Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders.

In the present study, the novel family genetic risk score (FGRS) method, a reliable quantification of latent genetic risk, was applied to posttraumatic stress disorder (PTSD) to examine associations between genetic liability and clinical features of PTSD among 3,097,180 individuals in the Swedish national registries. FGRS was calculated based on lifetime PTSD status for first‐ through fifth‐degree relatives and examined both in PTSD cases with any lifetime registration (PTSD total) and in cases with more than one registration (recurrent PTSD) in relation to sex, age at onset (AAO), recurrence, mode of ascertainment (inpatient [IP], outpatient specialty care [SC], primary care [PC]), and comorbidities. Sex differences were not found for recurrent PTSD, but for PTSD total, female registrants had a lower FGRS value compared to male registrants, M = ‐.017, 95% CI of difference [‐.029‐.005]. Higher FGRS was found at earlier AAO for PTSD total and recurrent PTSD, p s < .001, and scores were higher among individuals with comorbidities, p s < .001. Higher FGRS was related to the number of PTSD recurrences among both total PTSD and recurrent PTSD, p s < .001 (linear effect). For both PTSD types, FGRS scores were as follows: PC < SC < IP, p s < .001. The findings indicate that genetic risk for PTSD is associated with several clinical features of the disorder, which should be included in future studies of genetic risk for PTSD. Continued investigation of these clinical features in epidemiological and molecular genetic studies of PTSD is warranted to further validate the findings.