Bile acids are synthesized from cholesterol in the liver and released into the intestine to aid the digestion of dietary lipids. The host enzymes that contribute to bile acid synthesis in the liver ...and the regulatory pathways that influence the composition of the total bile acid pool in the host have been well established. In addition, the gut microbiota provides unique contributions to the diversity of bile acids in the bile acid pool. Gut microbial enzymes contribute significantly to bile acid metabolism through deconjugation and dehydroxylation reactions to generate unconjugated bile acids and secondary bile acids. These microbial enzymes (which include bile salt hydrolase (BSH) and bile acid-inducible (BAI) enzymes) are essential for bile acid homeostasis in the host and represent a vital contribution of the gut microbiome to host health. Perturbation of the gut microbiota in disease states may therefore significantly influence bile acid signatures in the host, especially in the context of gastrointestinal or systemic disease. Given that bile acids are ligands for host cell receptors (including the FXR, TGR5 and Vitamin D Receptor) alterations to microbial enzymes and associated changes to bile acid signatures have significant consequences for the host. In this review we examine the contribution of microbial enzymes to the process of bile acid metabolism in the host and discuss the implications for microbe-host signalling in the context of C. difficile infection, inflammatory bowel disease and other disease states.
Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of ...circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.
Dietary fibre has long been established as a nutritionally important, health-promoting food ingredient. Modern dietary practices have seen a significant reduction in fibre consumption compared with ...ancestral habits. This is related to the emergence of low-fibre “Western diets” associated with industrialised nations, and is linked to an increased prevalence of gut diseases such as inflammatory bowel disease, obesity, type II diabetes mellitus and metabolic syndrome. The characteristic metabolic parameters of these individuals include insulin resistance, high fasting and postprandial glucose, as well as high plasma cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Gut microbial signatures are also altered significantly in these cohorts, suggesting a causative link between diet, microbes and disease. Dietary fibre consumption has been hypothesised to reverse these changes through microbial fermentation and the subsequent production of short-chain fatty acids (SCFA), which improves glucose and lipid parameters in individuals who harbour diseases associated with dysfunctional metabolism. This review article examines how different types of dietary fibre can differentially alter glucose and lipid metabolism through changes in gut microbiota composition and function.
Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be ...determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe–host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Pparγ, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIγ), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia.
The expected duration of menopausal vasomotor symptoms (VMS) is important to women making decisions about possible treatments.
To determine total duration of frequent VMS (≥ 6 days in the previous 2 ...weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post-FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence.
The Study of Women's Health Across the Nation (SWAN) is a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled at 7 US sites. From February 1996 through April 2013, women completed a median of 13 visits. Analyses included 1449 women with frequent VMS.
Total VMS duration (in years) (hot flashes or night sweats) and post-FMP persistence (in years) into postmenopause.
The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, >11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS.
Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women.
Aside from facilitating solubilisation and absorption of dietary lipids and lipid‐soluble vitamins, amphipathic bile acids (BAs) also act as bioactive signalling molecules. A plethora of conjugated ...or unconjugated primary and bacterially modified secondary BA moieties have been identified, with significant divergence between species. These molecules are excreted into the external environment of the intestinal lumen, yet nuclear and membrane receptors that are sensitive to BAs are expressed internally in the liver, intestinal and neural tissues, amongst others. The diversity of BAs and receptors underpins the multitude of distinct bioactive functions attributed to BAs, but also hampers elucidation of the physiological mechanisms underpinning these actions. In this Topical Review, we have considered the potential of BAs as cross‐barrier signalling molecules that contribute to interoceptive pathways informing the central nervous system of environmental changes in the gut lumen. Activation of BAs on FGF19‐secreting enterocytes, enteroendocrine cells coupled to sensory nerves or intestinal immune cells would facilitate indirect signalling, whereas direct activation of BA receptors in the brain is likely to occur primarily under pathophysiological conditions when concentrations of BAs are elevated.
figure legend
Illustration of the microbial modification of hepatic primary bile acids into secondary bile acids. In addition to facilitating lipid digestion and absorption, bile acids act as bioactive signalling molecules by binding to bile acid receptors expressed on enterocytes, neural afferent‐coupled enteroendocrine cells and immune cells.
Bile acids have emerged as important signaling molecules in the host, as they interact either locally or systemically with specific cellular receptors, in particular the farnesoid X receptor (FXR) ...and TGR5. These signaling functions influence systemic lipid and cholesterol metabolism, energy metabolism, immune homeostasis, and intestinal electrolyte balance. Through defined enzymatic activities, the gut microbiota can significantly modify the signaling properties of bile acids and therefore can have an impact upon host health. Alterations to the gut microbiota that influence bile acid metabolism are associated with metabolic disease, obesity, diarrhea, inflammatory bowel disease (IBD),
Clostridium difficile
infection, colorectal cancer, and hepatocellular carcinoma. Here, we examine the regulation of this gut-microbiota-liver axis in the context of bile acid metabolism and indicate how this pathway represents an important target for the development of new nutraceutical (diet and or probiotics) and targeted pharmaceutical interventions.
Bile acid (BA) signatures are altered in many disease states. BA metabolism is an important microbial function to assist gut colonization and persistence, as well as microbial survival during gastro ...intestinal (GI) transit and it is an important criteria for potential probiotic bacteria. Microbes that express bile salt hydrolase (BSH), gateway BA modifying enzymes, are considered to have an advantage in the gut. This property is reported as selectively limited to gut-associated microbes. Food-associated microbes have the potential to confer health benefits to the human consumer. Here, we report that food associated Lactobacillus plantarum strains are capable of BA metabolism, they can withstand BA associated stress and propagate, a recognised important characteristic for GIT survival. Furthermore, we report that these food associated Lactobacillus plantarum strains have the selective ability to alter BA signatures in favour of receptor activation that would be beneficial to humans. Indeed, all of the strains examined showed a clear preference to alter human glycol-conjugated BAs, although clear strain-dependent modifications were also evident. This study demonstrates that BA metabolism by food-borne non-pathogenic bacteria is beneficial to both microbe and man and it identifies an evolutionary-conserved characteristic, previously considered unique to gut residents, among food-associated non-pathogenic isolates.
The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and ...secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.
Bacteria produce an array of diverse, dynamic and often complex lipid structures, some of which function beyond their typical role in membrane structure. The model organism,
, has three major ...membrane lipids, which are glycerophosphoglycerol (phosphatidylglycerol), glycerophosphoethanolamine (phosphatidylethanolamine) and cardiolipin. However, it is now appreciated that some bacteria have the capacity to synthesize a range of lipids, including glycerophosphocholines, glycerophosphoinositols, 'phosphorous-free'
-acyl amines, sphingolipids and plasmalogens. In recent years, some of these bacterial lipids have emerged as influential contributors to the microbe-host molecular dialogue. This review outlines our current knowledge of bacterial lipid diversity, with a focus on the membrane lipids of microbiome-associated bacteria that have documented roles as signalling molecules.
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