ABSTRACT
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
Subject(s)
Bile Acids and Salts/blood , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Liver Neoplasms/blood , Adult , Aged , Case-Control Studies , Cohort Studies , Female , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions. DESIGN: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice. RESULTS: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists. CONCLUSIONS: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Intestines/microbiology , Liver Diseases, Alcoholic/etiology , Microbiota/physiology , Pectins/pharmacology , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/agonists , Basic Helix-Loop-Helix Transcription Factors/genetics , Carbazoles/pharmacology , Disease Models, Animal , Fecal Microbiota Transplantation , Feces/chemistry , Female , Humans , Intestines/physiopathology , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/metabolism , Metabolome/drug effects , Mice , Mice, Knockout , Microbiota/drug effects , Pectins/therapeutic use , Prebiotics , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/geneticsABSTRACT
Recent data suggest that herbal and dietary supplements are the second most common cause of liver injury. We herein report a case of acute liver injury in a 68-year old female caused by ingestion of Aloe vera. Upon discontinuation of the oral Aloe vera, liver function tests (LFT) returned to normal levels. Thus, it is crucial to consider the use of herbal products as causative agents of acute liver injury.