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.

No abstract

The correlations among serum ferritin and diastolic blood pressure, HDL quotient, glucose area under the curve, and SI suggest that serum ferritin could be a marker of the insulin resistance syndrome. Serum ferritin may also be an independent determinant of poor metabolic control in the diabetic patient.

Type 2 diabetes and the insulin resistance syndrome have been hypothesized to constitute manifestations of an ongoing acute-phase response. We aimed to study an interleukin-6 (IL-6) gene polymorphism in relation to insulin sensitivity (I L-6 is the main cytokine involved in an acute-phase response). Subjects homozygous for the C allele at position -174 of the IL-6 gene (SfaNI genotype), associated to lower plasma IL-6 levels, showed significantly lower integrated area under the curve of serum glucose concentrations (AUC glucose ) after an oral glucose tolerance test, lower blood glycosylated hemoglobin, lower fasting insulin levels, lower total and differential white blood cell count (a putative marker of peripheral IL-6 action), and an increased insulin sensitivity index than carriers of the G allele, despite similar age and body composition. A gene dosage effect was especially remarkable for AUC g l u c o s e (6.4 vs. 9.3 vs. 9 . 7 mmol/l in C/C, C/G, and G/G individuals, respectively). The serum concentration of fully glycosylated cortisol binding globulin (another marker of IL-6 action), suggested by concanavalin A adsorption, was lower in C/C subjects than in G/G individuals (32.6 ± 2.9 vs. 37.6 ± 4.6 mg/l, P = 0.03). In summary, a polymorphism of the I L-6 gene influences the relationship among insulin sensitivity, postload glucose levels, and peripheral white blood cell count. Diabetes 49:517-520, 2000 I t has been hypothesized that type 2 diabetes and the insulin resistance syndrome are partly a manifestation of an ongoing acute-phase response (1,2). This hypothesis is based on the findings of increased blood concentrations of markers of the acute-phase response, including C-reactive protein, serum amyloid-A, -1 acid glycoprotein, sialic acid, and cortisol (1-4).Interleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of the acute-phase reaction, immune responses, and hematopoiesis. Plasma IL-6 levels are elevated in type 2 diabetic patients, particularly in those with features of the insulin resistance syndrome (1,2). Although the concentrations of multiple components of the acute-phase response increase together, not all of them increase uniformly in all patients. These variations indicate that the components of the acute-phase response are individually regulated, and this may be explained in part by differences in the pattern of production of specific cytokines (5). Recently, it has been reported that a polymorphism in the 5 flanking region of the I L-6 gene alters the transcriptional response to stimuli such as endotoxin and IL-1 (6).In addition to its role in acute-phase response, IL-6 has been recently shown to be released by adipose tissue, and this release is greater in obese subjects, especially in those with a higher waist-to-hip ratio (7). Furthermore, IL-6 increases p o s t p r a n d i a l l y, in parallel to glucose and insulin levels, in the interstitial fluid of subcutaneous adipose tissue (8). This increase suggests that IL-6 might modulate adipose glucose metabolism in the...

A distinct microbiota profile and microbiome is present in GDM. Acinetobacter has been recently shown to induce IL-10 in mice. GDM could constitute a state of placental microbiota-driven altered immunologic tolerance, making placental microbiota a new target for therapy in GDM.