Gut-liver Crosstalk Research Articles

Intestinal and hepatic benefits of BBR-EVO on DSS-induced experimental colitis in mice.

Ulcerative colitis (UC), characterized by disrupted intestinal barrier integrity and chronic inflammation, was modeled in mice via dextran sulfate sodium (DSS) induction. This study explored the therapeutic potential of berberine-evodiamine (BBR-EVO), bioactive components of the traditional Chinese medicine Yulian decoction, in DSS colitis. BBR-EVO intervention ameliorated weight loss, diarrhea, colonic shortening, and histopathological damage in colitic mice. The substance increased antioxidant activity while reducing high levels of pro-inflammatory cytokines in the colon, including as TNF-α, IL-1β, and IL-6. BBR-EVO inhibited the DSS-induced decrease in the tight junction proteins ZO-1 and occludin, according to immunohistochemistry. 16S rRNA sequencing demonstrated BBR-EVO partially attenuated DSS-elicited intestinal dysbiosis, reducing opportunistic pathogens and restoring diminished beneficial taxa. Critically, BBR-EVO alleviated secondary hepatic injury in colitic mice, mitigating immune cell infiltration, oxidative stress, cytokine production, and ultrastructural damage, likely by beneficially modulating gut-liver crosstalk. This study reveals BBR-EVO, derived from a traditional Chinese medicine, confers multi-target protective effects in experimental colitis and associated hepatic pathology, warranting further evaluation as a potential therapy for inflammatory bowel diseases like UC. The mechanisms may involve simultaneous augmentation of intestinal barrier integrity, inhibition of inflammation, microbiota regulation, and gut-liver axis optimization.

Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.

Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.

Perinatal exposure to perfluorooctane sulfonate and the risk of hepatic inflammation in rat offspring: Perturbation of gut-liver crosstalk

Perfluorooctane sulfonate (PFOS) exposure is associated with harmful hepatic outcomes. Growing evidence indicates that crosstalk between the gut microbiome, immune system, and liver plays a vital role in the pathogenesis of liver diseases. However, the underlying mechanism is not fully understood. In the present study, we aimed to investigate the effects of PFOS exposure during pregnancy and lactation on hepatic inflammation in rat offspring. Features of hepatic inflammation and increased levels of aspartate-amino transferase (AST) were found in pups on postnatal day 28 (PND28) in PFOS-exposed groups. Gut microbiota analysis identified Chitinophaga, Ralstonia, and Alloprevotella as the key genera in distinguishing the PFOS-exposed group from the control group. Metabolic and transcriptomic analyses found that PFOS exposure resulted in 48 differentially expressed metabolites (DEMs) in the serum, 62 DEMs in the liver, and 289 differentially expressed genes (DEGs) in the liver of PND28 pups. The immune response is significantly enriched in PFOS-exposed liver on PND28; multi-omics analysis indicated that PFOS might lead to immune response perturbation by disturbing the metabolic profiling in the liver. The changed gut microbiota was significantly related to the serum level of the liver function index. Specifically, Alloprevotella, Chitinophage, Ruminococcus, and Allobaculum were significantly associated with the metabolic abundance changes of 4-Hydroxydebrisoquine, L-Norvaline, and Eremopetasinorol, and the gene expression changes of Acat211, Msmol, Idi1, Sqle, and Gadd45b in the liver. These findings suggest that early-life PFOS exposure may be associated with adverse hepatic inflammation in young offspring via disruption of the gut-liver crosstalk, which may provide mechanistic clues for clarifying the hepatotoxicity in offspring associated with perinatal PFOS exposure.

Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt

Portal hypertension develops in patients with advanced chronic liver diseases (CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for portal hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal hypertension before and after TIPS intervention to identify and characterise potential mediators influencing gut-liver cross-talk. The plasma of 23 patients displaying advanced CLD with portal hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric (LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99-118), Histone-lysine N-methyltransferase(MLL3)(3019-3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614-630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), uric acid, dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel potential biomarkers for portal hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.

Effects of triglyceride and ethyl ester forms of EPA on hepatic lipid metabolism in mice with non-alcoholic fatty liver disease

In this study, the beneficial effects of EPA in ethyl esters (EE) and triacylglycerides (TAG) forms on high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) were studied and compared. Results indicated that both EPA-TAG and EPA-EE can alleviate pathological features of NAFLD, such as hepatic lipid accumulation and lobular inflammation, with a more pronounced protective effects observed in EPA-TAG treated mice. The integrated hepatic transcriptomic, metabolic and gut microbiota profiles suggest that EPA-TAG and EPA-EE improved hepatic steatosis by suppression of food intake and lipogenesis, promotion of lipid and phospholipid PUFA remodeling, ketogenesis and fatty acids oxidation, possibly via activating the AMPK/adipocytokine signaling pathway. The protective effect of EPA was also associated with the regulation of intestinal flora structure. In general, EPA-TAG was found to be more effective than EPA-EE in preventing HFD-induced NAFLD by reducing appetite, improving hepatic lipid metabolism, increasing energy expenditure, and enhancing gut-liver cross-talk.

