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Schematic representation of the vicious cycle that follows the pathological perturbation of the intestinal microbiota.
Source publication
The gut microbiota plays a crucial role in regulating many physiological systems of the host, including the metabolic and immune system. Disturbances in microbiota composition are increasingly correlated with disease; however, the underlying mechanisms are not well understood. Recent evidence suggests that changes in microbiota composition directly...
Context in source publication
Context 1
... bacteria that produce cholesterol reductase convert cholesterol into the less soluble coprostanol leading to reduced intestinal absorption. (5) Production of short-chain fatty acids (scFAs). Propionate has been shown to reduce cholesterol synthesis, while acetate has the opposite effect. (6) Reduction of cellular cholesterol uptake. Direct interaction of probiotics with intestinal epithelial cells may lower expression of cholesterol transporters such as NPC1L1. Based on these potential mechanisms, a wealth of clinical studies have now shown efficacy of BSH-active probiotics in lowering cholesterol and triglyceride levels [131]. However, detailed investigation of probiotic BSH activity is needed as probiotics express different BSHs and different BSHs can have different effects on weight gain and plasma lipid levels [31]. It would be interesting to investigate whether these differences in probiotic BSH activities might contribute to the effects on weight loss or gain observed after probiotic treatment [144]. In this review, we have discussed how the microbiota in the gastrointestinal tract regulates the metabolism of BA species. Microbial enzymes modify BAs and the resulting BA metabolites impact both metabolism as well as host immunity. The composition of the microbiota is causatively related to BA pool size and BA species diversity and perturbations of the microbiota leads to BA dysregulation as observed in IBD and metabolic disease. With the discovery of receptors (e.g., FXR and TGR5) that recognize specific BAs, the field of research and application now incorporates both local and systemic inflammatory processes next to processes related to digestion and metabolism. BA receptors are not only expressed by tissues involved in BA metabolism such as the liver, gallbladder and intestine, but also by cells from the innate and adaptive immune system and the overall inhibitory effects on systemic inflammation suggests the importance of maintaining BA homeostasis [145]. Dysbiosis is often associated with a loss of BSH-expressing bacteria, which impacts host-microbe interactions and influences immune homeostasis, cholesterol metabolism and host weight gain. In this setting, BSH-expressing probiotics offer attractive natural means of normalizing BSH activity both directly, via supplementing lost BSH-activity, or indirectly through normalization of the intestinal microbiota (Figure 3). Diet, antibiotic use and/or disease are factors that may cause disturbances in the gut microbiota composition. Changes in microbiota composition impact on BA pool size and composition through alterations in deconjugation and dehydroxylation activities. The subsequent change in BA metabolites directly and indirectly, through BA receptors FXR and TGR5, modulate dietary fat and vitamin metabolism, epithelial barrier integrity and intestinal immune homeostasis. Loss of barrier integrity leads to inflammatory processes that contribute to dysbiosis. Dietary interventions with probiotics or synbiotics can be used to change or alleviate the vicious circle. Probiotics may be used to treat dysbiosis by normalizing the gut microbiota composition or BSH-expressing probiotics may be used to supplement lost ...
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Citations
... Dysregulated bile acid homeostasis can lead to malabsorption syndromes and nutritional deficiencies [78]. In addition, an imbalance in bile acid regulation can contribute to the development of IBD, such as Crohn's disease and ulcerative colitis, where altered bile acid composition and levels, as well as signaling pathways, may exacerbate intestinal inflammation and barrier dysfunction [79]. Certain secondary bile acids have been implicated in promoting carcinogenesis and increased risk of colorectal cancer [80][81][82][83]. ...
Maintaining bile acid homeostasis is essential for metabolic health. Bile acid homeostasis encompasses a complex interplay between biosynthesis, conjugation, secretion, and reabsorption. Beyond their vital role in digestion and absorption of lipid-soluble nutrients, bile acids are pivotal in systemic metabolic regulation. Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Bile acids are essential signaling molecules that regulate many critical biological processes, including lipid metabolism, energy expenditure, insulin sensitivity, and glucose metabolism. Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms, hormonal dysregulation, interactions with the gut microbiota, and changes in the expression and function of bile acid transporters and receptors. This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity, T2DM, and MASLD. We aim to underscore the significance of bile acids as potential diagnostic markers and therapeutic agents in the context of metabolic diseases, providing insights into their application in translational medicine.
