Gut microbiota-derived tryptamine impairs insulin sensitivity

Gut-microbiota plays a pivotal role in development of type 2 diabetes (T2D), yet the molecular mechanism remains elusive. Here, we show that tryptamine, a microbial metabolite of tryptophan, impairs glucose tolerance and insulin sensitivity. Tryptamine presents a higher level in monkeys with spontaneous diabetes and human with T2D and positively correlated with the glucose tolerance. In parallel, tryptamine level was suppressed by dietary fibers intervention in T2D subjects and negatively correlated with improvement of glucose tolerance. The inhibitory effect of tryptamine on insulin signaling as shown was dependent on a trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Monoassociation of T2D-associated tryptamine-producing bacteria Ruminococcus gnavus impairs insulin sensitivity in pseudo germ-free mice. Our findings indicate gut microbiota-derived tryptamine contributes to the development of insulin resistance in T2D and may serve as a new target for intervention. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * AhR : Aryl hydrocarbon receptor CAGs : Co-abundance groups FBG : Fasting blood glucose FMT : Fecal microbiota transplant GI : Gastrointestinal HbA1c : Hemoglobin A1C HFD : High fat diet HOMA-IR : Homeostatic Model Assessment for Insulin Resistance IAA : Indole-3-acetic acid IR : Insulin resistance ITT : Insulin tolerance test IVGTT : Intravenous glucose tolerance test OGTT : Oral glucose tolerance test TC : Total cholesterol TG : Total glycerides TAAR1 : Trace amine-associated receptor 1 Trp : Tryptophan TDC : Tryptophan decarboxylase T2D : Type 2 diabetes WAT : white adipose tissue [1]: pending:yes