Characterization of individual bile acids in vivo utilizing a novel low bile acid mouse model.

Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.

Microbiota-gut-liver-brain axis and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.

Regulatory effect of β-glucan secreted by Rhizobium pusense on triglyceride metabolism and their relationships with the modulation of intestinal microbiota in mice fed a high-fat diet.

The present study investigated the regulatory effects of β-glucan secreted by Rhizobium pusense (RPG) on triglyceride metabolism and gut microbiota in mice fed a high-fat diet. The results indicated that supplementation with RPG significantly reduced body weight gain, blood glucose levels, and the tissue index of epididymal white adipose tissue (eWAT) and subcutaneous adipose tissue (SAT). Conversely, it increased the tissue index of brown adipose tissue (BAT). Furthermore, RPG supplementation effectively decreased the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the serum. Regarding its influence on the triglyceride (TG) mechanism, RPG decreased TG levels in both serum and liver, while elevating TG levels in feces. Moreover, it moderated the composition of gut microbiota in mice fed a high-fat diet, particularly altering functionally relevant intestinal microbial phylotypes, leading to enhanced levels of short-chain fatty acids (SCFAs) in feces. Additionally, RPG treatment regulated the mRNA and protein levels of genes responsible for TG metabolism in the AMPK pathway, indicating an impact on TG synthesis and excretion in the liver. Pearson's correlation network analysis demonstrated strong correlations between key microbial phylotypes responsive to RPG intervention and parameters associated with TG metabolic disorders. SCFA levels were also found to correlate with the mRNA expression levels of genes involved in TG metabolism. Finally, lipidomics analyses were performed to investigate the underlying mechanisms of RPG intervention (glycerophospholipid metabolic pathway) and to identify potential lipid biomarkers, such as TG (18:2/20:4/22:6), TG (18:1/20:4/22:6), TG (20:1/18:1/22:4), PC (17:0/20:4), TG (18:1/20:4/22:5), PC (22:4/22:6), PC (20:0/22:6), PC (20:0e/20:4), DG (18:3e/18:2), DG (10:0/18:2), DG (18:2/14:2), TG (10:0/18:2/20:4), TG (16:1/14:3/18:2) and TG (16:0/14:2/22:6). Overall, our results suggest that RPG could activate the hepatic AMPK signaling pathway by regulating gut microbiota and metabolites through gut-liver crosstalk to exert a lipid-lowering effect in mice fed a high-fat diet and improve obesity.

Regulation of hepatic lipid metabolism by intestine epithelium-derived exosomes

Abstract The “gut-liver axis” is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways, such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut’s influence on liver steatosis remains unknown. Here, we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis. Our study demonstrates that intExos regulate hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.

Current Therapeutics in Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.

New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk.

Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.

THU-241 - Gut-liver crosstalk in hepatocellular carcinoma and non-selective beta-blockers: is there a link?

THU-241 - Gut-liver crosstalk in hepatocellular carcinoma and non-selective beta-blockers: is there a link?

Metformin acts in the gut and induces gut-liver crosstalk

Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.

SCD1 is nutritionally and spatially regulated in the intestine and influences systemic postprandial lipid homeostasis and gut-liver crosstalk

Stearoyl-CoA desaturase-1 is an endoplasmic reticulum (ER)-membrane resident protein that inserts a double bond into saturated fatty acids, converting them into their monounsaturated counterparts. Previous studies have demonstrated an important role for SCD1 in modulating tissue and systemic health. Specifically, lack of hepatic or cutaneous SCD1 results in significant reductions in tissue esterified lipids. While the intestine is an important site of lipid esterification and assimilation into the body, the regulation of intestinal SCD1 or its impact on lipid composition in the intestine and other tissues has not been investigated. Here we report that unlike other lipogenic enzymes, SCD1 is enriched in the distal small intestine and in the colon of chow-fed mice and is robustly upregulated by acute refeeding of a high-sucrose diet. We generated a mouse model lacking SCD1 specifically in the intestine (iKO mice). These mice have significant reductions not only in intestinal lipids, but also in plasma triacylglycerols, diacylglycerols, cholesterol esters, and free cholesterol. Additionally, hepatic accumulation of diacylglycerols is significantly reduced in iKO mice. Comprehensive targeted lipidomic profiling revealed a consistent reduction in the myristoleic (14:1) to myristic (14:0) acid ratios in intestine, liver, and plasma of iKO mice. Consistent with the reduction of the monounsaturated fatty acid myristoleic acid in hepatic lipids of chow fed iKO mice, hepatic expression of Pgc-1α, Sirt1, and related fatty acid oxidation genes were reduced in chow-fed iKO mice. Further, lack of intestinal SCD1 reduced expression of de novo lipogenic genes in distal intestine of chow-fed mice and in the livers of mice fed a lipogenic high-sucrose diet. Taken together, these studies reveal a novel pattern of expression of SCD1 in the intestine. They also demonstrate that intestinal SCD1 modulates lipid content and composition of not only intestinal tissues, but also that of plasma and liver. Further, these data point to intestinal SCD1 as a modulator of gut-liver crosstalk, potentially through the production of novel signaling lipids such as myristoleic acid. These data have important implications to understanding how intestinal SCD1 may modulate risk for post-prandial lipemia, hepatic steatosis, and related pathologies.

