Diet high in linoleic acid dysregulates the intestinal endocannabinoid system and increases susceptibility to colitis in Mice

ABSTRACT

Inflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro. These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.

KEYWORDS:

• IBD
• PUFAs
• soybean oil
• olive oil
• oxylipins
• adherent invasive E.Coli
• HNF4α
• gut microbiome
• metabolomics
• epithelial barrier function

Acknowledgments

We thank DuPont for Plenish oil. Model in Figure 9 was created with BioRender.com.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The bacterial rRNA ITS sequences have been deposited in the National Center for Biotechnology Information (NCBI)’s Sequence Read Archive (SRA) under the SRA BioProject Accession PRJNA622821 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA622821/). The metabolomics data supporting the findings of this study are available within the article and the supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2229945

Additional information

Funding

NIH R01 DK053892, DK127082 (FMS); Crohn’s Colitis Foundation Career Development Award 454808 (PD); UCR Metabolomics Core Seed Grant (FMS, PD); FY17-18 P&F Grant from the NIH/UC Davis WCMC DK097154 (JB, PD). NIH R35 GM124724, R01 AI157106 (AH); Crohn’s and Colitis Foundation Senior Research Award, NIH R01 DK091281, American Gastroenterological Association IBD Research Award (DFM). NIH R01 AI153195 (MGN). Additional support was provided by the USDA Intramural project 2032-51530-022-00D and 2032-51530-025-00D (JWN). The USDA is an equal opportunity provider and employer. USDA National Institute of Food and Agriculture Hatch project CA-R-NEU-5680 (FMS).