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Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease.

Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5.

Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size.

Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity.

Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Keywords: Bile acids and salts, Gastrointestinal microbiome, Non-alcoholic fatty liver disease, Receptors, cytoplasmic and nuclear, Receptors, G-protein-coupled

Source:
Diabetes and metabolism Journal
RELATED

Why pain under your right side ribs may signal gallbladder trouble

If you’ve ever felt a sharp, cramping pain under your ribs on the right side of your abdomen, it likely signals a problem with your gallbladder. The gallbladder is a small organ that stores and concentrates bile created by the liver. Bile helps digest fats from the foods we eat. Issues like gallstones or inflammation can prevent proper bile flow and cause gallbladder pain.

Gallstones form when hardened deposits of cholesterol and bile salts build up in the gallbladder or bile ducts. These stones irritate the gallbladder wall, which can trigger painful spasms. Gallstones also block the release of bile, causing it to back up into the gallbladder. This added pressure on the organ results in the agonizing pain under the ribs. This same pain can be referred to an area between the shoulder blades.

In addition to gallstones, inflammation from infections, bile duct issues, and other gallbladder diseases can all impair its ability to release bile. Without enough bile, the gallbladder never fully empties and bile becomes sludgy and concentrated. The excess bile can also crystallise into new gallstones, fuelling the problem.

Symptoms of an underperforming gallbladder extend beyond pain under the ribs. Some other signs include constipation, indigestion after meals, bloating, light coloured stools, nausea, and vomiting.

Making dietary changes to maintain bile flow may help relieve gall bladder pain. These include eating bitter herbs, staying hydrated, and limiting processed foods. Supplements that include whole beet concentrate like BetaTCP can improve the flow of bile in a few days, clearing the pain and improving digestion.

Don’t ignore recurring pain under your ribs as it often indicates problems in the biliary system.

Total flavonoids of Astragalus Ameliorated Bile Acid Metabolism Dysfunction in Diabetes Mellitus

Evid Based Complement Alternat Med.

Astragalus Radix is one of the common traditional Chinese medicines used to treat diabetes. However, the underlying mechanism is not fully understood.

Flavones are a class of active components that have been reported to exert various activities. Existing evidence suggests that flavones from Astragalus Radix may be pivotal in modulating progression of diabetes.

In this study, total flavones from Astragalus Radix (TFA) were studied to observe its effects on metabolism of bile acids both in vivo and in vitro. C57BL/6J mice were treated with STZ and high-fat feeding to construct diabetic model, and HepG2 cell line was applied to investigate the influence of TFA on liver cells.

We found a serious disturbance of bile acids and lipid metabolism in diabetic mice, and oral administration or cell incubation with TFA significantly reduced the production of total cholesterol (TCHO), total triglyceride, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and low-density lipoprotein (LDL-C), while it increased the level of high-density lipoprotein (HDL-C). The expression of glucose transporter 2 (GLUT2) and cholesterol 7α-hydroxylase (CYP7A1) was significantly upregulated on TFA treatment, and FXR and TGR5 play pivotal role in modulating bile acid and lipid metabolism.

This study supplied a novel understanding towards the mechanism of Astragalus Radix on controlling diabetes.

Bile acid metabolism and the pathogenesis of type 2 diabetes

Curr Diab Rep.

T2D is a growing health problem world-wide, but the currently available strategies for therapy and prevention are insufficient. Recent observations indicate that bile acid homeostasis is altered in T2D. Bile acids are metabolic regulators that act as signaling molecules through receptor-dependent and -independent pathways. The most prominent signaling molecules mediating bile acid signaling are the nuclear receptor FXR and the membrane receptor TGR5. Both are implicated in the regulation of lipid, glucose and energy metabolism. Dysregulation of these pathways might contribute to the development of T2D and associated metabolic complications. Interestingly, data from studies with bile acids or bile acid sequestrants indicate that the manipulation of bile acid homeostasis might be an attractive approach for T2D therapy. In this review, we summarize the mechanisms of bile-acid-mediated metabolic control that might be of relevance in the pathogenesis of T2D.
Keywords: Animals, Bile Acids and Salts, metabolism, Diabetes Mellitus, Type 2, metabolism, physiopathology, Dyslipidemias, metabolism, physiopathology, Humans, Obesity, metabolism, physiopathology

Keywords: Bile acids, T2D, FXR, TGR5, bile acid sequestrants, obesity, dyslipidemia, NAFL

Gut microbial metabolites in depression: understanding the biochemical mechanisms

Microbial Cell

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products.

Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism.

This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play in the context of emotional behaviour.

The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behaviour.

We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behaviour: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation.

Elucidating these mechanisms is essential to expand our understanding of the aetiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules.

Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.

 

Gut microbiota–bile acid–IL22 axis orchestrates PCOS

Nature

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2.

The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4.

This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels.

Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility.

Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype.

This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

Study suggests hot flashes could be precursor to diabetes

Medical Xpress

Hot flashes, undoubtedly the most common symptom of menopause, are not just uncomfortable and inconvenient, but numerous studies demonstrate they may increase the risk of serious health problems, including heart disease. A new study suggests that hot flashes (especially when accompanied by night sweats) also may increase the risk of developing diabetes.

As reported in “Vasomotor symptom characteristics: are they risk factors for incident diabetes?” data was analyzed from the more than 150,000 postmenopausal women who participated in the Women’s Health Initiative (WHI) to confirm that the occurrence of hot flashes was associated with an elevated diabetes risk. Of the total population studied, 33% of the women had experienced hot flashes. Any incidence of hot flashes was associated with an 18% increased diabetes risk, and this risk continued to climb on the basis of the severity and duration of the hot flashes. Moreover, diabetes risk was the most pronounced for women reporting any type of night sweats but only if the onset of hot flashes occurred late in the menopause transition.

Diabetes is a serious health risk currently affecting 15% of women aged 55 years and older. Its incidence is expected to more than double by 2050. Compared with men with diabetes, women with diabetes have a higher risk of being hospitalized for or dying from diabetes and its complications, which makes the timely identification and management of diabetes through lifestyle intervention or medical management critical.

This study showed that, after adjustment for obesity and race, women with more severe night sweats, with or without hot flashes, still had a higher risk of diabetes,” says Dr. JoAnn Pinkerton, NAMS executive director. “Menopause is a perfect time to encourage behaviour changes that reduce menopause symptoms, as well as the risk of diabetes and heart disease. Suggestions include getting regular exercise and adequate sleep, avoiding excess alcohol, stopping smoking, and eating a heart-healthy diet. For symptomatic women, hormone therapy started near menopause improves menopause symptoms and reduces the risk of diabetes.”

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Sandra Ishkanes
Functional Medicine Practitioner
BSc MA DipION

sandra@gynecologic.dream.press
Brighton, UK

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Connecting women, science and spirit, the Gynelogic Sunday Supplement delivers a bi-monthly dose of  news, views and reviews, as seen through my lady lens.