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  • Antibiotic treatment suggests that cancer promoting bacteria

    2021-09-22

    Antibiotic treatment suggests that cancer-promoting bacteria arise from the cp-690550 of Grp109a mice. How does the lack of Gpr109a signaling lead to expansion of potentially cancer-promoting bacteria? Is this phenomenon related to improper development of intestinal Treg cells? Biome with cancer-promoting and cancer-protecting function seems to coexist and factors (host genetics, diet, etc.) altering this balance would probably have functional consequence for the host (Schwabe and Jobin, 2013). Future studies would be required to address these issues. The intestinal mucosa is bombarded by signals derived from the magma of bacteria and bacterial products present in the intestinal environment. This disparate collection of microbial cues is unlikely to elicit a uniform response from the gut. For example, the microbial structural component polysaccharide A present on Bacteroides fragilis contributes to intestinal homeostasis by promoting differentiation of Foxp3+ Treg cells (Round and Mazmanian, 2010), whereas segmented filamentous bacterium (SFB) favors the differentiation of CD4+ T helper cells into Th17 cells, a more proinflammatory phenotype (Ivanov et al., 2009). Similarly, as reported here and in other studies, microbial-derived metabolites (SCFA) also trigger an immune response from the host. How are these numerous and disparate microbial cues (structural products, metabolites, etc.) integrated into a cohesive and coordinate response by the host? This dichotomy between the deleterious and protecting function of the microbiota and associated microbial products clearly illustrate challenges facing researchers working on this complex system. Regardless, manipulating host immune response by altering microbial composition and activities through dietary intervention and/or specific host receptors could represent a powerful mean to promote and/or maintain intestinal homeostasis. Understanding the various elements implicated in the complex dialog between bacteria and the host holds much promise for pathologies such as IBD and CRC.
    Introduction Adipocytes express a number of cell surface receptors that contribute to their ability to sense metabolic changes in the surrounding environment, including GPR109A and GPR81. In 2003, GPR109A was identified as the receptor for the beneficial lipid-altering drug, niacin [1], [2], [3]. However, under physiological conditions, plasma concentrations of niacin do not reach levels high enough to activate the receptor, making it unlikely to be the endogenous ligand. In 2005, Taggart et al. demonstrated that β-hydroxybutyrate, a ketone body produced by the liver, is an endogenous ligand for GPR109A [4]. β-Hydroxybutyrate activates GPR109A and inhibits adipocyte lipolysis at concentrations seen during a 2–3day fast, with an EC50 of 767±57μM [4]. β-Hydroxybutyrate may represent a homeostatic mechanism for surviving starvation by acting in a negative feedback manner to inhibit lipolysis. In this manner, β-hydroxybutyrate can regulate its own production by decreasing the serum level of fatty acid precursors available for hepatic ketogenesis [4] and possibly preserving lipid stores during a prolonged fast [5]. GPR109A is predominantly expressed in adipocytes of white and brown adipose tissue, and is expressed to a lesser extent in keratinocytes and immune cells, including dermal dendritic cells, monocytes, macrophages and cp-690550 neutrophils [1], [2], [3], [6], [7], [8]. GPR81 shares a 52% amino acid sequence identity in humans to GPR109A [1], [2], [3]. In addition, GPR81 is localized more specifically to the adipose tissue [3]. In 2008, lactate was discovered to be the endogenous ligand for GPR81 [9], [10]. Plasma lactate levels reach concentrations capable of activating the receptor during bouts of intense exercise, with an EC50 of ∼5mM [10]. Infusion of lactate reduces lipolysis in vivo[11], [12], [13] as does treatment of adipocytes in vitro[14], [15]. The effect of lacate to reduce lipolysis is mediated through activation of GPR81 [9], [10]. However, these effects are somewhat controversial, as studies have demonstrated that the receptor is not involved in the regulation of lipolysis during intensive exercise when lactate concentrations are elevated [16].