Gut microbiota in diabetes and HIV: Inflammation is the link

Vicente Estrada; Noemi Gonzalez

摘要

Type-2 diabetes mellitus (T2D) is a common disease characterized by hyperglycemia, insulin resistance and relative reduction in insulin secretion. Its prevalence has markedly increased in parallel to the obesity epidemic associated with a sedentary lifestyle in the Western world. The etiology of T2D is exceptionally complex and includes a combination of varying degrees of insulin resistance and insulin deficiency, with multiple genetic and environmental factors involved. A chronic state of low- grade inflammation is postulated as the mediator that links obesity with insulin resistance, but its cause is not well-known. The relationship between microbiota, obesity, and T2D has been extensively studied. In a seminal work of Turnbaugh et al. [1] it was shown that microbiota transplantation from genetically obese mice to germ-free mice induced a significant weight gain, in comparison to those mice that received microbiota transplantation from thin mice. Obese mice show alteration in the diversity or structure of the intestinal microbiota, a situation known as dysbiosis, with a relative abundance of Firmicutes with a corresponding decrease in the amount of Bacteroidetes. This relative abundance of the genus Firmicutes could be responsible for an increase in the capacity to digest some indigestible polysaccharides, giving rise to monosaccharides and short-chain fatty acids (SCFA) capable of being absorbed by the host, thus obtaining more energy from caloric intake [2]. In T2D there is a reduction in the proportion of butyrate-producing bacteria with the ability to protect the intestinal mucosa [3]. This increase in intestinal permeability coupled with dysbiosis with a preponderance of bacteria capable of inducing inflammation could be the link between DM2, chronic inflammation, and microbiota. The reduced production of butyrate and other short-chain fatty acids (SCFA) may affect the production of specific intestinal peptides that influence body weight, glucose metabolism, gut barrier function, and.energy hemostasis. Also, the gut microbiota of T2D patients, mainly by the action of bacteria of the genus Firmicutes, can alter the metabolism of bile salts involved in insulin and GLP-1 production [4].HIV infection is associated with a significant inflammatory response and immune activation which does not entirely fade with antiretroviral therapy. Reduced diversity in gut microbiome composition has been shown in some studies, and there is an independent association between alpha-diversity of the microbiome and peripheral levels of CD4 lymphocyte in na?ve HIV-infected patients. Given the close interaction between the intestinal microbiota and gut immunity, it is suggestive to assume that the HIV patient's microbiota is partly responsible for these alterations. A direct effect of HIV on the gut mucosal barrier has been hypothesized as a cause of dysbiosis; this may induce a leak in gut mucosa resulting in increased translocation of bacterial products from the gut producing systemic inflammation [5]. A direct correlation has been found between levels of microbial translocation and representation of the Proteobacteria phylum in feces, suggesting that microbiome composition affects gut mucosa permeability. The proinflammatory state induced by HIV is also associated to derangements of tryptophan metabolism through an induction human indoleamine-2, 3-dioxygenase-1 (IDO-1), which results in the production of immunosuppressive kynurenine derivatives which impair mucosal immunity, resulting in bacterial translocation [6].Therefore, T2D and HIV infection have in common some gut microbiome alterations associated with a proinflammatory state. In the study published in EBioMedicine, JY Moon et al. [7] study the association between T2M or HIV infection and the differences in gut microbiota and plasma metabolomics. The authors examine the intestinal microbiota and a broad spectrum of metabolite profile of a population of women with diabetes with HIV. The selection of women avoids the bias of the influence of sexual orientation on the composition of the microbiota since men who have sex with men (MSM) show a significantly richer and more diverse fecal microbiota than non-MSM regardless of HIV infection [8]. The control group includes women at risk of HIV, making them fully comparable to the experimental group. The main findings are that in patients with T2D, regardless of HIV, there is a reduction in the relative proportion of several bacterial genera (Finegoldia, Anaerococcus, Sneathia, and Adlercreutzia). These bacteria are known to produce butyrate, which is associated to anti-inflammation and insulin sensitivity improvement; also, the presence of these bacteria is inversely related with kynurenine/tryptophan ratio, an indicator of tryptophan catabolism and involved in inflammation and bacterial translocation. The authors observed higher plasma levels of several metabolites of tryptophan catabolism and branched-chain amino acid and