... Intestinal microbiota can influence the production of intestinal metabolites, which mediate the interaction between intestinal bacteria and the host [18]. BAs, which act as beneficial intestinal metabolites, significantly affect the regulation of metabolic homeostasis and local immunomodulation by binding to TGR5 [60]. Previous studies have found that LCA and DCA can reduce intestinal inflammation in part, depending on TGR5, which promotes intestinal epithelial regeneration [20,21]. ...
Aim
Disturbed intestinal microbiota has been implicated in the inflammatory microenvironment of the colon, which usually results in ulcerative colitis (UC). Given the limitations of these drugs, it is important to explore alternative means of protecting the gut health from UC. This study aimed to investigate the potential of polysaccharides as beneficial nutrients in the regulation of the gut microbiota, which determines the inflammatory microenvironment of the colon.
Materials and methods
Mice were treated with dextran sulfate sodium (DSS) to evaluate the effects and mechanisms of Lycium barbarum polysaccharide (LBP) in remodeling the inflammatory microenvironment and improving gut health. Body weight and disease activity indices were monitored daily. Hematoxylin and eosin staining was used to analyze colon dynamics. The levels of inflammatory indicators and expression of MUC-2, claudin-1, ZO-1, and G-protein-coupled receptor 5 (TGR5) were determined using assay kits and immunohistochemistry, respectively. 16S rRNA high-throughput sequencing of the intestinal microbiota and liquid chromatography-tandem mass spectrometry for related bile acids were used.
Results
LBP significantly improved the colonic tissue structure by upregulating MUC-2, claudin-1, and ZO-1 protein expression. The bacterial genus Dubosiella was dominant in healthy mice, but significantly decreased in mice treated with DSS. LBP rehabilitated Dubosiella in the sick guts of DSS mice to a level close to that of healthy mice. The levels of other beneficial bacterial genera Akkermansia and Bifidobacterium were also increased, whereas those of the harmful bacterial genera Turicibacter, Clostridium_sensu_stricto_1, Escherichia-Shigella, and Faecalibaculum decreased. The activity of beneficial bacteria promoted the bile acids lithocholic and deoxycholic acids in mice with UC, which improved the gut barrier function through the upregulation of TGR5.
Conclusion
The inflammatory microenvironment in the gut is determined by the balance of the gut microbiota. LBP showed great potential as a beneficial nutrient for rehabilitating Dubosiella which is dominant in the gut of healthy mice. Nutrient-related LBP may play an important role in gut health management.
... Bile acids have classically been recognised as molecules that are produced by the liver and circulate between the liver and intestine where they aid in the solubilisation and absorption of dietary fat. More recently it has become apparent that these molecules play important roles in inflammation and metabolism signalling through receptors that include FXR and TGR5 [reviewed in (17,31)]. Bile Bile acids induce IL-1a and IL-1b secretion from LPS-primed BMDCs. ...
Bile acids are amphipathic molecules that are synthesized from cholesterol in the liver and facilitate intestinal absorption of lipids and nutrients. They are released into the small intestine upon ingestion of a meal where intestinal bacteria can modify primary into secondary bile acids. Bile acids are cytotoxic at high concentrations and have been associated with inflammatory diseases such as liver inflammation and Barrett’s Oesophagus. Although bile acids induce pro-inflammatory signalling, their role in inducing innate immune cytokines and inflammation has not been fully explored to date. Here we demonstrate that the bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) induce IL-1α and IL-1β secretion in vitro in primed bone marrow derived dendritic cells (BMDCs). The secretion of IL-1β was found not to require expression of NLRP3, ASC or caspase-1 activity; we can’t rule out all inflammasomes. Furthermore, DCA and CDCA were shown to induce the recruitment of neutrophils and monocytes to the site of injection an intraperitoneal model of inflammation. This study further underlines a mechanistic role for bile acids in the pathogenesis of inflammatory diseases through stimulating the production of pro-inflammatory cytokines and recruitment of innate immune cells.
... Through further statistical analysis of the proportion of bile acid molecules in each group, it can be concluded that SCH can significantly increase the proportion of LCA, DCA, and Hyodeoxycholic acid (HDCA) (Fig. 8G), which was correlated with the increase in the abundance of beneficial bacteria such as Lactobacillus [33]. Related studies have shown that DCA and LCA can bind to the bile acid receptor TGR5 or FXR and exert immune effects, such as maintaining intestinal barrier homeostasis and inhibiting the release of epithelial cytokines [34,35]. When SCH was used to treat mice with colitis, it increased the ratio of DCA, LCA, and HDCA in the intestine. ...
