Dietary Lipid Type, Rather Than Total Number of Calories, Alters Outcomes of Enteric Infection in Mice.

Dietary lipids modulate immunity, yet the means by which specific fatty acids affect infectious disease susceptibility remains unclear. Deciphering lipid-induced immunity is critical to understanding the balance required for protecting against pathogens while avoiding chronic inflammatory diseases. To understand how specific lipids alter susceptibility to enteric infection, we fed mice isocaloric, high-fat diets composed of corn oil (rich in n-6 polyunsaturated fatty acids [n-6 PUFAs]), olive oil (rich in monounsaturated fatty acids), or milk fat (rich in saturated fatty acids) with or without fish oil (rich in n-3 PUFAs). After 5 weeks of dietary intervention, mice were challenged with Citrobacter rodentium, and pathological responses were assessed. Olive oil diets resulted in little colonic pathology associated with intestinal alkaline phosphatase, a mucosal defense factor that detoxifies lipopolysaccharide. In contrast, while both corn oil and milk fat diets resulted in inflammation-induced colonic damage, only milk fat induced compensatory protective responses, including short chain fatty acid production. Fish oil combined with milk fat, unlike unsaturated lipid diets, had a protective effect associated with intestinal alkaline phosphatase activity. Overall, these results reveal that dietary lipid type, independent of the total number of calories associated with the dietary lipid, influences the susceptibility to enteric damage and the benefits of fish oil during infection.

Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis.

Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA) and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil) and diets supplemented with ω-3 PUFA (corn oil+fish oil) for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection-induced responses resulting in sepsis. We conclude that as an anti-inflammatory agent, ω-3 PUFA supplementation during infection may prove detrimental when host inflammatory responses are critical for survival.

Diets rich in n-6 PUFA induce intestinal microbial dysbiosis in aged mice.

Controversies have emerged regarding the beneficial v. detrimental effects of dietary n-6 PUFA. The alteration of the intestinal microbiota, a phenomenon termed dysbiosis, occurs during several chronic inflammatory diseases, but has not been well studied in an aged population. With present 'Western' diets predominantly composed of n-6 PUFA, we hypothesised that PUFA-rich diets cause intestinal dysbiosis in an aged population. C57BL/6 mice (aged 2 years) were fed a high-fat (40% energy), isoenergetic and isonitrogenous diet composed of rapeseed oil, maize oil or maize oil supplemented with fish oil. We examined ileal microbiota using fluorescence in situ hybridisation and stained tissues by immunofluorescence for the presence of immune cells and oxidative stress. We observed that feeding high-fat diets rich in n-6 PUFA promoted bacterial overgrowth but depleted microbes from the Bacteroidetes and Firmicutes phyla. This corresponded with increased body mass and infiltration of macrophages and neutrophils. Fish oil supplementation (rich in long-chain n-3 PUFA like DHA and EPA) restored the microbiota and inflammatory cell infiltration and promoted regulatory T-cell recruitment. However, fish oil supplementation was associated with increased oxidative stress, evident by the increased presence of 4-hydroxynonenal, a product of lipid peroxidation. These results suggest that an n-6 PUFA-rich diet can cause dysbiosis and intestinal inflammation in aged mice. However, while fish oil supplementation on an n-6 PUFA diet reverses dysbiosis, the combination of n-6 and n-3 PUFA, like DHA/EPA, leads to increased oxidative stress, which could exacerbate gastrointestinal disorders in the elderly.