The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn’s Disease

Abstract

Background and aims Crohn’s disease (CD) is associated with complex microbe-host interactions, involving changes in microbial communities, and gut barrier defects, leading to the translocation of microorganisms to surrounding adipose tissue (AT). We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes. Methods Visceral (VAT) and subcutaneous (SAT) AT biopsies, serum and plasma were obtained from patients with active (n=21) or inactive (n=12) CD, and from healthy controls (n=15). Adipose-derived stem cells (ASCs) and AT macrophages (ATMs) were isolated from VAT biopsies. Results Plasma succinate levels were significantly higher in patients with active CD than in controls and were intermediate in those with inactive disease. Plasma succinate correlated with the inflammatory marker high-sensitivity C-reative protein. Expression of the succinate receptor SUCNR1 was higher in VAT, ASCs and ATMs from the active CD group than from the inactive or control groups. Succinate treatment of ASCs elevated the expression of several beige AT markers from controls and from patients with inactive disease, including uncoupling protein-1 (UCP1). Notably, beige AT markers were prominent in ASCs from patients with active CD. Secretome profiling revealed that ASCs from patients with active disease secrete beige AT-related proteins, and co-culture assays showed that bacteria also trigger the white-to-beige switch of ASCs from patients with CD. Finally, AT depots from patients with CD exhibited a conversion from white to beige AT together with high UCP1 expression, which was corroborated by in situ thermal imaging analysis. Conclusions Succinate and bacteria trigger white-to-beige AT transition in CD. Understanding the role of beige AT in CD might aid in the development of therapeutic or diagnostic interventions.

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn’s Disease

“…All experiments were performed in cells at P3–4. Adipose tissue (VAT)-derived macrophages (ATMs) were also isolated from the SVF of biopsies, as described [ 47 , 48 , 49 , 50 ].…”

“…We used an untargeted proteomics approach consisting of liquid chromatography coupled to tandem mass spectrometry to compare and identify differences in protein levels secreted into the extracellular (conditioned) medium by ASCs isolated from the creeping fat of the control group (n = 6) and anti-TNF group (n = 3). We reanalyzed a subcohort of our proteomic data [ 50 ] looking for differences in protein abundance between ASCs isolated from anti-TNF-treated and -untreated patients.…”

“…Acquired spectra were analyzed using the Proteome Discoverer software suite (v2.3, Thermo Fisher Scientific) and the Mascot search engine (v2.6, Matrix Science Ltd., Boston, MA, USA), as described [ 50 , 52 ]. Proteomic data were evaluated to identify significant differences ( p < 0.05) in proteins between both groups using the DEP package that provides an integrated analysis workflow for robust and reproducible analysis of mass spectrometry proteomics data [ 53 ].…”

Targeting mitochondrial metabolites and nucleic acids as an anti-inflammatory strategy

“…Succinate plays a critical role in regulating proinflammatory responses. Succinate levels are increased in multiple inflammatory diseases (Monfort-Ferré et al, 2022;Xu et al, 2022). Glutaminedependent anaplerosis and GABA (γ-aminobutyric acid) shunt activity increase in M1 macrophages which leads to the build-up of succinate (Monfort-Ferré et al, 2022).…”

“…In recent years, many discoveries have been made on the immunoregulatory role of mitochondria (Nakahira et al, 2010;Hooftman and ONeill, 2019;Monfort-Ferré et al, 2022;Hooftman et al, 2023). Two anti-inflammatory therapeutics already in use, dimethyl fumarate (DMF) and metformin, in fact, target mitochondria.…”