Conjugated Bile Research Articles

Abstract Mo041: Bile Acid Dysregulation in Response to Right Heart Failure and Hepatic Congestion

Introduction: Right heart failure (RHF), the result of impaired RV contractility and/or severe right-sided valvulopathies, is a clinical syndrome that commonly results in chronically elevated central venous pressures and hepatic congestion. Hepatic dysfunction in patients with heart failure portends a poor prognosis. In part, this may be due to the liver’s pivotal role in bile acid synthesis and processing. In addition to the classic role of a digestive surfactant, bile acids serve as important and dynamic signaling molecule. The present study characterizes a unique bile acid profile found in patients with RHF. Research Question: We hypothesize that RHF and hepatic congestion results in a dysregulation of bile acids. These untoward changes in bile acids concentrations may provide both important prognostic value and novel mechanistic pathways in congestive liver disease. Aims: 1) To characterize systemic and hepatic vein bile acid concentrations in patients with right heart failure. 2) To phenotype a mouse model of hepatic congestion and understand the mechanistic effects of specific bile acids on liver biology Methods: We enrolled a total of 60 patients who were referred for right heart catheterization (RHC). Patient demographics, echocardiograms, and routine laboratory tests were captured at enrollment. Blood was sampled from the IVC and hepatic vein during RHC. Bile acids were quantified from serum using liquid chromatography-tandem mass spectrometry. To model hepatic congestion, mice underwent ligation of the IVC. Blood and tissue samples were harvested and underwent mass spectrometry evaluation for the bile acid composition and immunohistochemistry was performed to characterize the immune landscape, respectively. Results: We captured a total of 12 control samples from patients with normal filling pressures, 25 patients with left heart failure (LHF), and 23 patients with RF. Patients with RHF had poorer survival outcomes compared to control or LHF. Patients with RHF had significant increases in specific conjugated bile acids when compared to control or LHF (Figure 1). Conclusions: In this study, we identified several conjugated bile acids that are uniquely elevated in patients with RHF compared to LHF and control. Additionally, patients with RHF had poorer survival. Collectively, these data suggest bile acids may serve as important biomarkers and signaling molecules in the pathogenesis of cardiogenic liver disease.

Lactobacillus rhamnosus GG ameliorates triptolide-induced liver injury through modulation of the bile acid-FXR axis

Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.

Metabolic outcomes in obese mice undergoing one-anastomosis gastric bypass (OAGB) with a long or a short biliopancreatic limb.

One-anastomosis gastric bypass (OAGB) has gained importance as a simple, safe, and effective operation to treat morbid obesity. We previously found that Roux-en-Y gastric bypass surgery with a long compared with a short biliopancreatic limb (BPL) leads to improved weight loss and glucose tolerance in obese mice. However, it is not known whether a long BPL in OAGB surgery also results in beneficial metabolic outcomes. Five-week-old male C57BL/6J mice fed a high-fat diet (HFD) for 8 weeks underwent OAGB surgery with defined BPL lengths (5.5 cm distally of the duodenojejunal junction for short and 9.5 cm for long BPL), or sham surgery combined with caloric restriction. Weight loss, glucose tolerance, obesity-related comorbidities, endocrine effects, gut microbiota, and bile acids were assessed. Total weight loss was independent of the length of the BPL after OAGB surgery. However, a long BPL was associated with lower glucose-stimulated insulin on day 14, and an improved glucose tolerance on day 35 after surgery. Moreover, a long BPL resulted in reduced total cholesterol, while there were no differences in the resolution of metabolic dysfunction-associated steatotic liver disease (MASLD) and adipose tissue inflammation. Tendencies of an attenuated hypothalamic-pituitary-adrenal (HPA) axis and aldosterone were present in the long BPL group. With both the short and long BPL, we found an increase in primary conjugated bile acids (pronounced in long BPL) along with a loss in bacterial Desulfovibrionaceae and Erysipelotrichaceae and simultaneous increase in Akkermansiaceae, Sutterellaceae, and Enterobacteriaceae. In summary, OAGB surgery with a long compared with a short BPL led to similar weight loss, but improved glucose metabolism, lipid, and endocrine outcomes in obese mice, potentially mediated through changes in gut microbiota and related bile acids. Tailoring the BPL length in humans might help to optimize metabolic outcomes after bariatric surgery.NEW & NOTEWORTHY Weight loss following OAGB surgery in obese mice was not influenced by BPL length, but a longer BPL was associated with improved metabolic outcomes, including glucose and lipid homeostasis. These changes could be mediated by bile acids upon altered gut microbiota. Further validation of these findings is required through a randomized human study.

