Emerging evidence suggests that gut microbiota is critical in the maintenance of physiological homeostasis. The present study was designed to test the hypothesis that dysbiosis in gut microbiota is associated with hypertension since genetic, environmental, and dietary factors profoundly influence both gut microbiota and blood pressure. Bacterial DNA from fecal samples of two rat models of hypertension and a small cohort of patients was used for bacterial genomic analysis. We observed a significant decrease in microbial richness, diversity, and evenness in the spontaneously hypertensive rat, in addition to an increased Firmicutes to Bacteroidetes ratio. These changes were accompanied with decreases in acetate- and butyrate-producing bacteria. Additionally, the microbiota of a small cohort of human hypertension patients was found to follow a similar dysbiotic pattern, as it was less rich and diverse than that of control subjects. Similar changes in gut microbiota were observed in the chronic angiotensin II infusion rat model, most notably decreased microbial richness and an increased Firmicutes to Bacteroidetes ratio. In this model, we evaluated the efficacy of oral minocycline in restoring gut microbiota. In addition to attenuating high blood pressure, minocycline was able to rebalance the dysbiotic hypertension gut microbiota by reducing the Firmicutes to Bacteroidetes ratio. These observations demonstrate that high BP is associated with gut microbiota dysbiosis, both in animal and human hypertension. They suggest that dietary intervention to correct gut microbiota could be an innovative nutritional therapeutic strategy for hypertension.
An imbalance of commensal bacteria and their gene products underlies mucosal and, in particular, gastrointestinal inflammation and a predisposition to cancer. Lactobacillus species have received considerable attention as examples of beneficial microbiota. We have reported previously that deletion of the phosphoglycerol transferase gene that is responsible for lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus (NCK2025) rendered this bacterium able to significantly protect mice against induced colitis when delivered orally. Here we report that oral treatment with LTA-deficient NCK2025 normalizes innate and adaptive pathogenic immune responses and causes regression of established colonic polyps. This study reveals the proinflammatory role of LTA and the ability of LTA-deficient L. acidophilus to regulate inflammation and protect against colonic polyposis in a unique mouse model. dendritic cells | regulatory T cells | anti-inflammatory I dentifying bacterial gene products that enhance protective versus pathogenic inflammation in the gut is critical to rebalance homeostasis in gastrointestinal (GI) chronic inflammatory diseases and malignancies. Commensal Lactobacillus species (i.e., Lactobacillus acidophilus) are normal inhabitants of the natural microbiota in the human GI tract (1, 2). L. acidophilus stimulates innate cells to produce inflammatory and regulatory cytokines through interaction of their surface layer proteins and other cell surface components (3-7). To investigate the potential role of lipoteichoic acid (LTA) of L. acidophilus in the induction of inflammatory signals, we deleted the phosphoglycerol transferase gene (LBA0447) that synthesizes LTA. LTA is a zwitterionic glycolipid found in the cell wall of several Gram-positive bacterial strains, including L. acidophilus, which stimulates dendritic cells (DCs) through Toll-like receptor 2, resulting in cytokine release (8, 9). Disruption of LTA synthesis generated a L. acidophilus derivative (NCK2025) that mitigates colitis in mice (10). Based on these observations and those of others (11,12), it was proposed that LTA induces inflammation and that its absence significantly attenuates overt intestinal inflammation.Inflammation has a tumor-promoting role in mice with polyposis and in human colon cancer (13)(14)(15)(16)(17). T regulatory cells (Tregs) critically regulate inflammation and play a protective role in polyposis (15, 18) and colon cancer (19-21). However, chronic interaction of Tregs with proinflammatory cells and their cytokines can reverse the anti-inflammatory properties of these cells and render them proinflammatory (15,16,22,23). Consensus suggests that interactions between lymphocytes and myeloid cells regulate pro-vs. antitumor immunity (17, 24), and we hypothesized that the gut microbiota plays an essential role in control of this balance. We used L. acidophilus NCK2025, deficient in LTA, to investigate the moderation of pathogenic inflammation within the tumor microenvironment in a unique mouse model of colonic polyposis...
Intestinal immune regulatory signals govern gut homeostasis. Breakdown of such regulatory mechanisms may result in inflammatory bowel disease (IBD). Lactobacillus acidophilus contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA), which interact with pattern recognition receptors to mobilize immune responses. Here, to elucidate the role of SlpA in protective immune regulation, the NCK2187 strain, which solely expresses SlpA, was generated. NCK2187 and its purified SlpA bind to the C-type lectin SIGNR3 to exert regulatory signals that result in mitigation of colitis, maintenance of healthy gastrointestinal microbiota, and protected gut mucosal barrier function. However, such protection was not observed in Signr3 À/À mice, suggesting that the SlpA/SIGNR3 interaction plays a key regulatory role in colitis. Our work presents critical insights into SlpA/SIGNR3-induced responses that are integral to the potential development of novel biological therapies for autoinflammatory diseases, including IBD.
The intestinal epithelium is equipped with sensing receptor mechanisms that interact with luminal microorganisms and nutrients to regulate barrier function and gut immune responses, thereby maintaining intestinal homeostasis. Herein, we clarify the role of the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific Casr−/− mice. Epithelial CaSR deficiency diminished intestinal barrier function, altered microbiota composition, and skewed immune responses towards proinflammatory. Consequently, Casr−/− mice were significantly more prone to chemically induced intestinal inflammation resulting in colitis. Accordingly, CaSR represents a potential therapeutic target for autoinflammatory disorders, including inflammatory bowel diseases.
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