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

Jobe, Modou, Agbla, Schadrac C, Todorcevic, Marijana, Darboe, Bakary, Danso, Ebrima, De Barros, Jean-Paul Pais, Lagrost, Laurent, Karpe, Fredrik and Prentice, Andrew M (2022) Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia. INTERNATIONAL JOURNAL OF OBESITY, 46 (10). pp. 1892-1900.

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Official URL: http://dx.doi.org/10.1038/s41366-022-01193-1

Abstract

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>In lean women (n = 48; fat mass index (FMI) 9.6 kg/m<sup>2</sup>), women with obesity (n = 62; FMI 23.6 kg/m<sup>2</sup>) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m<sup>2</sup>) 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.<h4>Results</h4>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.<h4>Conclusions/interpretation</h4>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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Endotoxemia, Diabetes Mellitus, Type 2, Obesity, Inflammation, Mannitol, Lipopolysaccharides, Lactulose, Lipoproteins, Chylomicrons, Immunoglobulin G, Immunoglobulin M, RNA, Messenger, Interleukin-6, Gambia, Female
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health
Depositing User:	Symplectic Admin
Date Deposited:	25 Jan 2023 14:02
Last Modified:	25 Jan 2023 14:02
DOI:	10.1038/s41366-022-01193-1
Open Access URL:	https://doi.org/10.1038/s41366-022-01193-1
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3167888