Bile conjugation and its effect on in vitro lipolysis of emulsions

Bile Salts (BS) are responsible for stimulating lipid digestion in our organism. Gut microbiota are responsible for the deconjugation process of primary conjugated to secondary unconjugated BS. We use two structurally distinct BS and characterize the rate of lipolysis as a compound parameter. A static in-vitro digestion model as well as meta-analysis of literature data has been performed to determine the most influential factors affecting the lipid digestion process. The results demonstrate that lipolysis of emulsions using conjugated BS (NaTC, FFA = 60.0 %, CMC in SIF = 5.58 mM, MSR of linoleic acid = 0.21, rate of adsorption = -0.057 mN/m.s) enhances the release of FFA compared to deconjugated BS (NaDC, FFA = 49.5 %, CMC in SIF = 2.49 mM, MSR of linoleic acid = 0.16 rate of adsorption = -0.064 mN/m.s). These results indicate that conjugation plays an important role in controlling the rate of lipolysis in our organism which can be in turn, tuned by the microflora composition of our gut, ultimately controlling the rate of deconjugation of the BS.

Aflatoxin B1 induces liver injury by disturbing gut microbiota-bile acid-FXR axis in mice.

Aflatoxin B1 (AFB1) is one of major pollutant in food and feed worldwide. The purpose of this study is to investigate the mechanism of AFB1-induced liver injury. Our results showed that AFB1 caused hepatic bile duct proliferation, oxidative stress, inflammation and liver injury in mice. AFB1 exposure induced gut microbiota dysbiosis and reduced fecal bile salt hydrolase (BSH) activity. AFB1 exposure promoted hepatic bile acid (BA) synthesis and changed intestinal BA metabolism, especially increased intestinal conjugated bile acids levels. AFB1 exposure inhibited intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) signaling. Furthermore, the mice received fecal microbiota transplantation from AFB1-treated mice induced liver injury, reduced intestinal FXR signaling and increased hepatic BA synthesis. Finally, the intestine-restricted FXR agonist treatment decreased hepatic BA synthesis, ROS level, inflammation and liver injury in AFB1-treated mice. This study suggests that modifying the gut microbiota, altering intestinal BA metabolism and/or activating intestinal FXR/FGF-15 signaling may be of value for the treatment of AFB1-induced liver disease.

Ethnicity Associated Microbial and Metabonomic Profiling in Newly Diagnosed Ulcerative Colitis.

Ulcerative colitis (UC) differs across geography and ethnic groups. Gut microbial diversity plays a pivotal role in disease pathogenesis and differs across ethnic groups. The functional diversity in microbial-driven metabolites may have a pathophysiologic role and offer new therapeutic avenues. Demographics and clinical data were recorded from newly diagnosed UC patients. Blood, urine and faecal samples were collected at three time points over one year. Bacterial content was analysed by 16S rRNA sequencing. Bile acid profiles and polar molecules in three biofluids were measured using liquid-chromatography mass spectrometry (HILIC) and nuclear magnetic resonance spectroscopy. We studied 42 patients with a new diagnosis of UC (27 South Asians; 15 Caucasians) with 261 biosamples. There were significant differences in relative abundance of bacteria at the phylum, genus and species level. Relative concentrations of urinary metabolites in South Asians were significantly lower for hippurate (positive correlation for Ruminococcus) and 4-cresol sulfate (Clostridia) (p<0.001) with higher concentrations of lactate (negative correlation for Bifidobacteriaceae). Faecal conjugated and primary conjugated bile acids concentrations were significantly higher in South Asians (p=0.02 and p=0.03 respectively). Results were unaffected by diet, phenotype, disease severity and ongoing therapy. Comparison of time points at diagnosis and at 1 year did not reveal changes in microbial and metabolic profile. Ethnic-related microbial metabolite associations were observed in South Asians with UC. This suggests a predisposition to UC may be influenced by environmental factors reflected in a distinct gene-environment interaction. The variations may serve as markers to identify risk factors for UC and modified to enhance therapeutic response.

Versatile Triad Alliance: Bile Acid, Taurine and Microbiota.

