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.
Highlights d Diverse mobile genetic elements in gut microbes encode vitamin B 12 transporters d Transfer of CTns with B 12 transporters complement transport-deficient strains d CTns with B 12 transporters offer competitive advantages during in vitro growth d In vivo conjugation restores ability to use B 12 in transportdeficient Bacteroides
Soybean oil (SO), the most prevalent cooking oil in the United States, consists primarily of linoleic acid (LA, C18:2 omega-6), a polyunsaturated fatty acid positively linked to the development of ulcerative colitis (UC) in humans. Here, we show that dietary SO increases intestinal epithelial barrier permeability and susceptibility to colitis in mice. It also disrupts the balance of isoforms encoded by the UC susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α), which in turn impacts barrier function and IBD susceptibility. The SO diet causes gut dysbiosis, including an increased abundance of an adherent, invasive Escherichia coli (AIEC) which can use LA as a carbon source. Metabolomic analysis indicates that gut bacteria and the SO diet can alter levels of LA and its oxylipin and endocannabinoid metabolites in the gut. Our results suggest that an SO-enriched diet increases susceptibility to colitis due to effects on intestinal HNF4α, microbiota and LA metabolites.
Veterans of the Persian Gulf War (GW) continue to suffer from Gulf War Illness (GWI) characterized by cognitive deficit and fatigue. Our group and others have suggested possible involvement of the microbiota-gut-brain axis in GWI pathology (Kozlova et a., 2021a; 2021b). The current study tested the hypothesis that probiotic treatment (P) prevents GWI symptoms, and systemic and neuro-inflammation. Adult male C57Bl/6N mice were separated into 4 groups (n=16/group): GW group was exposed to 8.7 mg/kg/d pyridostigmine bromide (PB) in saline (150uL/30g bw, oral gavage), 1.3 mg/kg PER in 100% DMSO (dermal), and 33% DEET in 70% EtOH (dermal) for 28 days (5 days/week). CON/S group was sham-treated. CON/S+P and GW+P groups were treated with a probiotic (P) cocktail of L. reuteri, L. rhamnosus, L. casei, B. longum (108 CFU/mL, oral gavage) 3 times/week for 2 weeks prior to and during sham/GW agent treatment and until sacrifice (post-treatment (PT) 150). All groups were subjected to restraint stress (5 min/d for 28 d). RT-qPCR on fecal pellets showed bacteria colonization of all strains except L. rhamnosus and B. longum after administration of 6-7 doses. At PT1, all strains showed increased colonization relative to baseline, which persisted to PT150, except B. longum. Body weight, fat, lean mass at PT150 showed no changes among groups. An exercise endurance (EE) test was performed to measure differences in fatigue. GW mice tired faster relative to CON/S at PT56 which persisted at PT150. Probiotic normalized exercise endurance to CON/S levels at PT56. On the passive avoidance test all groups behaved normally at PT50 but GW showed deficits on day 1 acquisition trial of fear learning when tested again 14 weeks later at PT150. GW+P behaved similarly to CON/S. Strength and depression-like behavior was examined before and after exercise stress to simulate post-exertional malaise. Mean percent time spent mobile on tail suspension test (TST) were significantly lower for GW but not GW+P at PT50. All groups were normal at PT150. There was no effect of GW agents or probiotics on the hanging wire test. Systemic and neuroinflammatory markers: C-reactive protein (CRP), high mobility group box 1 (HMGB1), and interleukin-6 (IL-6) were examined using ELISA. Liver and plasma CRP was increased in GW group but not GW+P in liver (p=0.06 in plasma). Plasma HMGB1 was reduced and brain IL-6 was elevated in GW mice but not GW+P. Immunofluorescence analysis in fixed hippocampal sections showed more Iba-1 positive cells in CA1 and DG in GW vs CON/S, while GW+P showed no significant changes vs CON/S. These results show that GW mice can be used to model long-lasting fatigue and other GWI symptoms as well as systemic and neuro-inflammation concurrently. After exercise stress GW agents produced depression. Importantly, probiotic treatment improved exercise endurance, depression, systemic and neuro-inflammation in GW mice, indicating its potential therapeutic use in GWI. Clara Berdasco and Elena Kozlova are co-first authors. Supported by DoD #W81XWH-19-1-0802 (MCC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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