYPs) in the liver of mice. In this respect, CYP3A enzymes may be very sensitive to gut microbiome-targeted interventions, as significant changes in CYP3A expression and activity in response to DSS-induced colitis and/or butyrate treatment have also been observed. With regard to medications used in IBD and microbiota-targeted therapeutic approaches, it is important to deepen our knowledge of the effect of gut inflammation, and therapeutic interventions were followed concerning the ability of the organism to metabolize drugs. This gut-liver axis, mediated through inflammation as well as microbiome-derived metabolites, may affect the response to IBD therapy.
- Publication type
- Journal Article MeSH
Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut-liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.
- MeSH
- Anti-Bacterial Agents adverse effects pharmacology therapeutic use MeSH
- Anti-Inflammatory Agents pharmacology MeSH
- Butyrates * pharmacology MeSH
- Metronidazole pharmacology MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Dextran Sulfate adverse effects MeSH
- Gastrointestinal Microbiome * MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Colitis, Ulcerative * chemically induced drug therapy MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Various environmental factors affecting the human microbiota may lead to gut microbial imbalance and to the development of pathologies. Alterations of gut microbiota have been firmly implicated in digestive diseases such as hepatic encephalopathy, irritable bowel syndrome and diverticular disease. However, while these three conditions may all be related to dysfunction of the gut-liver-brain axis, the precise pathophysiology appears to differ somewhat for each. Herein, current knowledge on the pathophysiology of hepatic encephalopathy, irritable bowel syndrome, and diverticular disease are reviewed, with a special focus on the gut microbiota modulation associated with these disorders during therapy with rifaximin. In general, the evidence for the efficacy of rifaximin in hepatic encephalopathy appears to be well consolidated, although it is less supported for irritable bowel syndrome and diverticular disease. We reviewed current clinical practice for the management of these clinical conditions and underlined the desirability of more real-world studies to fully understand the potential of rifaximin in these clinical situations and obtain even more precise indications for the use of the drug.
Termín s cirhózou asociovaná imunitná dysfunkcia predstavuje široké spektrum zmien v lokálnej a systémovej imunitnej odpovedi. CAID je charakterizovaná súčasnou prítomnosťou systémového zápalu a imunitného deficitu, ktorých intenzita prejavu závisí od stupňa pokročilosti ochorenia, predisponujúcich a precipitujúcich faktorov. Kľúčovú úlohu v patogenéze CAID zohráva spojenie črevo–pečeň. Porucha ich vzájomnej súhry, ako aj zmeny v zložení mikrobiómu, vedú k poškodeniu črevnej bariéry a následnej permanentnej antigénnej stimulácii, ktorá vedie k novému prozápalovému nastaveniu imunitného systému. Táto zmena charakterizuje nízkozápalový fenotyp CAID. Opakované zosilnenia mikrobiálnej translokácie a opakované pôsobenie precipitujúceho faktora vedú k vzplanutiu systémového zápalu a prelomeniu imunitnej tolerancie. Výsledkom je dysregulovaná hyperinflamačná imunitná odpoveď, ktorá reprezentuje vysokozápalový fenotyp CAID. Zmena fenotypu je podkladom pre progresiu cirhózy do štádia dekompenzácie. Miera systémového zápalu zodpovedá jednotlivým subtypom dekompenzácie, pričom najvyšší stupeň dosahuje pri ACLF, ktoré reprezentuje fulminantný imunofenotyp CAID. K rozvoju dysfunkcie jednotlivých orgánových systémov prispievajú okrem orgánovo špecifických mechanizmov aj hyperinflamačná imunitná odpoveď, imunopatologické a imunometabolické mechanizmy. Trvajúca dysregulovaná prozápalová odpoveď vedie k postupnému vyčerpaniu imunity a preprogramovaniu vrodených a získaných imunitných buniek. Navodená imunoparalýza je príčinou problémových infekcií a predstavuje indolentný imunofenotyp CAID.
The term cirrhosis-associated immune dysfunction represents a wide spectrum of alterations in the local and systematic immune response. CAID is characterised by parallel ongoing systematic inflammation and immune deficiency, the intensity of manifestation of which depends on the stage of the disease, predisposing and precipitating factors. The gut-liver axis plays a key role in the pathogenesis of CAID. Impaired interplay between the gut and liver and changes in microbiome composition are responsible for damage to the intestinal barrier and continuous antigen stimulation, leading to the new proinflammatory setting of the immune system, which represents the low-grade inflammation phenotype CAID. Episodic aggravation of microbial translocation and episodic effect of precipitating factors cause a burst of systematic inflammation and breakthrough of the immune tolerance. The result is dysregulated hyperinflammatory immune response, which represents the high-grade inflammation phenotype of CAID. The change of the phenotype stays in the background of transition to decompensated cirrhosis. The systemic inflammation increases across the subtypes of decompensation with the highest degree reached in the ACLF, which represents the fulminant immunophenotype of CAID. Hyperinflammatory immune response, immunopathologic and immunometabolic changes act synergistically with organ-specific mechanisms in the development of organ dysfunctions. Lasting dysregulated pro-inflammatory reaction leads to immunity exhaustion and innate and adaptive immune cells reprogramming. This immune paralysis is the cause of problematic infections and represents the indolent immunophenotype of CAID.
- MeSH
- Liver Cirrhosis * immunology therapy MeSH
- Humans MeSH
- Immunity, Innate MeSH
- Immunologic Deficiency Syndromes * immunology therapy MeSH
- Inflammation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients. METHODS: Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response. RESULTS: Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline. CONCLUSION: Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.
- MeSH
- Administration, Oral MeSH
- Cholestenones blood MeSH
- Adult MeSH
- Fibroblast Growth Factors blood metabolism MeSH
- Liver metabolism MeSH
- Clinical Protocols MeSH
- Chenodeoxycholic Acid administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Cathartics administration & dosage MeSH
- Aged MeSH
- Cholangitis, Sclerosing blood drug therapy metabolism MeSH
- Intestines metabolism MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. METHODS: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. RESULTS: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. CONCLUSIONS: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.