Taurine is the most abundant free amino acid in the body, and is mainly derived from the diet, but can also be produced endogenously from cysteine. It plays multiple essential roles in the body, including development, energy production, osmoregulation, prevention of oxidative stress, and inflammation. Taurine is also crucial as a molecule used to conjugate bile acids (BAs). In the gastrointestinal tract, BAs deconjugation by enteric bacteria results in high levels of unconjugated BAs and free taurine. Depending on conjugation status and other bacterial modifications, BAs constitute a pool of related but highly diverse molecules, each with different properties concerning solubility and toxicity, capacity to activate or inhibit receptors of BAs, and direct and indirect impact on microbiota and the host, whereas free taurine has a largely protective impact on the host, serves as a source of energy for microbiota, regulates bacterial colonization and defends from pathogens. Several remarkable examples of the interaction between taurine and gut microbiota have recently been described. This review will introduce the necessary background information and lay out the latest discoveries in the interaction of the co-reliant triad of BAs, taurine, and microbiota.

Predictive value of serum bile acids as metabolite biomarkers for liver cirrhosis: a systematic review and meta-analysis.

A large number of studies have explored the potential biomarkers for detecting liver cirrhosis in an early stage, yet consistent conclusions are still warranted. To conduct a review and a meta-analysis of the existing studies that test the serum level of bile acids in cirrhosis as the potential biomarkers to predict cirrhosis. Six databases had been searched from inception date to April 12, 2021. Screening and selection of the records were based on the inclusion criteria. The risk of bias was assessed with the Newcastle-Ottawa quality assessment scale (NOS). Mean difference (MD) and confidence intervals 95% (95% CI) were calculated by using the random effect model for the concentrations of bile acids in the meta-analysis, and I2 statistic was used to measure studies heterogeneity. This study was registered on PROSPERO. A total of 1583 records were identified and 31 studies with 2679 participants (1263 in the cirrhosis group, 1416 in the healthy control group) were included. The quality of included studies was generally high, with 25 studies (80.6%) rated over 7 stars. A total of 45 bile acids or their ratios in included studies were extracted. 36 increased in the cirrhosis group compared with those of the healthy controls by a qualitative summary, 5 decreased and 4 presented with mixing results. The result of meta-analysis among 12 studies showed that 13 bile acids increased, among which four primary conjugated bile acids showed the most significant elevation in the cirrhosis group: GCDCA (MD = 11.38μmol/L, 95% CI 8.21-14.55, P < 0.0001), GCA (MD = 5.72μmol/L, 95% CI 3.47-7.97, P < 0.0001), TCDCA (MD = 3.57μmol/L, 95% CI 2.64-4.49, P < 0.0001) and TCA (MD = 2.14μmol/L, 95% CI 1.56-2.72, P < 0.0001). No significant differences were found between the two groups in terms of DCA (MD = -0.1μmol/L, 95% CI -0.18 to -0.01, P < 0.0001) and LCA (MD = -0.01μmol/L, 95% CI -0.01 to -0.02, P < 0.0001), UDCA (MD = -0.14μmol/L, 95% CI -0.04 to -0.32, P < 0.0001), and TLCA (MD = 0μmol/L, 95% CI 0-0.01, P < 0.0001). Subgroup analysis in patients with hepatitis B cirrhosis showed similar results. Altered serum bile acids profile seems to be associated with cirrhosis. Some specific bile acids (GCA, GCDCA, TCA, and TCDCA) may increase with the development of cirrhosis, which possibly underlay their potential role as predictive biomarkers for cirrhosis. Yet this predictive value still needs further investigation and validation in larger prospective cohort studies.

Dietary fiber-based regulation of bile salt hydrolase activity in the gut microbiota and its relevance to human disease

ABSTRACT Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

Systemic bile acids potentiate airway hyperresponsiveness and modulate Th17 cell function in obesity-associated asthma

Abstract Obesity-associated asthma is phenotypically characterized by low grade inflammation and resistance to standard therapies. Like many other asthma endotypes, the molecular mechanisms contributing to obesity-associated asthma are diverse and ambiguous. A panoply of metabolites that act as signaling mediators are altered by obesity and may also promote lung dysfunction and a pro-asthma phenotype. Recent metabolomics studies indicate that bile acid profiles are altered in individuals with asthma, thus these metabolites were investigated in a murine model of obesity-associated asthma and clinically. In obese mice with allergic airway disease (AAD), the levels of β-muricholic acid (βMCA) and tauro-β-muricholic (tβMCA) were significantly increased in serum and positively correlated with impaired lung function. Two conjugated bile acids, glycocholic acid (GCA) and glycoursodeoxycholic acid (GUDCA), were elevated in the plasma of high body mass index (BMI) individuals and correlated with both BMI and airway hyperreactivity as measured by FEV1, forced expiratory volume in one second. In vitro differentiated T helper (Th) cells were treated with tβMCA and βMCA, which resulted in changes in T cell metabolism that were specific to Th17 cells. In addition, tβMCA treatment increased IL-17 production from Th17 cells upon stimulation. Finally, the anti-inflammatory and metabolic regulatory activities of nitro-oleic acid (NO2-OA) were evaluated in the murine model of obesity-associated asthma. NO2-OA reduced levels of βMCA and tβMCA, with a concomitant reduction in tissue resistance and elastance, providing a potential approach to improving the current standard of care for obese individuals with asthma. Supported by R01HL146445 (MLM), S10OD023402 (SGW), R61HL157069 (SGW, BAF, FH), R01HL132550 (BAF)

