There is increasing evidence of the influence of the gut microbiota on hypertension and its complications, such as chronic kidney disease, stroke, heart failure, and myocardial infarction. This is not surprising considering that the most common risk factors for hypertension, such as age, sex, medication, and diet, can also impact the gut microbiota. For example, sodium and fermentable fiber have been studied in relation to both hypertension and the gut microbiota. By combining second- and, now, third-generation sequencing with metabolomics approaches, metabolites, such as short-chain fatty acids and trimethylamine N-oxide, and their producers, have been identified and are now known to affect host physiology and the cardiovascular system. The receptors that bind these metabolites have also been explored with positive findings—examples include known short-chain fatty acid receptors, such as G-protein coupled receptors GPR41, GPR43, GPR109a, and OLF78 in mice. GPR41 and OLF78 have been shown to have inverse roles in blood pressure regulation, whereas GPR43 and GPR109A have to date been demonstrated to impact cardiac function. New treatment options in the form of prebiotics (eg, dietary fiber), probiotics (eg, Lactobacillus spp.), and postbiotics (eg, the short-chain fatty acids acetate, propionate, and butyrate) have all been demonstrated to be beneficial in lowering blood pressure in animal models, but the underlying mechanisms remain poorly understood and translation to hypertensive patients is still lacking. Here, we review the evidence for the role of the gut microbiota in hypertension, its risk factors, and cardiorenal complications and identify future directions for this exciting and fast-evolving field.

BACKGROUND: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 (G-protein-coupled receptor 41) and GPR43 (G-protein-coupled receptor 43), which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown. METHODS: Cardiovascular phenotype was assessed in untreated and Ang II (angiotensin II) treated hypertensive wild-type and GPR41/43 knockout (KO) double knockout male mice fed diets with different levels of fiber content. Some mice received TLR4 (toll-like receptor 4)-antagonist treatment and bone marrow chimeras. SNPs (single-nucleotide polymorphisms) associated with GPR41 and GPR43 expression were assessed in UK Biobank participants. RESULTS: Untreated GPR41/43KO mice had unaltered blood pressure but had greater cardiac and renal collagen deposition with higher macrophage numbers in the kidney compared with wild-type mice. Ang II–treated GPR41/43KO mice showed higher systolic blood pressure, cardiorenal weights and collagen deposition, and increased gut permeability, which allows the translocation of gastrointestinal bacterial components such as lipopolysaccharides into the circulation. The use of an antagonist to the lipopolysaccharide receptor, TLR4, a potent proinflammatory signaling molecule, restored the cardiovascular phenotype in GPR41/43KO mice. The lack of GPR41/43 expression in the immune compartment was sufficient to lead to a worsened hypertensive phenotype. We also demonstrate that GPR41/43 is, at least partially, responsible for the blood pressure–lowering and cardioprotective effects of a high-fiber diet. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41 and GPR43 are more prevalent in participants with hypertension. CONCLUSIONS: Our findings highlight that lack of short-chain fatty acid-receptor signaling via both GPR41 and GPR43 increases risk of high blood pressure, suggesting treatments that target these receptors could be a novel strategy to prevent or treat hypertension.

Alzheimer’s disease (AD) is a neurodegenerative disorder with poorly understood etiology. AD has several similarities with other “Western lifestyle” inflammatory diseases, where the gut microbiome and immune pathways have been associated. Previously, we and others have noted the involvement of metabolite-sensing GPCRs and their ligands, short-chain fatty acids (SCFAs), in protection of numerous Western diseases in mouse models, such as Type I diabetes and hypertension. Depletion of GPR43, GPR41, or GPR109A accelerates disease, whereas high SCFA yielding diets protect in mouse models. Here, we extended the concept that metabolite-sensing receptors and SCFAs may be a more common protective mechanism against Western diseases by studying their role in AD pathogenesis in the 5xFAD mouse model. Both male and female mice were included. Depletion of GPR41 and GPR43 accelerated cognitive decline and impaired adult hippocampal neurogenesis in 5xFAD and WT mice. Lack of fiber/SCFAs accelerated a memory deficit, whereas diets supplemented with high acetate and butyrate (HAMSAB) delayed cognitive decline in 5xFAD mice. Fiber intake impacted on microglial morphology in WT mice and microglial clustering phenotype in 5xFAD mice. Lack of fiber impaired adult hippocampal neurogenesis in both W and AD mice. Finally, maternal dietary fiber intake significantly affects offspring’s cognitive functions in 5xFAD mice and microglial transcriptome in both WT and 5xFAD mice, suggesting that SCFAs may exert their effect during pregnancy and lactation. Together, metabolite-sensing GPCRs and SCFAs are essential for protection against AD, and reveal a new strategy for disease prevention.Significance StatementAlzheimer’s disease (AD) is one of the most common neurodegenerative diseases; currently, there is no cure for AD. In our study, short-chain fatty acids and metabolite receptors play an important role in cognitive function and pathology in AD mouse model as well as in WT mice. SCFAs also impact on microglia transcriptome, and immune cell recruitment. Out study indicates the potential of specialized diets (supplemented with high acetate and butyrate) releasing high amounts of SCFAs to protect against disease.

Atopic dermatitis (AD) is a globally prevalent skin inflammation with a particular impact on children. Current therapies for AD are challenged by the limited armamentarium and the high heterogeneity of the disease. A novel promising therapeutic target for AD is the microbiota. Numerous studies have highlighted the involvement of the skin and gut microbiota in the pathogenesis of AD. The resident microbiota at these two epithelial tissues can modulate skin barrier functions and host immune responses, thus regulating AD progression. For example, the pathogenic roles of Staphylococcus aureus in the skin are well-established, making this bacterium an attractive target for AD treatment. Targeting the gut microbiota is another therapeutic strategy for AD. Multiple oral supplements with prebiotics, probiotics, postbiotics, and synbiotics have demonstrated promising efficacy in both AD prevention and treatment. In this review, we summarize the association of microbiota dysbiosis in both the skin and gut with AD, and the current knowledge of the functions of commensal microbiota in AD pathogenesis. Furthermore, we discuss the existing therapies in manipulating both the skin and gut commensal microbiota to prevent or treat AD. We also propose potential novel therapies based on the cutting-edge progress in this area.

Circulating cell-free mtDNA (ccf-mtDNA) is presumably derived from injured tissue or cells in the body and has been suggested to be a potential biomarker in several diseases. In the present study, we investigated whether ccf-mtDNA levels could serve as a biomarker of diabetic patients without Coronary Heart Disease (CHD) and correlate with their incidence to develop CHD. Ccf-mtDNA levels in plasma and the traditional CHD risk factors were determined in 50 type 2 diabetes (DM) with CHD and 50 DM without CHD patients and 50 age- and sex-matched healthy controls. MtDNA levels were assessed by measuring the NADH dehydrogenase 1 gene using quantitative real-time PCR. ROC curve analyses of plasma mtDNA in DM with or without CHD were also determined. Multivariate logistic regression analyses were conducted to determine the correlation between the mtDNA levels and traditional CHD risk factors. The plasma ccf-mtDNA levels and CRP were significantly elevated in DM compared with healthy controls, and a consistent increase of mtDNA in diabetes with CHD compared to those without CHD. The area under the ROC curves of mtDNA in DM patients versus DM patients with CHD and healthy controls was 0.843 and 0.898, respectively. Correlation analyses showed that the mtDNA levels were significantly correlated with that of C-reactive protein (CRP) in patients with CHD. Ccf-mtDNA was elevated in type 2 diabetes with CHD and correlated with CRP levels. Both may be considered a prognostic biomarker of CHD development.