Dataset Information

Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation.

ABSTRACT: Intestinal dysbiosis is prominent in systemic sclerosis (SSc), but it remains unknown how it contributes to microvascular injury and fibrosis that are hallmarks of this disease. Trimethylamine (TMA) is generated by the gut microbiome and in the host converted by flavin-containing monooxygenase (FMO3) into trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular and metabolic diseases. Using cell culture systems and patient biopsies, we now show that TMAO reprograms skin fibroblasts, vascular endothelial cells, and adipocytic progenitor cells into myofibroblasts via the putative TMAO receptor protein R-like endoplasmic reticulum kinase (PERK). Remarkably, FMO3 was detected in skin fibroblasts and its expression stimulated by TGF-β1. Moreover, FMO3 was elevated in SSc skin biopsies and in SSc fibroblasts. A meta-organismal pathway thus might in SSc link gut microbiome to vascular remodeling and fibrosis via stromal cell reprogramming, implicating the FMO3-TMAO-PERK axis in pathogenesis, and as a promising target for therapy.

SUBMITTER: Kim SJ

PROVIDER: S-EPMC9287188 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation.

Kim Seok-Jo SJ Bale Swarna S Verma Priyanka P Wan Qianqian Q Ma Feiyang F Gudjonsson Johann E JE Hazen Stanley L SL Harms Paul W PW Tsou Pei-Suen PS Khanna Dinesh D Tsoi Lam C LC Gupta Nilaksh N Ho Karen J KJ Varga John J

iScience 20220626 7

Intestinal dysbiosis is prominent in systemic sclerosis (SSc), but it remains unknown how it contributes to microvascular injury and fibrosis that are hallmarks of this disease. Trimethylamine (TMA) is generated by the gut microbiome and in the host converted by flavin-containing monooxygenase (FMO3) into trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular and metabolic diseases. Using cell culture systems and patient biopsies, we now show that TMAO reprograms skin ...[more]

PMID: 35856022

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Project description:BackgroundOsteoporosis (OP) is a prevalent metabolic bone disease characterized by bone loss and structural deterioration, which increases the risk of fracture especially in older people. Recent research has shown that gut microbes play an important role in OP. Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been implicated in the pathogenesis of diseases, including Alzheimer's and cerebrovascular disease. This study aimed to examine the effect of TMAO in OP.MethodsIn this study, we firstly investigated the relationship between TMAO and OP. Serum samples were collected from patients with OP (n=10), and healthy participants (n=10), and the TMAO level in the serum was detected by ELISA assay. Then, bone marrow mesenchymal stem cells (BMSCs) were treated with TMAO, and we observed its effect on adipogenic and osteogenic differentiation, cell proliferation, reactive oxygen species (ROS) release, and inflammatory cytokine[interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNF-α)] levels. Finally, we illustrated the underlying mechanism through which TMAO influenced BMSCs functions.ResultsCompared to the healthy group, highly significant TMAO levels were observed in the serum of the OP patients. When studied in vitro, TMAO treatment significantly promoted BMSCs adipogenesis and attenuated osteogenesis, increased ROS release and pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production, and inhibited cell proliferation. Furthermore, we found that activation of the nuclear factor-κB (NF-κB) signaling pathway was necessary for TMAO to induce pro-inflammatory cytokine production, ROS release, and adipogenic and osteogenic differentiation in BMSCs.ConclusionsElevated TMAO levels have a strong negative correlation with the degree of bone mineral density (BMD) in OP. TMAO regulates BMSCs cell function by activating the NF-κB signaling pathway, which affects the balance of bone metabolism, leading to acceleration of bone loss and further progression of OP.

Dataset Information

Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation.

Publications

Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation.

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