Bacterial bile salt hydrolase in host metabolism: Potential for influencing gastrointestinal microbe-host crosstalk

Controlled, reductionist approaches are required in order to obtain a more complete understanding of the functional capabilities of the gut microbiota. We recently identified microbial bile salt hydrolase (BSH) activity as a gut microbial activity that has the capacity to profoundly alter both local (gastrointestinal) and systemic (hepatic) host functions. Using both germ free and conventionally-raised mouse models we demonstrated that gastrointestinal expression of BSH results in local bile acid deconjugation with concomitant alterations in lipid and cholesterol metabolism, signaling functions and weight gain. Key mediators of cholesterol homeostasis (Abcg5/8), gut homeostasis (RegIIIγ) and circadian rhythm (Dbp) were influenced by elevated BSH in our study. In this addendum we discuss the implications of this work for the rational development of probiotics with the potential to modulate host weight gain.     

Changes in bile acids,FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242

The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.     

Changes in bile acids,FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242

The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.     

Melatonin,energy metabolism,and obesity: a review

Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti‐obesogen and the weight‐reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G‐protein‐coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin‐signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin‐resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift‐work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.     

Targeting bile acid metabolism in obesity reduction: A systematic review and meta‐analysis

A systematic review and meta‐analysis was conducted of studies that address the association of bile acid (BA) with obesity and of studies on the effects of treatment in patients with obesity on BA metabolism, assessed from systemic BA, fibroblast growth factor 19 (FGF19), 7α‐hydroxy‐4‐cholesten‐3‐one (C4) level, and faecal BA. We searched PubMed, Embase, and the Cochrane Library from inception to 1 August 2019 using the keywords obesity, obese, body mass index, and overweight with bile acid, FGF19, FXR, and TGR5. Two reviewers independently searched, selected, and assessed the quality of studies. Data were analysed using either fixed or random effect models with inverse variance weighting. Of 3771 articles, 33 papers were relevant for the association of BA with obesity of which 22 were included in the meta‐analysis, and 50 papers were relevant for the effect of obesity interventions on BA of which 20 were included in the meta‐analysis. Circulating fasting total BA was not associated with obesity. FGF19 was inversely and faecal BA excretion was positively associated with obesity. Roux‐en‐Y gastric bypass (RYGB) and sleeve gastrectomy (SG) modulated BA metabolism, ie, increased BA and FGF19. Our results indicate that BA metabolism is altered in obesity. Certain bariatric surgeries including RYGB and SG modulate BA, whether these underlie the beneficial effect of the treatment should be investigated.     

Night eating syndrome: implications for severe obesity

Night eating syndrome (NES) was first identified in 1955 by Stunkard, a psychiatrist specialising in eating disorders (ED). Over the last 20 years considerable progress has been made in defining NES as a significant clinical entity in its own right and it has now been accepted for inclusion in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) due for publication in 2013. NES is considered a dysfunction of circadian rhythm with a disassociation between eating and sleeping. Core criteria include a daily pattern of eating with a significantly increased intake in the evening and/or night time, as manifested by one or both of the following: at least 25% of food intake is consumed after the evening meal or at least two episodes of nocturnal eating per week. An important recent addition to core criteria includes the presence of significant distress and/or impairment in functioning. Stunkard''s team recommend further investigation on the pathogenesis of NES, in particular its relationship with traumatic life events, psychiatric comorbidity, the age of onset of NES and course of NES over time. The relationship between NES and other ED also requires further clarification as night-eaters exhibit some features of other ED; previous guidance to separate NES from other ED may have hindered earlier characterisation of NES. Evidence from European and American studies suggests NES features strongly in populations with severe obesity. The complex interplay between depression, impaired sleep and obesity-related comorbidity in severely obese individuals makes understanding NES in this context even more difficult. This review examines evidence to date on the characterisation of NES and concludes by examining the applicability of current NES criteria to individuals with severe obesity.     

Role of phosphatidylcholine saturation in preventing bile salt toxicity to gastrointestinal epithelia and membranes

