Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia

Abstract

Aims/hypothesis: Translocation of bacterial debris from the gut causes metabolic endotoxemia (ME) that results in insulin resistance, and may be on the causal pathway to obesity-related type 2 diabetes. To guide interventions against ME we tested two hypothesised mechanisms for lipopolysaccharide (LPS) ingress: a leaky gut and chylomicron-associated transfer following a high-fat meal.

Methods: In lean women (n = 48; fat mass index (FMI) 9.6 kg/m²), women with obesity (n = 62; FMI 23.6 kg/m²) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m²) we used the lactulose-mannitol dual-sugar permeability test (LM ratio) to assess gut integrity. Markers of ME (LPS, EndoCAb IgG and IgM, IL-6, CD14 and lipoprotein binding protein) were assessed at baseline, 2 h and 5 h after a standardised 49 g fat-containing mixed meal. mRNA expression of markers of inflammation, macrophage activation and lipid metabolism were measured in peri-umbilical adipose tissue (AT) biopsies.

Results: The LM ratio did not differ between groups. LPS levels were 57% higher in the obesity-diabetes group (P < 0.001), but, contrary to the chylomicron transfer hypothesis, levels significantly declined following the high-fat challenge. EndoCAb IgM was markedly lower in women with obesity and women with obesity-diabetes. mRNA levels of inflammatory markers in adipose tissue were consistent with the prior concept that fat soluble LPS in AT attracts and activates macrophages.

Conclusions/interpretation: Raised levels of LPS and IL-6 in women with obesity-diabetes and evidence of macrophage activation in adipose tissue support the concept of metabolic endotoxemia-mediated inflammation, but we found no evidence for abnormal gut permeability or chylomicron-associated post-prandial translocation of LPS. Instead, the markedly lower EndoCAb IgM levels indicate a failure in sequestration and detoxification.

Fig. 1. Gut permeability and markers of LPS translocation, sequestration and the inflammatory response.

A Lactulose-mannitol assessment of gut permeability. Mannitol recovery assesses transcellular passage across enterocytes, lactulose recovery assesses paracellular passage and the lactulose-mannitol ratio assess permeability. B Predictive (age-adjusted) geometric mean of esterified 3HM and associated inflammatory and immunological markers at fasting, 2 h and 5 h post prandial. Plots shows geometric means and 95% confidence interval.

Fig. 2. Relative gene expression in subcutaneous adipose tissue biopsy.

LBP lipopolysaccharide binding protein, IL-6 interleukin-6, TNF tumour necrosis factor-α, PPARG Peroxisome Proliferator-Activated Receptor Gamma, LPL lipoprotein lipase, CD11c is a marker for monocytes and macrophages; CD206 (macrophage mannose receptor) is a marker for alternatively activated macrophages; CD68 is a marker for tissue macrophages; WO women with obesity, WOD women with obesity and diabetes.