Long term but not short term exposure to obesity related microbiota promotes host insulin resistance

Kevin P Foley,Emmanuel Denou,Jonathan D Schertzer,Brittany M Duggan,Soumaya Zlitni,Rebecca W Chan,Jennifer C Stearns

doi:10.1038/s41467-018-07146-5

Kevin P Foley, Emmanuel Denou + Show 5 more

Open Access

https://doi.org/10.1038/s41467-018-07146-5

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Abstract

The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. We find that changes in the composition of the fecal microbiota precede changes in glucose tolerance when mice are fed obesogenic, low fiber, high fat diets (HFDs). Antibiotics alter glycemia during the first week of certain HFDs, but antibiotics show a more robust improvement in glycemic control in mice with protracted obesity caused by long-term feeding of multiple HFDs. Microbiota transmissible dysglycemia and glucose intolerance only occur when germ-free mice are exposed to obesity-related microbes for more than 45 days. We find that sufficient host exposure time to microbiota derived from HFD-fed mice allows microbial factors to contribute to insulin resistance, independently from increased adiposity in mice. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota.

Highlights

The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets
The microbiota has emerged as a factor in obesity, but less is known about how the microbiota could connect the progression of obesity to prediabetes and glycemic control
Three ill-defined concepts were: (1) the timing of changes in the constituents of the microbiota relative to the onset of obesity and glucose intolerance, (2) whether diet-induced changes in intestinal microbes could alter glycemia independently of altered adiposity, and (3) whether long or short term exposure to intestinal microbes from obesogenic diets contribute to dysglycemia

Summary

Introduction

The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. Ectopic lipid accumulation in the skeletal muscle and liver is associated with glucose intolerance after the first few days of HFD feeding, whereas metabolic tissue inflammation plays a more prominent role in propagating glucose intolerance after months of HFDfeeding in mice[13] It is not clear if diet-induced changes in the microbiota contribute to the mechanisms underpinning acute versus chronic insulin resistance and glucose intolerance. Our data support the concept that host exposure time is a key factor to consider in the development of dysglycemia and warrant caution in the assumption that continual evolution of the microbiota during long-term feeding of an obesogenic diet is required for poor host glucose control This time required for microbe factors to promote dysglycemia should be considered independent from obesity and despite rapid diet-induced changes in the microbiota

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