Host Bile Acid Research Articles

Metabolic immaturity and breastmilk bile acid metabolites are central determinants of heightened newborn vulnerability to norovirus diarrhea

The pathogenic outcome of enteric virus infections is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors, with metabolites serving as a key mediator. Noroviruses bind bile acid metabolites, which are produced by the host and then modified by commensal bacteria. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Working in an infant mouse model of norovirus infection, we demonstrate that microbiota and their bile acid metabolites protect from norovirus diarrhea, whereas host bile acids promote disease. We also find that maternal bile acid metabolism determines the susceptibility of newborn mice to norovirus diarrhea during breastfeeding. Finally, targeting maternal and neonatal bile acid metabolism can protect newborn mice from norovirus disease. In summary, neonatal metabolic immaturity and breastmilk bile acids are central determinants of heightened newborn vulnerability to norovirus disease.

Biliary atresia: the role of gut microbiome, and microbial metabolites.

Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases.

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.

Gallbladder microbial species and host bile acids biosynthesis linked to cholesterol gallstone comparing to pigment individuals.

Gallstones are crystalline deposits in the gallbladder that are traditionally classified as cholesterol, pigment, or mixed stones based on their composition. Microbiota and host metabolism variances among the different types of gallstones remain largely unclear. Here, the bile and gallstone microbial species spectra of 29 subjects with gallstone disease (GSD, 24 cholesterol and 5 pigment) were revealed by type IIB restriction site-associated DNA microbiome sequencing (2bRAD-M). Among them (21 subjects: 18 cholesterol and 3 pigment), plasma samples were subjected to liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics. The microbiome yielded 896 species comprising 882 bacteria, 13 fungi, and 1 archaeon. Microbial profiling revealed significant enrichment of Cutibacterium acnes and Microbacterium sp005774735 in gallstone and Agrobacterium pusense and Enterovirga sp013044135 in the bile of cholesterol GSD subjects. The metabolome revealed 2296 metabolites, in which malvidin 3-(6''-malonylglucoside), 2-Methylpropyl glucosinolate, and ergothioneine were markedly enriched in cholesterol GSD subjects. Metabolite set enrichment analysis (MSEA) demonstrated enriched bile acids biosynthesis in individuals with cholesterol GSD. Overall, the multi-omics analysis revealed that microbiota and host metabolism interaction perturbations differ depending on the disease type. Perturbed gallstone type-related microbiota may contribute to unbalanced bile acids metabolism in the gallbladder and host, representing a potential early diagnostic marker and therapeutic target for GSD.

Akkermansia muciniphila might improve anti-PD-1 therapy against HCC by changing host bile acid metabolism.

PD-1 monoclonal antibodies (mAb) have demonstrated remarkable efficacy in a variety of cancers, including Hepatocellular carcinoma (HCC). However, the patient response rates remain suboptimal, and a significant proportion of initial responders may develop resistance to this therapeutic approach. Akkermansia muciniphila (AKK), a microorganism implicated in multiple human diseases, has been reported to be more abundant in patients who exhibit favorable responses to PD-1mAb. However, the underlying mechanism has yet to be elucidated. In our study, we found that AKK could enhance the efficacy of PD-1mAb against HCC in a tumor-bearing mouse model. It promotes HCC tumor cells apoptosis and raise the CD8+ T proportion in the tumor microenvironment. Additionally, AKK downregulates PD-L1 expression in tumor cells. Furthermore, the analysis of metabonomics demonstrates that AKK induces alterations in the host's bile acid metabolism, leading to a significant increase in serum TUDCA levels. Considering the immunosuppresive roles of TUDCA in HCC development, it is plausible to speculate that AKK may reinforce the immunotherapy of PD-1mAb against HCC through its impact on bile acid metabolism.

Clostridium butyricum Strain CCFM1299 Reduces Obesity via Increasing Energy Expenditure and Modulating Host Bile Acid Metabolism.

