Oral Presentation ESA-SRB-AOTA 2019

Gut-derived serotonin is synthesised in sensory cells that influence peripheral metabolism (#95)

Alyce M Martin 1 , Julian M Yabut 2 , Amanda L Lumsden 1 , Richard L Young 3 , Jocelyn M Choo 4 5 , Amanda J Page 3 , Waliul I Khan 2 6 , Geraint B Rogers 4 5 , Gregory R Steinberg 2 6 7 , Damien J Keating 1 3
  1. Centre for Neuroscience and College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
  2. Centre for Metabolism, Obesity & Diabetes Research, McMaster University, Hamilton, Ontario, Canada
  3. Nutrition & Metabolism, South Australian Health and Medical Research Insititue, Adelaide, South Australia, Australia
  4. Microbiome Research Laboratory, Flinders University, Bedford Park, SA, Australia
  5. Microbiome & Host Health, South Australian Health and Medical Research Insititue, Adelaide, South Australia, Australia
  6. Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  7. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

Gut-derived 5-HT, produced by enterochromaffin (EC) cells within the mucosal lining of the gastrointestinal tract, is a known metabolic regulator and is augmented in human obesity and diabetes. However, very little is known about the cellular changes to EC cells which may contribute to the increase in plasma 5-HT observed under these conditions. The gut microbiome also has a substantial influence on host metabolism, however the mechanisms behind this are also not well understood. EC cells are important nutrient sensors within the gut and are influenced by the gut microbiome. We therefore aimed to (1) determine what changes to nutrient sensing occur in EC cells from obese humans and mice and (2) determine if the gut microbiome influences host metabolism via effects on gut-derived 5-HT.

We find that high fat diet (HFD) consumption alters EC cell nutrient sensing in a region-dependent manner. Specifically, broad sugar sensing by duodenal EC cells is reduced in primary EC cells from HFD mice, while only glucose sensing is affected in colonic EC cells. EC cell proliferation is increased 2-fold in obese humans and mice, and correlates with both fasting plasma glucose and circulating 5-HT. Furthermore, reduction of 5-HT synthesis and antibiotic-induced microbial dysbiosis independently improve glucose handling, but no additive effect of combining the two treatments is observed. This effect is not due to changes in energy expenditure, feeding behaviour or activity levels. This suggests that the gut microbiome acts through gut-derived 5-HT to influence host glucose handling and metabolism.