机译：2型糖尿病（T2D）是一种常见疾病，其特征是高血糖，胰岛素抵抗和胰岛素分泌相对减少。与西方国家久坐的生活方式引起的肥胖病流行同时，其流行率显着增加。 T2D的病因异常复杂，包括不同程度的胰岛素抵抗和胰岛素缺乏症的结合，涉及多种遗传和环境因素。低度炎症的慢性状态被认为是将肥胖与胰岛素抵抗联系起来的介体，但其病因尚不清楚。微生物群，肥胖和T2D之间的关系已得到广泛研究。在Turnbaugh等人的开创性著作中。 [1]研究表明，与从瘦型小鼠接受微生物菌群移植的小鼠相比，从遗传性肥胖小鼠到无菌小鼠的微生物菌群移植可显着增加体重。肥胖小鼠的肠道菌群多样性或结构发生了变化，这种情况被称为营养不良，伴有相对较大的Firmicutes，而拟杆菌的数量相应减少。 Firmicutes属的这种相对丰度可能导致消化某些难消化的多糖的能力增加，从而导致单糖和短链脂肪酸（SCFA）能够被宿主吸收，从而从热量摄入中获取更多能量[2]。在T2D中，能够保护肠粘膜的丁酸产生菌比例减少[3]。肠道通透性的增加，再加上伴有营养不良的细菌，能够引起炎症，这可能是DM2，慢性炎症和微生物群之间的联系。丁酸酯和其他短链脂肪酸（SCFA）产量的减少可能会影响特定肠肽的产生，从而影响体重，葡萄糖代谢，肠屏障功能和能量止血。另外，T2D患者的肠道菌群主要通过Firmicutes属细菌的作用，可以改变参与胰岛素和GLP-1产生的胆汁盐的代谢[4]。HIV感染与明显的炎症反应和免疫相关抗逆转录病毒疗法不会完全消失。在一些研究中，肠道微生物组组成的多样性降低，并且在未经HIV感染的患者中，微生物组的α多样性与CD4淋巴细胞的外周水平之间存在独立的关联。鉴于肠道菌群和肠道免疫力之间的密切相互作用，建议假定HIV患者的菌群部分负责这些改变。有人认为，艾滋病毒对肠粘膜屏障的直接作用是引起营养不良的原因。这可能会导致肠粘膜渗漏，导致细菌产生肠道炎症而引起的细菌转运增加[5]。在粪便中微生物的转运水平和门氏杆菌的存在之间存在直接的相关性，这表明微生物组的组成会影响肠道粘膜的通透性。 HIV诱导的促炎状态还通过诱导人类吲哚胺-2，3-dioxygenase-1（IDO-1）导致色氨酸代谢紊乱，导致产生抑制粘膜免疫力的免疫抑制性犬尿氨酸衍生物，导致细菌易位[6]。因此，T2D和HIV感染共有一些与促炎状态有关的肠道微生物组改变。在发表于EBioMedicine的研究中，JY Moon等人。 [7]研究T2M或HIV感染与肠道菌群和血浆代谢组学差异之间的关联。作者检查了患有艾滋病的糖尿病女性人群的肠道菌群和广泛的代谢产物谱。女性的选择避免了性取向对微生物群组成的偏见，因为与男性性行为（MSM）相比，男性表现出比非MSM更加丰富和多样的粪便微生物群，而与HIV感染无关[8]。对照组包括有感染艾滋病毒的妇女，这使其与实验组完全可比。主要发现是，无论是否感染HIV，患有T2D的患者中，几种细菌属（Finegoldia，Anaerococcus，Sneathia和Adlercreutzia）的相对比例均降低了。已知这些细菌会产生丁酸酯，这与抗炎和改善胰岛素敏感性有关。同样，这些细菌的存在与犬尿氨酸/色氨酸比率成反比，后者是色氨酸分解代谢的指标，并参与炎症和细菌易位。作者观察到血浆中色氨酸分解代谢和支链氨基酸和

Gut microbiota in diabetes and HIV: Inflammation is the link

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