Clostridium butyricum is a butyrate-producing microorganism which has beneficial effects on various diseases, including obesity. In our previous study, the anti-obesity Clostridium butyricum strain CCFM1299 (C20_1_1) was selected, but its anti-obesity mechanism was not clarified. Herein, CCFM1299 was orally administrated to high-fat-diet-treated C57BL/6J mice for 12 weeks to uncover the way the strain alleviates obesity. The results indicated that CCFM1299 alleviated obesity through increasing the energy expenditure and increasing the expression of genes related to thermogenesis in brown adipose tissue (BAT). Moreover, strain CCFM1299 could also affect the expression of immune-related genes in epididymal white adipose tissue (eWAT). This immunomodulatory effect might be achieved through its influence on the complement system, as the expression of the complement factor D (CFD) gene decreased significantly. From the view of metabolites, CCFM1299 administration increased the levels of ursodeoxycholic acid (UDCA) in feces and taurohyodeoxycholic acid (THDCA) in serum. Together, the anti-obesity potential of CCFM1299 might be attributed to the increase in energy consumption, the regulation of immune-related gene expression in eWAT, and the alteration of bile acid metabolism in the host. These provided new insights into the potential application of anti-obesity microbial preparations and postbiotics.

Altered gut microbiota–host bile acid metabolism in IBS-D patients with liver depression and spleen deficiency pattern

BackgroundDysregulation of gut microbiota–host bile acid (BA) co-metabolism is a critical pathogenic factor of diarrhea-predominant irritable bowel syndrome (IBS-D). Traditional Chinese Medicine (TCM), instructed by pattern differentiation, is effective in treating IBS-D, in which liver depression and spleen deficiency (LDSD) is the most prevalent pattern. Still, it is unclear the linkage between the LDSD pattern and the BA metabolic phenotype.PurposeThis study aimed to uncover the biological basis of the LDSD pattern from the BA metabolic perspective.MethodsPatients with IBS-D completed questionnaires regarding the irritable bowel severity scoring system (IBS-SSS), stool frequency, Stool Bristol scale, and Self-Rating Scales of mental health. Fasting blood and morning feces were collected to analyze the gut metagenome and BA-related indices/metabolites.ResultsIBS-D patients with LDSD had a higher incidence of BA overexcretion (41% vs. 23% non-LDSD) with significant elevations in fecal total BAs and serum BA precursor 7α-hydroxy-4-cholesten-3-one levels. Compared to controls or non-LDSD patients, LDSD patients had a featured fecal BA profile, with higher proportions of deoxycholic acid (DCA), 7-ketodeoxycholic acid, and lithocholic acid. It is consistent with the BA-metabolizing genomic changes in the LDSD gut microbiota characterized by overabundances of 7-dehydroxylating bacteria and BA-inducible genes (baiCD/E/H). The score of bowel symptoms (stool frequency and abdominal pain) showing greater severity in the LDSD pattern were positively correlated with bai-expressing bacterial abundances and fecal DCA levels separately.ConclusionWe clarified a differed BA metabolic phenotype in IBS patients with LDSD, which closely correlates with the severity of bowel symptoms. It demonstrates that gut microbiota and host co-metabolism of BAs would provide crucial insight into the biology of the LDSD pattern and its internal relationship with IBS progression.

Study of the Human Microbiota Under Physiological Conditions

Profiling the human intestinal environment under physiological conditions involves characterizing the various components and factors in the gut to understand its normal functioning. This profiling can encompass multiple aspects, including the microbiome, host immune response, metabolites, and the physical environment of the intestine. Shalon and colleagues developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. The collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins, and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched, and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in the stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins, and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease. Nature. 2023 May;617(7961):581-591. doi: 10.1038/s41586-023-05989-7.

