Probiotics Modulate Intestinal Expression of Nuclear Receptor and Provide Counter-Regulatory Signals to Inflammation-Driven Adipose Tissue Activation

Abstract

BackgroundAdipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue.AimsTo investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics.MethodsColitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium.ResultsProbiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release.ConclusionsMesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction.

Infliximab modifies mesenteric adipose tissue alterations and intestinal inflammation in rats with TNBS-induced colitis

“…Finally, experimental colitis reduced the expression of PPAR-g in mesenteric adipose tissue, and a reduction in adipocyte diameter was observed. Creeping fat from CD patients also exhibits reduced expression of PPAR-g [30] and adipocytes from these patients have a smaller diameter than normal adipose tissue [31]. Infliximab administration was able to reverse the decrease in PPAR-g expression and improve adipocyte size to the level of control animals.…”

The Role of the Mesentery in Crohnʼs Disease

“…178,179,[198][199][200] An effective treatment for CD is corresponding to modifications in MAT. For example, probiotic therapy was shown to improve the inflammation-driven metabolic dysfunction of peroxisome proliferator-activated receptors g and leptin 201 ; anti-TNF therapy was associated with modified production of adipokines and restoration of adipocyte morphology in MAT 198 ; and therapy with methotrexate resulted in diminished inflammation of MAT in an animal model. 200 Anti-TNF therapy can cause a significant increase in abdominal fat tissue.…”

The Role of Mesenteric Adipose Tissue in Crohn’s Disease

“…In CD, it has some specific functions related to the maintenance of the process, such as cytokine production, adipocyte differentiation, fibrocytes differentiation inhibition, and IκB/NF-κB activation [33,52,53]. On the one hand, studies have shown a decrease of the PPAR-γ in MAT from CD patients [53,54].…”

“…In CD, it has some specific functions related to the maintenance of the process, such as cytokine production, adipocyte differentiation, fibrocytes differentiation inhibition, and IκB/NF-κB activation [33,52,53]. On the one hand, studies have shown a decrease of the PPAR-γ in MAT from CD patients [53,54]. On the other hand, Desreumaux and collaborators showed that significant accumulation of intra-abdominal fat is associated with overexpression of PPAR Y and TNF-α in the MAT of the small bowel mesentery in CD patients, which suggests adipocytes as one of the sources of TNF-α production [55].…”