Bina Joe

Gut microbiota and bile acids are increasingly recognized to regulate blood pressure, but the mechanisms remain unclear. Takeda G-protein coupled receptor 5 (TGR5) is a major receptor for secondary bile acids. We hypothesized that loss of TGR5 function remodels gut microbiota and influences blood pressure. Using CRISPR/Cas9, TGR5 knockout (Tgr5KO) rats on the Dahl Salt-Sensitive (S) background were generated and characterized. Compared to the control S rats, Tgr5KO rats demonstrated significantly lower blood pressure, a distinct shift in gut microbiota composition, and an increase in the secondary bile acid, particularly, glycodeoxycholic acid. Supplementation of glycodeoxycholic acid to the control S rats produced a similar gut microbial shift and lowered blood pressure. Furthermore, cecal microbiota transplantation from Tgr5KO to control S rats lowered blood pressure in the recipient rats. This first loss-of-function study demonstrates that deletion of TGR5 remodels gut microbiota, increases glycodeoxycholic acid, and lowers blood pressure regardless of TGR5 signaling status, identifying a promising gut-liver axis target for lowering hypertension.

Aims: The transient receptor potential vanilloid 4 ion channel is widely expressed in the gastrointestinal tract and contributes to epithelial barrier regulation, mechanosensation and innate immune signaling. However, its role in shaping gut microbiota composition and intestinal metabolic homeostasis remains unclear. This study aimed to determine whether deletion of TRPV4 influences gut microbial composition and intestinal ammonia levels.Materials and Methods: Fecal microbiota from wild type and TRPV4 knockout mice were analyzed using taxonomic profiling and microbial diversity approaches. Alpha diversity and beta diversity metrics were used to evaluate microbial richness, evenness, phylogenetic diversity and community structure. Ammonia concentration and pH were measured in cecal and colonic contents.Key Findings: Phylogenetic diversity differed significantly between wild type and TRPV4 knockout mice whereas microbial richness and evenness were not altered. Beta diversity analysis revealed marked differences in microbial community composition between genotypes. The ratio of Bacillota to Bacteroidetes was reduced by approximately fifty percent in TRPV4 knockout mice due to decreased Bacillota and increased Bacteroidetes abundance. In addition, TRPV4 knockout mice exhibited significantly elevated ammonia levels in both the colon and cecum compared with wild type mice.Significance: Deletion of TRPV4 alters gut microbial community structure and intestinal nitrogen metabolism without affecting overall microbial richness or evenness. These findings identify TRPV4 as a novel regulator of gut microbiota composition and metabolic homeostasis and suggest that ion channel dependent signaling contributes to the regulation of gut microbial ecology and metabolite balance.

Cholemia, i.e., elevated circulating bile acids (BA), is an early feature of hepatobiliary disorders. However, cholemia often goes undetected because BA are not measured in routine health screenings. We hypothesized that the membrane-disrupting properties of BA might impact red blood cell (RBC) osmotic resistance (OR), potentially providing a means to detect cholemia. To test this, RBC OR was examined in multiple mouse models of cholemia, germ-free animals, and patients with cholestatic liver disease. RBC from cholemic mice exhibited markedly elevated OR against hypotonic NaCl, KCl and NH ₄ Cl solutions. Elevated OR was observed in an array of mouse models of cholemia, including mice with spontaneous portosystemic shunts, deficiencies in aryl hydrocarbon receptor, multidrug resistance protein 2 and farnesoid X receptor. The degree of OR correlated with serum BA levels. RBC OR increased upon ex vivo treatment with cholemic plasma or unconjugated BA. Conversely, the absence of gut microbiota in germ-free animals was associated with reduced BA levels and decreased RBC OR. Colonizing gut microbiota into germ-free animals via co-housing increased their RBC OR. RBC from patients with cholestatic liver disease also displayed increased OR, indicating potential human relevance. The elevated cholesterol-to-phospholipid ratio in the membranes of RBC from both cholemic mice and humans suggests increased membrane rigidity. Consistent with this, treatment with dimethyl sulfoxide to enhance membrane permeability reduced RBC OR. Taken together, these findings provide proof-of-concept that increased RBC OR is associated with cholemia and may serve as a basis for a whole-blood approach to its detection.

BACKGROUND: Altered gut microbiota composition has been implicated in the development of hypertension. Evidence suggests bacterial products and metabolites can enter circulation, act on peripheral tissues, and modulate blood pressure (BP). We identified extracellular vesicles (EVs) of bacterial origin (bacterial extracellular vesicles [bEVs]) in the circulation of spontaneously hypertensive stroke–prone rats (SHRSP). We hypothesized that bEVs mediate communication between microbiota and the host, and that bEVs from SHRSP microbiota contain unique cargo that promotes hypertension. METHODS: EVs were isolated from plasma and cecal content of SHRSP and Wistar-Kyoto (WKY) rats. Multiomics analysis, including 16S rRNA sequencing, small RNA sequencing, lipidomics, and proteomics were performed to assess the cargo of bEVs. BEVs from WKY and SHRSP were transplanted by oral gavage to WKY and SHRSP recipients, and the effects on BP and sympathetic activity were monitored. The potential role of bEVs on BP was also evaluated in Dahl salt sensitive (S) and obstructive sleep apnea models of hypertension. RESULTS: Significant differences were observed in WKY and SHRSP bEV cargo, including small RNAs, proteins, and PAMPs (pathogen-associated molecular patterns). Transplantation of SHRSP bEVs to WKY rats increased renal sympathetic nerve activity and elevated BP. Moreover, we showed that bEVs influence BP regulation in Dahl S and obstructive sleep apnea–induced hypertension. CONCLUSIONS: Our findings position bEVs as critical mediators of microbiota-host communication in BP regulation and demonstrate that bEVs from the altered SHRSP microbiota promote hypertension. Our findings shed new light on the role of bEVs in hypertension pathogenesis and offer new perspectives for diagnostics and therapeutic interventions.