The liver-gut-axis: initiator and responder to sepsis.

Purpose of reviewThe ‘gut-liver axis’ is thought to play an important role in pathogenesis of sepsis. Despite a wealth of experimental data to support the concept of reciprocal crosstalk between gut and liver through bacterial translocation and shaping of the microbiome by liver-derived molecules, for example bile acids, clinical data, and in particular diagnostic and therapeutic options, are limited.Recent findingsAssessment of organ failure in the current definition of sepsis is operationalized by means of the Sequential Organ Failure Assessment (SOFA) score, including exclusively bilirubin to reflect the complex functions of the liver but ignoring the gut. However, our understanding of the intestinal microbiome and how it is affected by critical illness has clearly improved. Microbiota maintain gut-barrier function and modulate the innate and adaptive immune system. The best-defined intervention affecting the gut microbiome, that is selective decontamination of the digestive tract (SDD) is clinically studied regarding prevention of nosocomial lung infection and antibiotic resistance patterns, although its impact on liver function has not been systematically evaluated in critical illness.SummaryCharacterization of liver function beyond bilirubin and the microbiome can be achieved with contemporary sequencing and metabolomic techniques. Such studies are essential to understand how gut-liver crosstalk and ‘dysbiosis’ affect susceptibility to and outcome of sepsis.

TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.

FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/- mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2 ; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Environmental Chemical Contribution to the Modulation of Bile Acid Homeostasis and Farnesoid X Receptor Signaling.

Maintaining bile acid (BA) homeostasis is important and regulated by BA activated receptors and signaling pathways. Farnesoid X receptor (FXR) and its regulated target networks in both the liver and the intestines are critical in suppressing BA synthesis and promoting BA transport and enterohepatic circulation. In addition, FXR is critical in regulating lipid metabolism and reducing inflammation, processes critical in the development of cholestasis and fatty liver diseases. BAs are modulated by, but also control, gut microflora. Environmental chemical exposure could affect liver disease development. However, the effects and the mechanisms by which environmental chemicals interact with FXR to affect BA homeostasis are only emerging. In this minireview, our focus is to provide evidence from reports that determine the effects of environmental or therapeutic exposure on altering homeostasis and functions of BAs and FXR. Understanding these effects will help to determine liver disease pathogenesis and provide better prevention and treatment in the future. SIGNIFICANCE STATEMENT: Environmental chemical exposure significantly contributes to the development of cholestasis and nonalcoholic steatohepatitis (NASH). The impact of exposures on bile acid (BA) signaling and Farnesoid X receptor-mediated gut-liver crosstalk is emerging. However, there is still a huge gap in understanding how these chemicals contribute to the dysregulation of BA homeostasis and how this dysregulation may promote NASH development.

Role of bile acids in liver diseases mediated by the gut microbiome.

The intensive crosstalk between the liver and the intestine performs many essential functions. This crosstalk is important for natural immune surveillance, adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites. The interaction between the gut microbiome and bile acids is bidirectional. The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes. Similarly, bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system. The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases, especially liver diseases. As essential mediators of the gut-liver crosstalk, bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1. Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases. We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.

Lycium barbarum polysaccharide combined with aerobic exercise ameliorated nonalcoholic fatty liver disease through restoring gut microbiota, intestinal barrier and inhibiting hepatic inflammation

Gut microbiota and intestinal permeability have been demonstrated to be the key players in the gut–liver cross talk in nonalcoholic fatty liver disease (NAFLD). Lycium barbarum polysaccharides (LBPs), which seem to be a potential prebiotic, and aerobic exercise (AE) have shown protective effects on NAFLD. However, their combined effects on intestinal microecology remain unclear. This study evaluated the effects of LBP, AE, and its combination (LBP + AE) on gut microbiota composition, intestinal barrier, and hepatic inflammation in NAFLD. LBP + AE showed high abundance and diversity of gut microbiota, restored the gut microbiota composition, increased some Bacteroidetes, short chain fatty acids, but decreased Proteobacteria and the ratio of Firmicutes/Bacteroidetes. Simultaneously, LBP, AE, and LBP + AE could restore the colonic and ileum tight junctions by increasing the expression of zonula occludens-1 and occludin. They also downregulated gut-derived lipopolysaccharides (LPSs), hepatic LPS-binding proteins, inflammatory factors, and related indicators of the LPS/TLR4/NF-κB signaling pathway for the liver. Our results implied that LBP could be considered a prebiotic agent, and LBP + AE might be a promising treatment for NAFLD because it could maintain gut microbiota balance, thereby restoring intestinal barrier and exerting hepatic benefits.