-
1.
Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.
Stepien, M, Lopez-Nogueroles, M, Lahoz, A, Kühn, T, Perlemuter, G, Voican, C, Ciocan, D, Boutron-Ruault, MC, Jansen, E, Viallon, V, et al
International journal of cancer. 2022;(8):1255-1268
-
-
Free full text
-
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.
-
2.
Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer's Disease.
Mulak, A
Journal of Alzheimer's disease : JAD. 2021;(2):461-477
-
-
Free full text
-
Abstract
Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer's disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.
-
3.
MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight.
Mendler, A, Pierzchalski, A, Bauer, M, Röder, S, Sattler, A, Standl, M, Borte, M, von Bergen, M, Rolle-Kampczyk, U, Herberth, G
Clinical and experimental immunology. 2020;(2):199-213
-
-
Free full text
-
Abstract
Bile acids (BAs) are produced by liver hepatocytes and were recently shown to exert functions additional to their well-known role in lipid digestion. As yet it is not known whether the mucosal-associated invariant T (MAIT) cells, which represent 10-15% of the hepatic T cell population, are affected by BAs. The focus of the present investigation was on the association of BA serum concentration with MAIT cell function and inflammatory parameters as well as on the relationship of these parameters to body weight. Blood samples from 41 normal weight and 41 overweight children of the Lifestyle Immune System Allergy (LISA) study were analyzed with respect to MAIT cell surface and activation markers [CD107a, CD137, CD69, interferon (IFN)-γ, tumor necrosis factor (TNF)-α] after Escherichia coli stimulation, mRNA expression of promyelocytic leukemia zinc finger protein (PLZF) and major histocompatibility complex class I-related gene protein (MR1), the inflammatory markers C-reactive protein (CRP), interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1α as well as the concentrations of 13 conjugated and unconjugated BAs. Higher body weight was associated with reduced MAIT cell activation and expression of natural killer cell marker (NKp80) and chemokine receptor (CXCR3). BA concentrations were positively associated with the inflammatory parameters CRP, IL-8 and MIP-1α, but were negatively associated with the number of activated MAIT cells and the MAIT cell transcription factor PLZF. These relationships were exclusively found with conjugated BAs. BA-mediated inhibition of MAIT cell activation was confirmed in vitro. Thus, conjugated BAs have the capacity to modulate the balance between pro- and anti-inflammatory immune responses.
-
4.
Signaling from Intestine to the Host: How Bile Acids Regulate Intestinal and Liver Immunity.
Biagioli, M, Carino, A
Handbook of experimental pharmacology. 2019;:95-108
Abstract
Primary bile acids (BAs) are generated in the liver as the end products of cholesterol catabolism; they are then conjugated and accumulated in the gallbladder. After a meal ingestion, BAs are reversed into the duodenum to facilitate the lipid absorption. At the intestinal level, the 95% of BAs are reabsorbed and redirected into enterohepatic circulation; indeed only a small amount of them are then subjected to chemical modifications by the intestinal microbiota, which plays a very important role in the generation of secondary bile acids and in regulating host's metabolism and activity of the immune system. Behind their role in nutrients absorption, bile acids act as signaling molecules, activating several receptors, known as bile acid-activated receptors (BARs), including the farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5). Both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine immunity. In particular, FXR and GPBAR1 are highly expressed in cells of innate immunity including intestinal and liver macrophages, dendritic cells, and natural killer T cells. In this chapter, we provide an overview on mechanisms through which FXR and GPBAR1 modulate the signaling between microbiota and intestinal and liver innate immune system. This overview could help to explain beneficial effects exerted by GPBAR1 and FXR agonists in the treatment of metabolic and immuno-mediated diseases.
-
5.
The gut microbial influence on cholestatic liver disease.
Kummen, M, Hov, JR
Liver international : official journal of the International Association for the Study of the Liver. 2019;(7):1186-1196
Abstract
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.
-
6.
New therapies target the toxic consequences of cholestatic liver disease.
Jansen, PLM
Expert review of gastroenterology & hepatology. 2018;(3):277-285
Abstract
In most cholestatic liver diseases the primary cholestasis-causing lesions are located in the biliary tree and may be of (auto)immune origin. Bile salts are responsible for the secondary toxic consequences. Bile salt and nuclear hormone directed therapies primarily aim at improving this secondary toxic injury. In primary biliary cholangitis, trials show statistically significant responses on biochemical endpoints. Preclinical studies suggest that FXR- and PPAR-agonists, inhibitors of the apical sodium-dependent bile salt transporter (ASBT-inhibitors) and the C23 UDCA derivative nor-UDCA are promising agents for the treatment of primary sclerosing cholangitis (PSC). Area covered: Pharmaceuticals that interfere with bile salt signaling in humans for the treatment of chronic cholestatic liver disease are reviewed. Expert commentary: Nuclear hormone receptors, bile salt transport proteins and receptors provide targets for novel therapies of cholestatic liver disease. These drugs show positive results on biochemical endpoints. For histological endpoints, survival and transplant-free survival, long-term trials are needed. For relief of symptoms, such as fatigue and pruritus, these drugs have yet to prove their value.
