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

Figure 1.

Experimental design.

Figure 2.

A diet high in LA increases susceptibility to colitis in IL10^−/− mice. IL10^−/− mice fed SO+f or Viv diet for 10 weeks.

Figure 3.

A diet high in LA increases colitis susceptibility and decreases barrier function in WT and α1HMZ mice.

Figure 4.

A diet high in LA increases immune dysfunction and decreases barrier function in WT and α1HMZ mice.

Figure 5.

A diet high in LA increases the abundance of SO-mAIEC in WT mouse intestines.

Figure 6.

Soybean oil increases oxylipins and decreases endocannabinoid system metabolites in SO-mAIEC cultured in vitro.

Figure 7.

A diet high in LA decreases barrier function and alters the metabolome in the intestines of conventionally raised and germ-free mice.

Figure 8.

Impact of LA on gut microbiome.

Figure 9.

Proposed model by which a soybean oil-based HFD increases susceptibility to colitis.