Primary bile acid activates Egr‑1 expression through the MAPK signaling pathway in gastric cancer.

Bile acids have been linked to pathomechanism and prognosis in various types of cancers. The present study aimed to investigate the effect of bile acids on the molecular change in gastric epithelial cancer cells and to evaluate gastric bile acid concentration in patients with early gastric cancer (EGC). Human gastric cancer cells (AGS and NCI-N87 cell lines) were treated with several bile acid types to determine their effect on molecular changes in the cells. Gastric levels of individual bile acids were measured (primary unconjugated or conjugated bile acids and secondary bile acids) in 39 participants (20 controls and 19 patients with EGC). Exposing gastric epithelial cancer cells to primary bile acids in vitro upregulated the expression of early growth response factor 1 (Egr-1) and the oncogenes including c-Jun, c-Myc and Snail, whereas a p42/44 MAPK inhibitor exposure reduced their expression. There was a significant difference in age and presence of atrophic gastritis with intestinal metaplasia in background mucosa between controls and patients with EGC. There were significant differences in the levels of unconjugated or conjugated primary bile acids between controls and EGC patients except lithocholic acid. After adjustment of age and presence of atrophic gastritis with intestinal metaplasia, the levels of cholic acid [adjusted odds ratio (aOR) 4.3; 95% confidence interval (CI): 1.2-16.2; P=0.029] and glycochenodeoxycholic acid [aOR 9.9; 95% CI: 1.3-75.3; P=0.027] were significantly higher in patients with EGC compared with controls. In conclusion, bile acids upregulate Egr-1 in gastric cancer cells via the MAPK signaling pathway, and higher gastric levels of primary bile acids are associated with EGC. Therefore, exposure of gastric cells to primary bile acids may play a role in gastric carcinogenesis.

Bile Acids, Gut Microbiome and the Road to Fatty Liver Disease.

This article describes the complex interactions occurring between diet, the gut microbiome, and bile acids in the etiology of fatty liver disease. Perhaps 25% of the world's population may have nonalcoholic fatty liver disease (NAFLD) and a significant percentage (∼20%) of these individuals will progress to nonalcoholic steatohepatitis (NASH). Currently, the only recommended treatment for NAFLD and NASH is a change in diet and exercise. A Western-type diet containing high fructose corn syrup, fats, and cholesterol creates gut dysbiosis, increases intestinal permeability and uptake of LPS causing low-grade chronic inflammation in the body. Fructose is a "lipogenic" sugar that induces long-chain fatty acid (LCFA) synthesis in the liver. Inflammation decreases the oxidation of LCFA, allowing fat accumulation in hepatocytes. Hepatic bile acid transporters are downregulated by inflammation slowing their enterohepatic circulation and allowing conjugated bile acids (CBA) to increase in the serum and liver of NASH patients. High levels of CBA in the liver are hypothesized to activate sphingosine-1-phosphate receptor 2 (S1PR2), activating pro-inflammatory and fibrosis pathways enhancing NASH progression. Because inflammation appears to be a major physiological driving force in NAFLD/NASH, new drugs and treatment protocols may require the use of anti-inflammatory compounds, such as berberine, in combination with bile acid receptor agonists or antagonists. Emerging new molecular technologies may provide guidance in unraveling the complex physiological pathways driving fatty liver disease and better approaches to prevention and treatment. © 2021 American Physiological Society. Compr Physiol 11:1-12, 2021.

Evaluation on absorption risks of amentoflavone after oral administration in rats.

