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

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.

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.

AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.

Mobilization of vitamin B12 transporters alters competitive dynamics in a human gut microbe.

The functional and genomic diversity of the human gut microbiome is shaped by horizontal transfer of mobile genetic elements (MGEs). Characterized MGEs can encode genes beneficial for their host's self-defense (e.g., antibiotic resistance) or ability to compete for essential or limited resources (e.g., vitamins). Vitamin B12 and related compounds (corrinoids) are critical nutrients that enable colonization by members of the common gut microbe phylum, the Bacteroidetes. Herein, we identify a distinct class of MGEs in the Bacteroidetes responsible for the mobilization and exchange of the genes required for transport of corrinoids, a group of cyclic tetrapyrrole cofactors including vitamin B12 (btuGBFCD). This class includes two distinct groups of conjugative transposons (CTns) and one group of phage. Conjugative transfer and vitamin B12 transport activity of two of the CTns were confirmed in vitro and in vivo, demonstrating the important role MGEs play in distribution of corrinoid transporters in the Bacteroidetes.