Serotonin Transporter Deficiency Induces Metabolic Alterations in the Ileal Mucosa

Author:

Calzadilla Nathan1,Jayawardena Dulari2ORCID,Qazi Aisha2,Sharma Anchal2,Mongan Kai2,Comiskey Shane2,Eathara Abhijith2,Saksena Seema23ORCID,Dudeja Pradeep K.23,Alrefai Waddah A.23,Gill Ravinder K.23ORCID

Affiliation:

1. Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA

2. Division of Gastroenterology & Hepatology, University of Illinois Chicago, Chicago, IL 60612, USA

3. Jesse Brown VA Medical Center, Chicago, IL 60612, USA

Abstract

Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERT−/− mice ileal mucosa. However, the precise host or microbial metabolites altered by SERT deficiency that may contribute to the pleiotropic phenotype of SERT KO mice are not yet understood. This study investigated the hypothesis that SERT deficiency impacts lipid and microbial metabolite abundances in the ileal mucosa, where SERT is highly expressed. Ileal mucosal metabolomics was performed by Metabolon on wild-type (WT) and homozygous SERT knockout (KO) mice. Fluorescent-activated cell sorting (FACS) was utilized to measure immune cell populations in ileal lamina propria to assess immunomodulatory effects caused by SERT deficiency. SERT KO mice exhibited a unique ileal mucosal metabolomic signature, with the most differentially altered metabolites being lipids. Such changes included increased diacylglycerols and decreased monoacylglycerols in the ileal mucosa of SERT KO mice compared to WT mice. Further, the ileal mucosa of SERT KO mice exhibited several changes in microbial-related metabolites known to play roles in intestinal inflammation and insulin resistance. SERT KO mice also had a significant reduction in the abundance of ileal group 3 innate lymphoid cells (ILC3). In conclusion, SERT deficiency induces complex alterations in the ileal mucosal environment, indicating potential links between serotonergic signaling, gut microbiota, mucosal immunity, intestinal inflammation, and metabolic syndrome.

Funder

National Institutes of Health

Crohn's and Colitis Foundation

United States Department of Veterans Affairs

Publisher

MDPI AG

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