The present study was aimed to systemically assess the absorption risks of amentoflavone (AMF). Physicochemical properties of AMF were evaluated using in vitro assays including water solubility and stability in both simulated gastric and intestinal fluids, as well as logD, pka and permeability studies in a monolayer Caco-2 model. The results together suggested that AMF was a compound with moderate intestinal absorption and the poor solubility was the key rate-limiting step for the oral absorption of AMF, and PVP-K30 were thus used as a solubilizer to improve its solubility and oral bioavailability. Furthermore, studies on pharmacokinetics and biliary excretion of AMF with tween 80 or PVP-K30 were performed after oral administration, and the results showed that the percentage of AMF conjugates in bile was determined up to be 96.73% and no AMF conjugates were detected in rat plasma. The above results revealed that the poor oral absorption of AMF may probably be attributed to the low solubility, high level of metabolism and hepatic first-pass effects. The relative bioavailability of AMF solubilized by PVP-K30 was about 2-fold than that of AMF suspended in 1% tween 80. The present study may help provide scientific insights to guide the rational design of AMF into more efficient formulation systems.

Dominant Bacterial Phyla from the Human Gut Show Widespread Ability To Transform and Conjugate Bile Acids.

Gut bacteria influence human physiology by chemically modifying host-synthesized primary bile acids. These modified bile acids, known as secondary bile acids, can act as signaling molecules that modulate host lipid, glucose, and energy metabolism and affect gut microbiota composition via selective antimicrobial properties. However, knowledge regarding the bile acid-transforming capabilities of individual gut microbes remains limited. To help address this knowledge gap, we screened 72 bacterial isolates, spanning seven major phyla commonly found in the human gut, for their ability to chemically modify unconjugated bile acids. We found that 43 isolates, representing 41 species, were capable of in vitro modification of one or more of the three most abundant unconjugated bile acids in humans: cholic acid, chenodeoxycholic acid, and deoxycholic acid. Of these, 32 species have not been previously described as bile acid transformers. The most prevalent bile acid transformations detected were oxidation of 3α-, 7α-, or 12α-hydroxyl groups on the steroid core, a reaction catalyzed by hydroxysteroid dehydrogenases. In addition, we found 7α-dehydroxylation activity to be distributed across various bacterial genera, and we observed several other complex bile acid transformations. Finally, our screen revealed widespread bacterial conjugation of primary and secondary bile acids to glycine, a process that was thought to only occur in the liver, and to 15 other amino acids, resulting in the discovery of 44 novel microbially conjugated bile acids. IMPORTANCE Our current knowledge regarding microbial bile acid transformations comes primarily from biochemical studies on a relatively small number of species or from bioinformatic predictions that rely on homology to known bile acid-transforming enzyme sequences. Therefore, much remains to be learned regarding the variety of bile acid transformations and their representation across gut microbial species. By carrying out a systematic investigation of bacterial species commonly found in the human intestinal tract, this study helps better define the gut bacteria that impact composition of the bile acid pool, which has implications in the context of metabolic disorders and cancers of the digestive tract. Our results greatly expand upon the list of bacterial species known to perform different types of bile acid transformations. This knowledge will be vital for assessing the causal connections between the microbiome, bile acid pool composition, and human health.

SEX AND SALT-RESPONSIVE CONJUGATION OF BILE ACIDS BY THE HOLOBIONT REGULATES HYPERTENSION

Objective: Men and women are differently prone to cardiovascular diseases. Salt-sensitive women are more likely to develop aggravated hypertension in response to an overloaded salt diet than men. Men and women also differ in gut microbiota, which regulates both bile acid composition and hypertension; however, whether sex may differentially influence the gut microbial production of bile acids, with attendant effects on hypertension, is not known. We hypothesized that reshaping of gut microbiota by dietary salt is sex-dependent and adversely affects bile acids to promote hypertension. Design and method: To test this hypothesis, groups of male and female salt-sensitive hypertensive (Dahl S) and salt-resistant normotensive (Dahl R) rats (n = 6/gp) on low (0.3% NaCl) or high (2% NaCl) diets were profiled for fecal microbiota by 16S sequencing and serum bile acids by targeted GC-TOF-MS metabolomics. Results: Hierarchical clustering analysis of bile acids with microbiotal profiles revealed that glycine- and taurine-conjugated bile acids were prominently negatively correlated with blood pressure (BP) in female rats, while only taurine-conjugated bile acids were negatively correlated with BP in male rats. These observations were corroborated by microbiotal and bile acid metabolomic profiling of human hypertensive samples from a population-based cohort (CARDIA). Next, to test whether hypertension can be prevented by supplementing substrates for bile acid conjugation, high salt fed S rats were administered with either taurine (3% v/v in drinking water) or glycine (1% v/v in drinking water) in drinking water, monitored for BP by telemetry, and profiled for bile acid metabolites. Both taurine and glycine feeding prevented hypertension in females (Systolic BP: taurine:176 ± 7∗, glycine: 182 ± 4∗, control: 197 ± 4 mmHg, n = 6–9/gp, ∗p &lt; 0.05) likely by rescuing levels of levels of respective conjugated bile acids, whereas only taurine, but not glycine, prevented hypertension in males (Systolic BP: taurine: 166 ± 2∗, glycine:184 ± 5, control: 184 ± 8 mmHg, n = 5–6/gp, ∗p &lt; 0.05). Conclusions: Our results connect sex-specific differences in salt-sensitive hypertension to the gut-liver axis and suggests that nutritional restoration of host taurine- or glycine-conjugated bile acids for women and host taurine-conjugated bile acids for men as potential therapeutics for salt-sensitive hypertension.

