Fish Oil Attenuates Omega-6 Polyunsaturated Fatty Acid-Induced Dysbiosis and Infectious Colitis but Impairs LPS Dephosphorylation Activity Causing Sepsis

Abstract

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.

Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

“…It has been shown that n-3 PUFA supplementation, and not total calories from fat, alters the gut microbial composition by enhancing numbers of Lactobacillus and Bifidobacteria spp. in adult mice (152) as well as in aged mice, which modulated both gut immunity and oxidative stress (153). In support of these data, other studies have shown that changes in gut microbiota composition by n-3 PUFA deficiency can be modulated by prebiotics such as FOS.…”

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

“…Recently there has been renewed interest in IAP activity and its role in promoting intestinal mucosal defense (15). Several studies have shown that LPS dephosphorylation mediated by IAP protects the host against LPS-induced inflammation as well as reducing the systemic translocation of enteric bacteria (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). To investigate whether IAP activity was playing a role in the increased susceptibility/morbidity of Muc2 Ϫ/Ϫ mice in our model, we stained for IAP and found that Muc2 Ϫ/Ϫ mice had reduced IAP expression as well as reduced LPS dephosphorylation activity (a measure of the activity of IAP) within their cecal tissues.…”

“…As described previously (18,24), to assess crude LPS detoxification activity, cecal tissues were homogenized in 500 l of homogenization buffer, followed by the addition of 5 l of phenylmethylsulfonyl fluoride (PMSF), a protease inhibitor. Homogenates were centrifuged at 13,200 rpm (4°C for 15 min) to remove the insoluble contents.…”

“…Furthermore, IAP-mediated LPS detoxification plays a role in preventing systemic translocation of LPS across the intestinal barrier (15)(16)(17)(18)(19)(20)(21). In the absence of this detoxification, systemic translocation of LPS triggers exaggerated inflammatory responses that can ultimately prove fatal to the host through proinflammatory cytokine-induced septic shock (22,23,24).…”

Linking fat intake, the intestinal microbiome, and necrotizing enterocolitis in premature infants

“…Using mice just weaned at 4 wk of age, Ghosh et al (14) compared a low fat n-6 PUFA diet to two high fat diets, one with n-6 PUFA and one containing n-6 and n-3 PUFA from FO. Significantly increasing the amount of arachidonic acid (20:4n-6, ARA), DHA, and EPA in the FO feeding group, there was also an increase in SFA.…”