Gut microbiota Turicibacter strains differentially modify bile acids and host lipids

Bacteria from the Turicibacter genus are prominent members of the mammalian gut microbiota and correlate with alterations in dietary fat and body weight, but the specific connections between these symbionts and host physiology are poorly understood. To address this knowledge gap, we characterize a diverse set of mouse- and human-derived Turicibacter isolates, and find they group into clades that differ in their transformations of specific bile acids. We identify Turicibacter bile salt hydrolases that confer strain-specific differences in bile deconjugation. Using male and female gnotobiotic mice, we find colonization with individual Turicibacter strains leads to changes in host bile acid profiles, generally aligning with those produced in vitro. Further, colonizing mice with another bacterium exogenously expressing bile-modifying genes from Turicibacter strains decreases serum cholesterol, triglycerides, and adipose tissue mass. This identifies genes that enable Turicibacter strains to modify host bile acids and lipid metabolism, and positions Turicibacter bacteria as modulators of host fat biology.

Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, had no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, was demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA in NAFLD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) and fecal microbiota transplantation (FMT) confirmed the critical role of gut microbiota in OCA treatment for NAFLD by effectively alleviating histopathological lesions and restoring liver function impaired by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia muciniphila, Bifidobacterium spp., Bacteroides spp., Alistipes spp., Lactobacillus spp., Streptococcus thermophilus, and Parasutterella excrementihominis. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing levels of serum hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of serum-conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the HFD-fed mice. Strong correlations were observed between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched by OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) mainly responsible for primary bile acid deconjugation. In conclusion, this study demonstrated that OCA intervention altered gut microbiota composition with specially enriched gut microbes modulating host bile acids, thus effectively alleviating NAFLD in the mice.

Profiling the human intestinal environment under physiological conditions

The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

Gut microbiome-derived isodeoxycholic acid promotes mucosal immune non-responsiveness

Abstract Perturbations to the commensal gut microbiota are associated with the increasing prevalence of food allergies. Our lab has reported that colonization of germ-free mice with feces from healthy, but not cow’s milk allergic, infants protects against anaphylaxis to a cow’s milk allergen. Protection was associated with higher levels of the secondary bile acid (SBA) isodeoxycholic acid (isoDCA) in the feces of healthy-colonized mice. IsoDCA has been reported to induce regulatory T cells (Tregs) which suppress inflammation. We hypothesize that isoDCA-driven induction of mucosal Tregs promotes non-responsiveness and protects against food allergy. To study this, we identified two Clostridiaspecies, Peptacetobacter hiranonisand Ruminococcus gnavus, that together produce isoDCA from taurocholic acid (TCA), an abundant host bile acid. Using a Group II intron-based system, we engineered R. gnavus Δrumgna_00694, a functional knock-out of a 3β-hydroxysteroid dehydrogenase required to produce isoDCA. In our system, P. hiranonisconverts TCA to deoxycholic acid (DCA) and R. gnavusWT, but not Δrumgna_00694, converts DCA to isoDCA. Ongoing experiments will compare isoDCA-dependent Treg induction in gut-associated lymphoid tissues of mice co-colonized with P. hiranonisand R. gnavusWT or Δrumgna_00694. Once optimized, this system can be used in our allergic sensitization model to investigate the role of SBA in protection against food allergy and maintenance of intestinal homeostasis.

Chlorothalonil induces obesity in mice by regulating host gut microbiota and bile acids metabolism via FXR pathways

As the most commonly used organochlorine pesticide nowadays, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet. This study found that the CHI based on ADI level could induce obesity in mice. In addition, CHI could induce an imbalance in the gut microbiota of mice. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the CHI could induce obesity in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, CHI could disturb the bile acids (BAs) metabolism of mice, causing the inhibition of the signal response of BAs receptor FXR and leading to glycolipid metabolism disorders in liver and epiWAT of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the CHI-induced obesity in mice. In conclusion, CHI was found to induce obesity in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of obesity, demonstrating the key role of gut microbiota in the toxic effects of pesticides.

Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that is characterized by increased serum bile acid and adverse fetal outcomes. The aetiology and mechanism of ICP are poorly understood; thus, existing therapies have been largely empiric. Here we show that the gut microbiome differed significantly between individuals with ICP and healthy pregnant women, and that colonization with gut microbiome from ICP patients was sufficient to induce cholestasis in mice. The gut microbiomes of ICP patients were primarily characterized by Bacteroides fragilis (B. fragilis), and B. fragilis was able to promote ICP by inhibiting FXR signaling via its BSH activity to modulate bile acid metabolism. B. fragilis-mediated FXR signaling inhibition was responsible for excessive bile acid synthesis and interrupted hepatic bile excretion to ultimately promote the initiation of ICP. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of value for ICP treatment.

Modulation of gut microbiota and fecal metabolites by corn silk among high-fat diet-induced hypercholesterolemia mice.

Corn silk (CS) is known to reduce cholesterol levels, but its underlying mechanisms remain elusive concerning the gut microbiota and metabolites. The aim of our work was to explore how altered gut microbiota composition and metabolite profile are influenced by CS intervention in mice using integrated 16S ribosomal RNA (rRNA) sequencing and an untargeted metabolomics methodology. The C57BL/6J mice were fed a normal control diet, a high-fat diet (HFD), and HFD supplemented with the aqueous extract of CS (80 mg/mL) for 8 weeks. HFD-induced chronic inflammation damage is alleviated by CS extract intervention and also resulted in a reduction in body weight, daily energy intake as well as serum and hepatic total cholesterol (TC) levels. In addition, CS extract altered gut microbial composition and regulated specific genera viz. Allobaculum, Turicibacter, Romboutsia, Streptococcus, Sporobacter, Christensenella, ClostridiumXVIII, and Rikenella. Using Spearman’s correlation analysis, we determined that Turicibacter and Rikenella were negatively correlated with hypercholesterolemia-related parameters. Fecal metabolomics analysis revealed that CS extract influences multiple metabolic pathways like histidine metabolism-related metabolites (urocanic acid, methylimidazole acetaldehyde, and methiodimethylimidazoleacetic acid), sphingolipid metabolism-related metabolites (sphinganine, 3-dehydrosphinganine, sphingosine), and some bile acids biosynthesis-related metabolites including chenodeoxycholic acid (CDCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and glycoursodeoxycholic acid (GUDCA). As a whole, the present study indicates that the modifications in the gut microbiota and subsequent host bile acid metabolism may be a potential mechanism for the antihypercholesterolemic effects of CS extract.

Comparative effect of ciprofloxacin and moxifloxacin on the modulation of bile acid profiles and gut microbiota in rats

Fluoroquinolones are an important class of antimicrobial agents to manage infectious diseases. However, knowledge about how host bile acids are modified by fluoroquinolones is limited. We investigated and compared the impact of fluoroquinolones on circulating bile acid profiles and gut microbiota from in vivo studies. We administered ciprofloxacin (100 mg/kg/day) or moxifloxacin (40 mg/kg/day) orally to male Wistar rats for seven days. Fifteen bile acids (BAs) from the serum and large intestine were quantified by HPLC-MS/MS. The diversity of gut microbiota after ciprofloxacin and moxifloxacin treatment was analyzed using high-throughput, next-generation sequencing technology. The two fluoroquinolone-treated groups had different BA profiles. Ciprofloxacin significantly reduced the hydrophobicity index of the BA pool, reduced secondary BAs, and increased taurine-conjugated primary BAs in both the serum and large intestine as compared with moxifloxacin. Besides, ciprofloxacin treatment altered intestinal microbiota with a remarkable increase in Firmicutes to Bacteroidetes ratio, while moxifloxacin exerted no effect. What we found suggests that different fluoroquinolones have a distinct effect on the host BAs metabolism and intestinal bacteria, and therefore provide guidance on the selection of fluoroquinolones to treat infectious diseases.

Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease.

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.