Background
According to the Chinese Pharmacopoeia , the fruit of Schisandra chinensis (Turcz.) Baill. (SC) is an important traditional Chinese medicine that can be used to treat diarrhea. Despite the increasing research on the anti-inflammatory and anti-oxidant aspects of SC, the studies on the anti-ulcerative colitis of Schisandrin (SCH), the main constituent of SC, are relatively few.
Methods
The mice used in the study were randomly distributed into 6 groups: control, model, 5-ASA, and SCH (20, 40, 80 mg/kg/d). The mice in the model group were administered 3% (w/v) dextran sulfate sodium (DSS) through drinking water for 7 days, and the various parameters of disease activity index (DAI) such as body weight loss, stool consistency, and gross blood were measured. ELISA was used to detect inflammatory factors, and bioinformatics combined with transcriptome analysis was done to screen and verify relevant targets. 16S rDNA high-throughput sequencing was used to analyze the composition of the gut microbiota(GM), while mass spectrometry was done to analyze the changes in the content of bile acids (BAs) in the intestine.
Results
Mice treated with SCH experienced significant weight gain, effectively alleviating the severity of colitis, and decreasing the levels of inflammatory factors such as TNF-α, IL-1β, IL-18, IL-6, and other related proteins (NLRP3, Caspase-1, SGK1) in UC mice. Furthermore, the analysis of GM and BAs in mice revealed that SCH increased the relative abundance of Lactobacilli spp , reduced the relative abundance of Bacteroides , and promoted the conversion of primary BAs to secondary BAs. These effects contributed to a significant improvement in the DSS-induced GM imbalance and the maintenance of intestinal homeostasis.
Conclusion
It seems that there is a close relationship between the SCH mechanism and the regulation of SGK1/NLRP3 pathway and the restoration of GM balance. Therefore, it can be concluded that SCH could be a potential drug for the treatment of UC.
... BAs, which are endogenous signaling molecules, can regulate local immunological function, intestinal hormone secretion, and gastrointestinal motility by interacting with receptors, such as FXR and TGR5. 65 The primary endogenous ligands for FXR and TGR5 are unconjugated BAs, including CDCA, DCA, LCA, and CA. Among these, CDCA has the strongest effect on FXR activation, 66 while LCA has the highest capacity to activate TGR5. ...
The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4β7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4β7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4β7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4β7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.
... Tryptophan metabolites such as indoles act as ligands for the aryl hydrocarbon receptor, a receptor having a notable role in the maintenance of intestinal homeostasis (Lloyd-Price et al. 2019; Rannug 2020; Kumar et al. 2021). In addition to promoting intestinal homeostasis, bile acid derivatives also activate farnesoid X receptors and G protein-coupled bile acid receptors to affect a wide range of host functions (Baars et al. 2015). Thus, microbial metabolites greatly influence the functioning and maintenance of the host immune system. ...
The evolution of mutualism and homeostasis between mammals and their commensal microorganisms makes sense from an ecological perspective. Microbiota and the immune system play a multifaceted role in the development and function of mammalian bodies. Many research studies have described the innate and adaptive immune system’s interactions with the trillions of microbes living in the gastrointestinal tracts of the human body. A dynamic multispecies community of bacteria, fungi, protozoa, and archaea is the key maker of gut microbiota which plays a fundamental role in triggering, training, and sustaining the human body’s immunity. The pathogenesis of many immune-mediated disorders is believed to be influenced by imbalances in microbiota–immunity interactions in genetically susceptible hosts. Environmental intrusions (such as diet, antibiotic use, or geographical changes) may alter the gut microbiome, impair host–microbiome interfaces, or alter the immune system, resulting in systemic dispersal of commensal microorganisms, pathogenic invasion, and divergent immune responses. This chapter aims to summarize the features of microbiota–immunity crosstalk, their game-changing roles in the establishment of disease, and the impact of metabolism, micronutrients, and environmental factors that orchestrate these interactions in different immune organs.KeywordsGut microbiomeInnate immunityAdaptive immunityMicronutrientsProbioticsMetabolites
... Bile acids are major chemical components of the human intestinal tract and are critical for food digestion, lipid absorption, host signalling and neurohormonal regulation of diverse physiological processes 5 . Bile acids have been implicated in a wide range of disorders, including inflammatory bowel disease (IBD) 32 , metabolic disorders 32 and neurological diseases 33,34 . Glycine-and taurine-conjugated forms of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are secreted from the liver and gallbladder into the duodenum and are then subjected to various microbial transformations ( Fig. 5a) 4,35 . ...