The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection.

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

Short communication: Chemical structure, concentration, and pH are key factors influencing antimicrobial activity of conjugated bile acids against lactobacilli

Effects of chemical structure, concentration, and pH on antimicrobial activity of conjugated bile acids were investigated in 4 strains of lactobacilli. Considerable differences were observed in the antimicrobial activity between the 6 human conjugated bile acids, including glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, and taurochenodeoxycholic acid. Glycodeoxycholic acid and glycochenodeoxycholic acid generally showed significantly higher antimicrobial activity against the lactobacilli, but glycocholic acid and taurocholic acid exhibited the significantly lower antimicrobial activity. Glycochenodeoxycholic acid was selected for further analysis, and the results showed its antimicrobial activity was concentration-dependent, and there was a significantly negative linear correlation (R2 > 0.98) between bile-antimicrobial index and logarithmic concentration of the bile acid for each strain of lactobacilli. Additionally, the antimicrobial activity of glycochenodeoxycholic acid was also observed to be pH-dependent, and it was significantly enhanced with the decreasing pH, with the result that all the strains of lactobacilli were unable to grow at pH 5.0. In conclusion, chemical structure, concentration, and pH are key factors influencing antimicrobial activity of conjugated bile acids against lactobacilli. This study provides theoretical guidance and technology support for developing a scientific method for evaluating the bile tolerance ability of potentially probiotic strains of lactobacilli.

Gut Microbes Take It to the Next Level? First Insights Into Farnesoid X Receptor Agonists of Microbial Origin.

The intestinal microbiome and its metabolites contribute to host (patho)physiology through signaling via host bile salt receptors(1) . To assess the overall chemical effects of the microbiome at the level of an entire animal, Quinn et al. conducted untargeted metabolome analysis of 29 different organs of germ-free and specific pathogen-free (SPF) mice. [Quinn RA, Melnik AV, Vrbanac A et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 2020;579:123-129] Unique microbial and metabolome profiles were evident along the GI tract.

Taurine Improves Lipid Metabolism and Increases Resistance to Oxidative Stress.

Calorie restriction (CR) by 30-40% decreases morbidity of age-related diseases and prolongs the lifespan of various laboratory animal species. Taurine (2-aminoethanesulfonic acid) is an important nutrient for lipid metabolism as it conjugates bile acids. Here, we investigated how taurine supplementation induces effects similar to the CR beneficial effects. Sprague Dawley rats were fed a diet containing different taurine concentrations (0, 0.5, 1.0, 3.0, 5.0%) to analyze the effects on growth, blood, and hepatic parameters. Rats fed a 5% taurine-supplemented diet showed a significant decrease in visceral fat weight, compared with control rats. Moreover, there were significant decreases in the serum total cholesterol, hepatic cholesterol and triglyceride concentrations in the taurine-supplemented groups compared with the control group in a dose-dependent manner. These results were associated with decreased mRNA expression of fatty acid synthase, and increased mRNA expression of carnitine palmitoyltransferase 1α. C57BL/6 mice were fed a 5.0% taurine-supplemented diet, and their response to 3-nitropropionic acid-induced oxidative stress was analyzed. The rate of weight loss due to oxidative stress decreased and the survival rate significantly increased in the taurine-supplemented groups compared with the control group. Finally, cells were treated with 100 μM taurine and their resistance to UV-induced oxidative stress was analyzed. We found that the p53-Chk1 pathway was less activated in taurine-treated cells compared with control cells. Furthermore, damage to cells evaluated by oxidative stress indicators revealed a reduction in oxidative damage with taurine treatment. These findings suggest that taurine partially acts as a CR mimetic.

Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-β and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.