Journal Article

Gut taste receptor type 1 member 3 is an intrinsic regulator of Western diet-induced intestinal inflammation

Song, Jae Won, Seong, Hobin, Lee, Keon-Hee, Shon, Woo-Jeong, You, Hyun Ju, Shin, Dong-Mi, Oh, Seung Hoon, Seong, Je Kyung

2023

Overview

Background Long-term intake of a Western diet (WD), characterized by a high-fat content and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms by which dietary changes contribute to IBD development remain unknown. Therefore, we examined the influence of long-term intake of a WD on intestinal inflammation and the mechanisms by which WD intake affects IBD development. Methods Mice fed normal diet or WD for 10 weeks, and bowel inflammation was evaluated through pathohistological and infiltrated inflammatory cell assessments. To understand the role of intestinal taste receptor type 1 member 3 (TAS1R3) in WD-induced intestinal inflammation, cultured enteroendocrine cells harboring TAS1R3, subjected to RNA interference or antagonist treatment, and Tas1r3 -deficient mice were used. RNA-sequencing, flow cytometry, 16S metagenomic sequencing, and bioinformatics analyses were performed to examine the involved mechanisms. To demonstrate their clinical relevance, intestinal biopsies from patients with IBD and mice with dextran sulfate sodium-induced colitis were analyzed. Results Our study revealed for the first time that intestinal TAS1R3 is a critical mediator of WD-induced intestinal inflammation. WD-fed mice showed marked TAS1R3 overexpression with hallmarks of serious bowel inflammation. Conversely, mice lacking TAS1R3 failed to exhibit inflammatory responses to WD. Mechanistically, intestinal transcriptome analysis revealed that Tas1r3 deficiency suppressed mTOR signaling, significantly increasing the expression of PPARγ (a major mucosal defense enhancer) and upregulating the expression of PPARγ target-gene (tight junction protein and antimicrobial peptide). The gut microbiota of Tas1r3 -deficient mice showed expansion of butyrate-producing Clostridia. Moreover, an increased expression of host PPARγ-signaling pathway proteins was positively correlated with butyrate-producing microbes, suggesting that intestinal TAS1R3 regulates the relationship between host metabolism and gut microflora in response to dietary factors. In cultured intestinal cells, regulation of the TAS1R3–mTOR–PPARγ axis was critical for triggering an inflammatory response via proinflammatory cytokine production and secretion. Abnormal regulation of the axis was observed in patients with IBD. Conclusions Our findings suggest that the TAS1R3–mTOR–PPARγ axis in the gut links Western diet consumption with intestinal inflammation and is a potential therapeutic target for IBD.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Antibodies / Antimicrobial peptides / Bioinformatics / Biomedicine / Biopsy / Butyrate-producing microbes / Butyrates - adverse effects / Care and treatment / Clostridia / Colitis / Colitis - chemically induced / Colitis - metabolism / Composition / Dextran / Dextran sulfate / Dextrans / Diet / Diet, Western - adverse effects / Digestive system / Disease Models, Animal / Flow cytometry / Food habits / Gastrointestinal tract / Gene expression / Gene sequencing / Gut-taste receptor / Health aspects / Immune response / Inflammation / Inflammation - metabolism / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - pathology / Inflammatory response / Influence / Intestinal microflora / Intestinal PPAR-γ / Intestine / Ligands / Medicine / Medicine & Public Health / Metabolism / Metagenomics / Mice / Mice, Inbred C57BL / Microbiota (Symbiotic organisms) / Microorganisms / Molecular modelling / mTOR signaling / Pathogenesis / Patients / Peptides / Peroxisome proliferator-activated receptors / PPAR gamma / Prevention / Proteins / Receptors / Research Article / Ribonucleic acid / Risk factors / RNA / RNA-mediated interference / Roles / Signal transduction / Signaling / Sucrose / Taste / Taste buds / Taste receptors / Therapeutic targets / TOR protein / TOR Serine-Threonine Kinases - adverse effects / Transcriptomes