Glyphosate, the active ingredient in herbicide Roundup, is the most widely used environmental contaminant that has been extensively studied for its potential carcinogenic effects. In the US alone, a staggering 81% of the US population ≥6 years of age is exposed to glyphosate. Notably, this coincides with the alarming rise in the incidence of hypertension, the single largest risk factor for global mortality through cardiovascular diseases. Here we asked if there is a link between glyphosate exposure and hypertension, the premise being that glyphosate targets the shikimate pathway present in gut microbiota coupled with more recent knowledge that gut microbiota causally regulate blood pressure. We hypothesized that glyphosate elevates hypertension through microbiota-mediated mechanisms and document a highly concerning detrimental effect of glyphosate by demonstrating a causal link between oral glyphosate exposure and significant elevation in blood pressure. Gut microbiota was identified as the central mediator of this effect. Mechanistically, glyphosate-mediated elevation in blood pressure was through disruption of both gut–liver and gut-vascular homeostasis via FXR-signaling and accumulation of the microbial metabolite shikimic acid, respectively. Together, these findings underscore the need to reconsider the unabated use of this herbicide, which adversely affects a cardinal sign of health.

The dietary switch to inulin, a fermentable fiber, reduced salt-sensitive hypertension and kidney injury in male and female Dahl SS rats, and caused gut microbiota composition shifts and increases in SCFA production (propionate and butyrate). Direct administration of propionate ameliorated salt-sensitivity in males, which coincided with renal T regulatory cell expansion. These findings provide the mechanistic basis for leveraging the microbiota and its metabolites through dietary interventions as a therapeutic for hypertension and kidney disease.

Physiological Genomics (PG) published its first issue in July 1999, with the goal of providing a forum for scientists to exchange ideas and scientific results related to the linkage between genetic information and physiological function. In this review, past and present editors reflect on PG’s role in the scientific community, the founding of the journal and the historical context in which it was formed within the American Physiological Society (APS). The editors reflect on a critical conference that united physiologists and geneticists and their determination for APS to take the lead in integrating these communities. In the past 25 years, key technologies for linking genes to physiology including methods for DNA sequencing, connecting genotype with phenotype, and monitoring gene expression, metabolites, and microbiota have all been revolutionized, creating a dynamic scientific environment that has resulted in highly impactful research across a wide range of fields. As methods, technologies, and data analysis tools have developed, PG has been a consistent forum for sharing cutting-edge research on the latest advances in the rapidly evolving field of linking molecular data to physiological function. This article highlights the key technological advances related to the connection between genes and physiology. The contribution of the journal to the scientific community during the time periods of each of the five Editors-in-Chief are summarized, illuminating key technological approaches featured in PG and scientific questions that were addressed. The article ends with a look forward, describing what the authors anticipate for the future of PG.

Hypertension is the single largest modifiable risk factor for chronic cardiovascular and renal diseases and strokes. Approximately 47% of American adults have hypertension. Despite the existence of pharmacological treatments, we remain highly vulnerable to the incidence of hypertension. Research in the past decade has identified microbiota as a previously unrecognized factor that regulates blood pressure. Because microbiota depends on the host food for its sustenance, diet presents as a potential factor to remodel microbiota composition and, thereby, affect blood pressure. Here, we survey the dietary sources of the 6 major food components: carbohydrates, proteins, fats, minerals, vitamins, and water for their ability to influence gut microbiota–mediated blood pressure regulation. Furthermore, beyond food components per se, we discuss how food additives and chemicals used in current agricultural practices could adversely remodel gut microbiota composition and contribute to hypertension. The goal of our work here is 2-prong: (1) to better understand why certain dietary components are beneficial over others for hypertensives because of their ability to remodel gut microbiota composition and (2) to advocate for further research and implementations of dietary interventions in the treatment of hypertension based on their ability to modulate gut microbiota.

BACKGROUND: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. METHODS: We used the same animal protocol previously used for the discovery of the reno-protective effect of β-hydroxybutyrate. Briefly, postweaning, male and female Dahl Salt-Sensitive rats were split into 2 groups and supplemented with or without 1,3-butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations RESULTS: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation, and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was Hmgcs2 (3-hydroxy-3-methylglutaryl CoA synthase 2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, Ptprc (protein tyrosine phosphatase receptor type C) and Lcp1 (lymphocyte cytosolic protein 1), which were suppressed. CONCLUSIONS: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.