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.
... The cholesterol-lowering effect of strains belonging to Lactobacillus genus was associated with the deconjugation of conjugated bile acids with the enzyme activity of coloylglycine hydrolase (Choloylglycine hydrolase, EC3.5.1.24), also known as BSH [13][14][15][16]. It has been reported that Lactobacillaceae species can perform different BSH enzyme activities in the presence of various bile salts [17][18][19][20]. ...
The bile salt hydrolase (BSH) activity is responsible for the cholesterol-lowering effect of the probiotic strains. The present study aimed to investigate the relationship between bsh gene-expression (GE) levels responsible for the BSH activity and the parameters of bile salt resistance of different Lactobacillaceae species. Accordingly, 11 Lactobacillaceae family strains with high cholesterol assimilation ratio (49.21–68.22%) determined by the o-phthalaldehyde method selected from 46 Lactobacillaceae species was evaluated for their features including acid tolerance, bile tolerance, and BSH activity. All tested strains survived at pH 2 medium and 0.3% (w/v) bile salt and showed positive BSH activity for glycocholic acid (GCA) and taurocholic acid (TCA). BSH gene expression was performed to provide clear information and to identify the key genes responsible for BSH activity. bsh3 genes were found highest GE level (P < 0.05) in Lactiplantibacillus plantarum and Lacticaseibacillus paracasei strains. The results showed that high cholesterol assimilation ratio were closely correlated with BSH activity and the parameters of bile salt resistance. The results of this study will support the development of a new approach based on phenotypic and genetic analysis to determine the bile salt parameters. The study will be useful for the selection of Lactobacillus strains with high bile salt resistance.
... observed: <1%) (Subbiah et al., 1976;Mok et al., 1977;Vantrappen et al., 1981;Kullak-Ublick et al., 1995;Hofmann, 1999;Meier and Stieger, 2002). Additionally, the large majority of biliary BAs consists of CDCA species (simulated:~41%, observed:~35%) while only a minority consists of LCA species (simulated:~1%, observed:~1%); in contrast, due to gut bacteria-mediated BA metabolism, the large majority of fecal BAs consists of LCA species (simulated:~48%, observed: 32%), whereas only a minority consists of CDCA species (simulated: 2%, observed: 2%) (Baars et al., 2015), which is reasonably captured by the model. The model is capable of performing simulations under fasted and fed conditions (three meals per day); meal signals result in the contraction of the gallbladder, resulting in oscillatory BA concentrations in the blood and liver ( Figures 2C, D), in agreement with reported, post-prandial increases in circulating BAs (LaRusso et al., 1974;Napolitano et al., 2014). ...
Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population (n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.
... Benzyl((1S,3aS,5aR,5bR,9R,11aR)-9-hydroxy-1-isopropyl-5a,5b, 8 13 ...
Farnesoid X receptor (FXR) has emerged as a promising therapeutic target for nonalcoholic steatohepatitis (NASH) because of its tightly interwoven relationship with bile acid homeostasis, inflammation, fibrosis, and glucose and lipid metabolism. Evidence showed that intestinal FXR antagonism exhibited remarkable metabolic improvements in mice. Herein, we developed a series of betulinic acid derivatives as potent intestinal FXR antagonists, and F6 was identified as the most potent one with an IC50 at 2.1 μM. F6 selectively inhibited intestinal FXR signaling and ameliorated the hepatic steatosis, inflammation, and fibrosis in Gubra-amylin NASH (GAN) and high-fat with methionine and choline deficiency (HFMCD) diet-induced NASH models. The beneficial effects were achieved by direct antagonism of intestinal FXR and feedback activation of hepatic FXR, thereby decreasing ceramides and repressing inflammasome activation in the liver. Collectively, our work substantially supports F6 as a promising drug candidate against NASH and demonstrates that antagonism of intestinal FXR signaling is a practical strategy for treating metabolic diseases.
