Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

Background-Angiotensin II induces both cardiac and vascular smooth muscle (VSM) hypertrophy. Recent studies suggest a central role for a phagocyte-type NADPH oxidase in angiotensin II-induced VSM hypertrophy. The possible involvement of an NADPH oxidase in the development of cardiac hypertrophy has not been studied. Methods and Results-Mice with targeted disruption of the NADPH oxidase subunit gp91 phox (gp91 phoxϪ/Ϫ ) and matched wild-type mice were subjected to subcutaneous angiotensin II infusion at a subpressor dose (0.3 mg/kg/day) for 2 weeks. Systolic blood pressure was unaltered by angiotensin II in either group. Angiotensin II significantly increased heart/body weight ratio, atrial natriuretic factor and ␤-myosin heavy chain mRNA expression, myocyte area, and cardiac collagen content in wild-type but not gp91 phoxϪ/Ϫ mice. Angiotensin II treatment increased myocardial NADPH oxidase activity in wild-type but not gp91 phoxϪ/Ϫ mice. Conclusions-A gp91phox -containing NADPH oxidase plays an important role in the development of angiotensin II-induced cardiac hypertrophy, independent of changes in blood pressure. Key Words: hypertrophy Ⅲ angiotensin Ⅲ free radicals Ⅲ myocardium A ngiotensin II (Ang II) plays an important role in the development and progression of cardiac hypertrophy. 1 ACE inhibitors and Ang II receptor antagonists attenuate cardiac hypertrophy, both experimentally and in hypertensive patients. 1 Multiple signaling pathways, eg, protein kinase C, mitogen-activated protein kinases (MAPKs), and others, are implicated in Ang II-induced cardiac hypertrophy. 2 Recent studies suggest that Ang II mediates vascular smooth muscle (VSM) hypertrophy via production of intracellular reactive oxygen species (ROS), which activate crucial signaling cascades and have mitogenic effects. 3,4 ROS production has also been implicated in cardiomyocyte hypertrophy. 2,5 Phagocyte-type NADPH oxidases, a major source of ROS in cardiovascular cells, are implicated in Ang II-induced VSM hypertrophy 4 and hypertension. 6 These oxidases are expressed in endothelium, 7,8 VSM, 4 adventitial fibroblasts, 9 and cardiomyocytes. 10 In endothelium and fibroblasts, gp91 phox is the major subunit responsible for enzyme activity, whereas in VSM, homologues such as nox1 may be more important. 11 To date, the potential role of a gp91 phoxcontaining NADPH oxidase in the development of cardiac hypertrophy has not been studied. MethodsExperiments were performed in accordance with the Guidance on the Operation of Animals (Scientific Procedures) Act, 1986 (UK) on male gp91 phoxϪ/Ϫ mice 12 (The Jackson Laboratory, Maine) and matched wild-type controls with the same genetic background (C57BL/6J). gp91 phox mRNA expression was analyzed by reverse transcriptionpolymerase chain reaction (RT-PCR) in left ventricle (LV) homogenate and isolated cardiomyocytes, using specific primers targeted to exon 3, which is disrupted in gp91 phoxϪ/Ϫ mice. 12 NADPH Oxidase ActivityIsolated gp91 phoxϪ/Ϫ and control hearts (nՆ4/group) were perfused with Ang II (0....