Inclusion of Soluble Fiber During Gestation Regulates Gut Microbiota, Improves Bile Acid Homeostasis, and Enhances the Reproductive Performance of Sows

Interaction between the dietary fiber and the gut microbes can regulate host bile acid metabolism. This study sought to explore the effects of guar gum combined with pregelatinized waxy maize starch (GCW) in a gestation diet on reproductive performance, gut microbiota composition, and bile acid homeostasis of sows. A total of 61 large white sows were randomly grouped into the control (n = 33) and 2% GCW (n = 28) groups during gestation. GCW diet increased birth-weight of piglets, and decreased the percentage of intrauterine growth restriction (IUGR) piglets. In addition, dietary GCW reduced gut microbial diversity and modulated gut microbial composition in sows on day 109 of gestation. The relative abundance of bile salt hydrolase (BSH) gene-encoding bacteria, Lactobacillus and Bacteroides decreased after GCW administration, whereas no significant difference was observed in the fecal level of total glycine-conjugated and taurine-conjugated bile acids between the two groups. Dietary GCW increased the relative abundance of Ruminococcaceae (one of few taxa comprising 7α-dehydroxylating bacteria), which was associated with elevated fecal deoxycholic acid (DCA) in the GCW group. GCW administration lowered the concentrations of plasma total bile acid (TBA) and 7α-hydroxy-4-cholesten-3-one (C4) (reflecting lower hepatic bile acid synthesis) at day 90 and day 109 of gestation compared with the control diet. Furthermore, the levels of plasma glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA) and glycohyocholic acid (GHCA) were lower in the GCW group compared with the control group. Spearman correlation analysis showed alterations in the composition of the gut microbiota by GCW treatment was associated with improved bile acid homeostasis and reproductive performance of sows. In conclusion, GCW-induced improves bile acid homeostasis during gestation which may enhance reproductive performance of sows.

Distinct Bile Acid Profiles in Patients With Chronic Hepatitis B Virus Infection Reveal Metabolic Interplay Between Host, Virus and Gut Microbiome.

Hepatitis B virus (HBV) can hijack the host bile acids (BAs) metabolic pathway during infection in cell and animal models. Additionally, microbiome was known to play critical role in the enterohepatic cycle of BAs. However, the impact of HBV infection and associated gut microbiota on the BA metabolism in chronic hepatitis B (CHB) patients is unknown. This study aimed to unveil the distinct BA profiles in chronic HBV infection (CHB) patients with no or mild hepatic injury, and to explore the relationship between HBV, microbiome and BA metabolism with clinical implications.Methods: Serum BA profiles were compared between CHB patients with normal ALT (CHB-NALT, n = 92), with abnormal ALT (CHB-AALT, n = 34) and healthy controls (HCs, n = 28) using UPLC-MS measurement. Hepatic gene expression in CHB patients were explored using previously published transcriptomic data. Fecal microbiome was compared between 30 CHB-NALT and 30 HCs using 16S rRNA sequencing, and key microbial function was predicted by PICRUSt analysis.Results: Significant higher percentage of conjugated BAs and primary BAs was found in CHB patients even without apparent liver injury. Combinatory BA features can discriminate CHB patients and HCs with high accuracy (AUC = 0.838). Up-regulation of BA importer Na+ taurocholate co-transporting peptide (NTCP) and down-regulation of bile salt export pump (BSEP) was found in CHB-NALT patients. The microbial diversity and abundance of Lactobacillus, Clostridium, Bifidobacterium were lower in CHB-NALT patients compared to healthy controls. Suppressed microbial bile salt hydrolases (BSH), 7-alpha-hydroxysteroid dehydrogenase (hdhA) and 3-dehydro-bile acid Delta 4, 6-reductase (BaiN) activity were found in CHB-NALT patients.Conclusion: This study provides new insight into the BA metabolism influenced both by HBV infection and associated gut microbiome modulations, and may lead to novel strategy for clinical management for chronic HBV infection.