Polyunsaturated fatty acids in a Western diet activate RXRα marks the spot for Crohn’s disease

The American Society for the Advancement of Science is obsessing with Western diet!

Probably, too much emphasis is given here to possibly exaggerated experiments with mice subjected to unusual food, genetic modifications etc.

Actually, the AAAS is pointing out obese people!

"The intestinal inflammation characteristic of Crohn’s disease is associated with a Western diet, which is high in ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), and with dysfunction of an intestinal epithelial cell subset called Paneth cells. Meyer et al. uncovered a role for activation of the nuclear receptor RXRα in Paneth cells by PUFAs in the pathogenesis of Crohn’s disease.

The small intestines of patients with Crohn’s disease, particularly those with a body mass index of ≥ 25, showed increased transcriptional activity of RXRα.

In Gpx4+/−IEC mice, which show Crohn’s disease–like enteritis when fed excess PUFAs, the transcriptional activity of RXRα and expression of RXRα target genes were increased.

A PUFA-enriched diet generated multiple ω-3 and ω-6 PUFA species in Gpx4+/−IEC mice, of which the ω-3 PUFA DHA and ω-6 PUFA arachidonic acid stimulated RXRα in a luciferase activity assay.

Mice with a Paneth cell–specific deficiency in Gpx4 (Gpx4ΔPC) developed intestinal inflammation, similar to that seen in Crohn’s disease, and had higher intestinal amounts of the chemokine CXCL1, whose promoter region contains an RXRα-binding site. The phenotype of Gpx4ΔPC mice was abolished by codeletion of RXRα in Paneth cells and reduced by administration of a neutralizing CXCL1 antibody or antagonists and agonists of RXRα. The authors suggested that the effect of RXRα agonists may be due to their competition with PUFAs for binding to RXRα.

One of these RXRα agonists, isotretinoin, is approved as an oral treatment for acne, and retrospective analysis showed that prior isotretinoin therapy decreased the odds of developing Crohn’s disease. These results implicate the activation of RXRα in Paneth cells by ω-3 and ω-6 PUFAs that are enriched in or are generated by a Western diet as a contributing factor to the development of Crohn’s disease, which could be limited by isotretinoin therapy."

From the highlights and abstract:

"Highlights

• CD epithelium exhibits increased transcriptional retinoid X receptor alpha (RXRα) activity

• ω-3 and ω-6 PUFAs in a Western diet induce transcriptional RXRα activity in IECs of mice

• PUFA-induced metabolic enteritis is mediated by RXRα in Paneth cells

• Isotretinoin ameliorates PUFA-induced enteritis and reduces the odds of developing CD

Summary

Westernization of diet, partly characterized by long-chain fatty acid excess, perturbs intestinal immune responses in Crohn’s disease (CD). The cellular and molecular framework of lipid sensing in intestinal inflammation remains enigmatic.

By small intestinal transcriptional profiling of CD, we identified increased transcriptional activity of retinoid X receptor alpha (RXRα) specifically in intestinal epithelial cells (IECs).

Transcriptional RXRα activity was induced in IECs of mice by ω-3 and ω-6 polyunsaturated fatty acid (PUFA) excess in a Western diet. PUFA-induced RXRα activity in Paneth cells governed chronic transmural enteritis by enabling the expression of CXCL1.
Oral exposure to isotretinoin ameliorated PUFA-induced metabolic enteritis in two mouse models, and isotretinoin therapy reduced the odds of developing CD in an analysis of electronic health care records from 170,597 patients. Collectively, we identify RXRα in Paneth cells as a metabolic stress sensor that enables enteritis, providing novel perspectives for the prevention and treatment of CD."

RXRα marks the spot for Crohn’s disease | Science Signaling (open access)

Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn’s disease (open access)

Graphical abstract