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

PLoS One. 2013;8(2):e55468. doi: 10.1371/journal.pone.0055468. Epub 2013 Feb 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Animals
  • Citrobacter rodentium / metabolism
  • Colitis / chemically induced*
  • Colitis / metabolism
  • Colitis / microbiology
  • Diet
  • Dietary Supplements
  • Dinoprostone / metabolism
  • Enterobacteriaceae Infections / metabolism
  • Enterobacteriaceae Infections / microbiology
  • Fatty Acids, Omega-3 / pharmacology*
  • Fatty Acids, Omega-3 / toxicity
  • Fatty Acids, Omega-6 / pharmacology*
  • Fatty Acids, Omega-6 / toxicity
  • Female
  • Fish Oils / pharmacology*
  • Interleukin-15 / metabolism
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Sepsis / chemically induced
  • Sepsis / metabolism
  • Sepsis / microbiology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Fish Oils
  • Interleukin-15
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Alkaline Phosphatase
  • Dinoprostone

Grant support

Grant Support was provided by the Intestinal Disease Education and Awareness Society; Bill & Melinda Gates Foundation; and Crohn’s and Colitis Foundation of Canada. D.D. and K.B were funded through scholarships from the Canadian Association of Gastroenterology. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.