-
7.
Nutritional Modulation of Innate Immunity: The Fat-Bile-Gut Connection.
Chevre, R, Silvestre-Roig, C, Soehnlein, O
Trends in endocrinology and metabolism: TEM. 2018;(10):686-698
Abstract
Altered nutritional behavior in Western societies has unleashed numerous metabolic disorders, intimately linked to profound disruptions of the immune system. Here we summarize how nutrition modulates innate immunity. We outline recent findings regarding nutrient signaling and we particularly focus on the collateral impact of nutrition on the microbiome and on the bile acid (BA) pool. We discuss how the integration of postprandial signals by the gut microbiota, along with the absorption routes of metabolites, differentially affects immune niches to orchestrate immune responses. Finally, we discuss the potential consequences of these signals in the light of trained immunity. A better understanding of nutrition signaling will permit the optimization of therapeutic and dietary strategies against the arising immune disorders.
-
8.
Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.
Zhang, L, Voskuijl, W, Mouzaki, M, Groen, AK, Alexander, J, Bourdon, C, Wang, A, Versloot, CJ, Di Giovanni, V, Wanders, RJ, et al
PloS one. 2016;(5):e0155143
Abstract
OBJECTIVE Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis. DESIGN An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified. RESULTS On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower. CONCLUSION SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.
-
9.
Bile Acids and the Potential Role in Primary Biliary Cirrhosis.
Yang, H, Duan, Z
Digestion. 2016;(3):145-153
Abstract
BACKGROUND Bile acids (BAs) play a potential role in regulating the whole-body metabolic homeostasis via the interaction with gut microbiome and the signal transduction as messengers, which establish a link between the primary biliary cirrhosis (PBC) and gut microbiome in many aspects, particularly with regard to the immune system of the body. PBC, as a chronic cholestatic liver disease characterised by the destruction of small intrahepatic bile ducts, causes fibrosis and potential cirrhosis without efficient therapies. SUMMARY Recent researches show BAs can induce the differentiation of hepatic stellate cells, suggesting that it may serve as a novel therapy to resist, even changeover the irreversible liver cirrhosis in PBC. Key Messages: In this review, we conclude and provide information on the possible mechanism of pleiotropic BAs in homeostasis of the gut microbiome and liver regeneration, and hope to broaden the therapy of PBC and promote the relevant drugs' development.
-
10.
Bile acid malabsorption in inflammatory bowel disease.
Vítek, L
Inflammatory bowel diseases. 2015;(2):476-83
Abstract
Bile acid malabsorption (BAM) is a common but an underestimated and often neglected sign of inflammatory bowel diseases (IBDs), especially those affecting the distal ileum. Clinically relevant BAM is most often present in patients with Crohn's ileitis and particularly in ileal-resected Crohn's disease patients. However, deterioration of bile acid (BA) metabolism occurs also in patients with IBD without ileal disease or in those in clinical remission, and the role of BAM in these patients is not well appreciated by clinicians. In a majority of cases, BAM in IBD is caused by impaired conjugated BA reabsorption, mediated by apical sodium/BA cotransporting polypeptide, localized at the luminal surface of the ileal enterocytes. As a consequence, numerous pathological sequelae may occur, including the malfunction of lipid digestion with clinical steatorrhea, impaired intestinal motility, and/or significant changes in the intestinal microflora environment. In this review, a detailed description of the pathophysiological mechanisms of BAM-related diarrhea is presented. Although BAM is present in a significant number of patients with Crohn's disease, its laboratory assessment is not routinely included in diagnostic workups, partially because of costs, logistical reasons, or the unavailability of the more sophisticated laboratory equipment needed. Simultaneously, novel findings related to the effects of the BA signaling pathways on immune functions (mediated through TGR5, cell membrane G protein-coupled BA receptor 1, nuclear farnesoid X receptor, nuclear pregnane X receptor, or nuclear vitamin D receptor) are discussed along with intestinal metabolism in its relationship to the pathogenesis of IBD.