To investigate the pathological role of microbiome-derived tryptamine and phenethylamine in the aspartame-induced insulin resistance

Project: Research project

Project Details

Description

Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal and clinical studies suggest that sweeteners consumption induces microbiome-dependent insulin resistance, raising the safety concern of NNS consumptions on human metabolic health. Currently, the mechanism by which NNS-induced microbiome alterations contribute to the insulin resistance remains largely unknown.

In our recent study (Nature Communications, 2023), we demonstrated that tryptamine and phenethylamine derived from microbiome-mediated catabolism of dietary aromatic amino acids impairs insulin sensitivity in metabolic syndrome. We showed that tryptamine and phenethylamine were positively associated with insulin resistance in patients with type 2 diabetes. Monoassociation of Ruminococcus gnavus, a human gut bacterium that majorly produces tryptamine and phenethylamine, impaired insulin sensitivity and glucose control in germ-free mice. Mechanistically, tryptamine and phenethylamine directly impaired insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. In our follow-up study, we further demonstrated that the levels of tryptamine and phenethylamine were significantly elevated in the faeces and sera of mice after 10-week supplementation with aspartame, a common sweetener that has been found to induce microbiome-dependent glycaemic alterations. We then analysed the catalytic ability of gut microbiota from aspartame-treated mice and vehicle-treated controls by batch culture studies using their fecal samples in vitro. Higher concentrations of tryptamine and phenethylamine were detected in the culture medium supplemented with the bacterial suspension of aspartame-treated fecal samples, suggesting that the aspartame supplementation led to the enrichment of tryptamine- and phenethylamine-producing bacteria. Notably, we found that aspartame-induced elevation of fecal tryptamine and phenethylamine was effectively suppressed by supplementation with pectin, a soluble dietary fibre that is known to be beneficial for the management of diabetes through modulation of gut microbiota. Based on these observations, we hypothesize that aspartame may lead to the insulin resistance through the enrichment of microbiome-derived tryptamine and phenethylamine.

To address the research hypothesis, we will investigate (1) the pathological role of microbiome-derived tryptamine and phenethylamine in the aspartame-induced insulin resistance & (2) the therapeutic potential of dietary intervention with pectin in alleviating aspartame-induced insulin resistance. This study will uncover molecular mechanisms and potential clinical consequences of non-nutritive sweeteners consumption on the human host and microbiome, potentially providing dietary recommendations, such as pectin supplementation, in preventing and managing aspartame-associated hyperglycemia and its metabolic complications.
StatusNot started
Effective start/end date1/01/2531/12/27

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