Background and Aim: The mechanism which protects the biliary and intestinal mucosa from the detergent properties of bile acids is not fully understood. We employed three contrasting in vitro model systems (human red blood cells, polarized intestinal [Caco‐2] cells, and synthetic liposomes), to compare the efficacy of saturated and unsaturated phosphatidylcholine (PC) to protect cells and membranes from bile salt injury. Methods: Hemolysis of red blood cells, electrical resistance across confluent monolayers of Caco‐2 cells, and disruption of synthetic PC liposomes were assessed after incubation with varying concentrations of bile salt (sodium deoxycholate) alone or in the presence of saturated or unsaturated PC. Results: The hemolytic activity of deoxycholate on red blood cells was observed at ≥2 mM, and could be blocked by equimolar concentration or greater of both saturated or unsaturated PC. In contrast, exposure of Caco‐2 cells to deoxycholate at ≥0.8 mM induced a maximal decrease in resistance, which was reversed by ≥0.8 mM unsaturated PC or 5 mM saturated PC. Similarly, synthetic liposomes were permeabilized by 0.8 mM deoxycholate and were protected by a lower concentration of unsaturated PC (2 mM) than saturated (5 mM). Conclusions: Cells can show variable resistance to bile salt toxicity. Extracellular PC, especially in the unsaturated state, can directly protect cell and artificial membranes from bile salt injury. These findings support a role for biliary PC in the formation of mixed micelles that have low cytotoxic properties.     

Circadian biology and sleep: missing links in obesity and metabolism?

This supplement highlights key talks presented at the Pennington Symposium. The collected papers provide a state of the art review of circadian biology at the basic and clinical levels in the context of nutrition, obesity and sleep medicine. Investigators from multiple disciplines attempted to translate new information concerning molecular mechanisms into practical clinical applications, as well as foster new research hypotheses and directions to this exciting field of science and medicine. Furthermore, we hope to spark the interest and attention of the next generation of scientists who will tackle the questions presented by the changing interface between technology, lifestyle and biological rhythms.     

Lactobacillus acidophilus NCFM affects vitamin E acetate metabolism and intestinal bile acid signature in monocolonized mice

Monocolonization of germ-free (GF) mice enables the study of specific bacterial species in vivo. Lactobacillus acidophilus NCFM^TM (NCFM) is a probiotic strain; however, many of the mechanisms behind its health-promoting effect remain unknown. Here, we studied the effects of NCFM on the metabolome of jejunum, cecum, and colon of NCFM monocolonized (MC) and GF mice using liquid chromatography coupled to mass-spectrometry (LC-MS). The study adds to existing evidence that NCFM in vivo affects the bile acid signature of mice, in particular by deconjugation. Furthermore, we confirmed that carbohydrate metabolism is affected by NCFM in the mouse intestine as especially the digestion of oligosaccharides (penta- and tetrasaccharides) was increased in MC mice. Additionally, levels of α-tocopherol acetate (vitamin E acetate) were higher in the intestine of GF mice than in MC mice, suggesting that NCFM affects the vitamin E acetate metabolism. NCFM did not digest vitamin E acetate in vitro, suggesting that direct bacterial metabolism was not the cause of the altered metabolome in vivo. Taken together, our results suggest that NCFM affects intestinal carbohydrate metabolism, bile acid metabolism and vitamin E metabolism, although it remains to be investigated whether this effect is unique to NCFM.     

Chrononutrition in cardiometabolic diseases: Current evidence and future perspectives

Chrononutrition is the field of nutritional science that investigates the relationship between food intake, timing of food intake, and their effects and influence on circadian rhythms and overall health. By aligning eating patterns with body's internal clock, optimisation of metabolic processes, improvements of various aspects of health can be achieved. Cardiovascular (CV) and metabolic diseases remain the leading cause of morbidity and mortality worldwide. Notably, in the US alone, approximately half of all cardiometabolic deaths are attributed to modifiable dietary factors, suggesting that dietary changes could result in dramatic increases in lifespan and its related quality of life. Social media have also a great impact on chrononutrition and their role cannot be neglected. The impact of social media on chrononutrition can be multifaceted: information dissemination, influence on eating habits, digital detox challenges, cultural influence and social jet lag. This special issue will provide novel insights and clarifications on chrononutrition, but also on additional controversial topics. The articles we selected should promote future preclinical and clinical studies to ultimately identify the most appropriate approaches to reduce the unacceptable high burden of CV and metabolic diseases.     

Bile salt independent flow during bile salt‐induced choleresis and cholestasis in the rat: role of biliary thiol secretion

Abstract: Aims/Background: Previous studies have shown that the generation of the so‐called “bile salt‐independent flow” (BSIF) may be partly dependent on the hepatic availability and rate of canalicular secretion of osmotically active substances such as glutathione (GSH) and derived thiols. This study examined the role of common bile salts (BS) on the BSIF formation under both choleretic and cholestatic conditions, and on the relationship of the BSIF to the biliary thiol secretion. Methods: Experiments were carried out in adult male Sprague‐Dawley rats both in situ in the isolated perfused rat liver and in vivo. The effect of choleretic and cholestatic doses of BS on the biliary BS secretion rate (BSSR), BS‐dependent flow (BSDF), and BSIF was evaluated. Results: In the perfused rat liver, the infusion of low and physiological doses of taurocholic acid stimulated the biliary BSSR, BSDF, and BSIF. This was associated with increased biliary thiol secretion and thiol‐dependent bile flow. In vivo administration of taurocholic acid, taurochenodeoxycholic acid or taurolithocholic acid in step‐wise increasing doses leading to cholestasis showed that the onset of cholestasis was not accompanied by a significant decline in the BSSR or BSDF but rather by a marked inhibition of the apparent BSIF. During cholestasis, the three BS produced a significant reduction of biliary thiol secretion, with a marked decrease in thiol‐dependent bile flow sufficient to account for a major proportion of BSIF inhibition. This decline in thiol secretion occurred before the drop in biliary BS secretion and was more pronounced than the reduction in BS output. No change in hepatic thiol content was observed. Administration of free or glyco‐conjugated BS also resulted in a significant decrease of BSIF during the cholestatic period, suggesting a common role for BSIF inhibition in BS‐induced cholestasis. Conclusion: The changes in bile flow during BS‐induced choleresis and cholestasis are mediated by changes in the portion of the BSIF regulated by the thiol secretion.     

Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for management

Irritable bowel syndrome (IBS) may, in part at least, result from a dysfunctional interaction between the indigenous flora and the intestinal mucosa which, in turn, leads to immune activation in the colonic mucosa. Some propose a role for bacterial overgrowth as a common causative factor in the pathogenesis of symptoms in IBS; other evidence points to more subtle qualitative changes in the colonic flora; both hypotheses remain to be confirmed but the likelihood that bacterial overgrowth will prove to be a major factor in IBS now seems remote. Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and, perhaps, localized, quantitative and/or qualitative changes in the colonic flora. How probiotics exert their effects remain to be defined but an anti-inflammatory effect seems likely. While this approach to the management of IBS is in its infancy, it is evident that manipulation of the flora, whether through the administration of antibiotics or probiotics, deserves further attention in IBS.     

Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulation

Type 2 diabetes is a common disorder with high risk of macrovascular and microvascular complications. These complications are largely driven by hyperglycaemia, dyslipidaemia and hypertension, for which aggressive treatment is thus warranted. Achieving and maintaining control of all three risk factors is especially difficult, however, and new therapeutic approaches could be useful. Bile acids have a well-established and important role in cholesterol homeostasis. Normally, their levels are maintained primarily by ileal reabsorption and enterohepatic recycling. Bile acid sequestrants bind bile acids in the intestine, reduce this recycling and deplete the bile acid pool, thereby stimulating use of hepatic cholesterol for bile acid synthesis, which leads to accelerated removal of LDL from the plasma and a decrease in LDL-cholesterol levels. Interestingly, recent evidence suggests that bile acid sequestrants can lower glucose levels to a clinically meaningful degree. This review presents this evidence and the possible mechanisms by which these glucose-lowering effects occur and discusses the apparently unique ability of bile acid sequestrants among lipid-lowering agents to significantly improve two cardiovascular risk factors, hyperglycaemia and dyslipidaemia. There is renewed interest in the use of bile acid sequestrants in individuals with type 2 diabetes, most of whom would benefit from additional reductions in both LDL-cholesterol and glycaemia.     

The role of dietary salt in metabolism and energy balance: Insights beyond cardiovascular disease

Dietary salt (NaCl) is essential to an organism's survival. However, today's diets are dominated by excessive salt intake, which significantly impacts individual and population health. High salt intake is closely linked to cardiovascular disease (CVD), especially hypertension, through a number of well-studied mechanisms. Emerging evidence indicates that salt overconsumption may also be associated with metabolic disorders. In this review, we first summarize recent updates on the mechanisms of salt-induced CVD, the effects of salt reduction and the use of salt substitution as a therapy. Next, we focus on how high salt intake can impact metabolism and energy balance, describing the mechanisms through which this occurs, including leptin resistance, the overproduction of fructose and ghrelin, insulin resistance and altered hormonal factors. A further influence on metabolism worth noting is the reported role of salt in inducing thermogenesis and increasing body temperature, leading to an increase in energy expenditure. While this result could be viewed as a positive metabolic effect because it promotes a negative energy balance to combat obesity, caution must be taken with this frame of thinking given the deleterious consequences of chronic high salt intake on cardiovascular health. Nevertheless, this review highlights the importance of salt as a noncaloric nutrient in regulating whole-body energy homeostasis. Through this review, we hope to provide a scientific framework for future studies to systematically address the metabolic impacts of dietary salt and salt replacement treatments. In addition, we hope to form a foundation for future clinical trials to explore how these salt-induced metabolic changes impact obesity development and progression, and to elucidate the regulatory mechanisms that drive these changes, with the aim of developing novel therapeutics for obesity and CVD.