Luminal Bioavailability of Orally Administered ω-3 PUFAs in the Distal Small Intestine, and Associated Changes to the Ileal Microbiome, in Humans with a Temporary Ileostomy.

Gael Nana,Amanda D Race,Caroline Young,Philip Quirke,Giles J Toogood,Suparna Mitra,Sarah L Perry,Paul M Loadman,Henry Watson,Mark A Hull,Henry M Wood

doi:10.1093/jn/nxab113

Abstract

ABSTRACTBackgroundOral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut.ObjectivesWe investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum.MethodsIleostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC–tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing.ResultsThere was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P < 0.05) and reduced abundance of other genera, including Actinomyces (r2 > 0.94, P < 0.05).ConclusionsOral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy. This study is registered on the ISRCTN registry as ISRCTN14530452.

Highlights

Omega-3 (ω-3) PUFAs are licensed for treatment of severe hypertriglyceridemia and prevention of cardiovascular events in high-risk individuals [1]. ω-3 PUFAs are widely used as a nutritional supplement, either in complex “fish oil” mixtures or, more commonly, in concentrated “nutraceutical” forms [2].We have reported that oral administration of 4 g of a 1:1 mix of the 2 main marine-derived ω-3 PUFAs, namely EPA (20:5ω-3) and DHA (22:6ω-3), daily for 8 wk is associated with a reversible change in the fecal microbiome in middle-aged volunteers [3]. ω-3 PUFA use was associated with increased abundance of SCFA-producing bacterial taxa such as Lactobacillus, Roseburia, and Sutterella [3]
Oral administration of EPA 2 g daily reduces rectal adenoma number and size in patients with familial adenomatous polyposis [4] and decreases “sporadic” conventional colorectal adenoma risk in the distal colon and rectum [5], which is consistent with the hypothesis that anti–colorectal cancer (CRC) activity of ω-3 PUFA is, at least in part, mediated by increased luminal concentrations of SCFAs, the receptors for which are expressed predominantly in the distal colon [6]
Consistent with previous reports describing the bacterial structure of ileal fluid, we found that the dominant genera in ileal content prior to ω-3 PUFA supplementation consisted of Bacteroides, Clostridium, Escherichia/Shigella, Turcibacter, Haemophilus, and Streptococcus (Supplemental Figure 2, Figure 5A) [25]

Summary

Introduction

Omega-3 (ω-3) PUFAs are licensed for treatment of severe hypertriglyceridemia and prevention of cardiovascular events in high-risk individuals [1]. ω-3 PUFAs are widely used as a nutritional supplement, either in complex “fish oil” mixtures or, more commonly, in concentrated “nutraceutical” forms [2].We have reported that oral administration of 4 g of a 1:1 mix of the 2 main marine-derived ω-3 PUFAs, namely EPA (20:5ω-3) and DHA (22:6ω-3), daily for 8 wk is associated with a reversible change in the fecal microbiome in middle-aged volunteers [3]. ω-3 PUFA use was associated with increased abundance of SCFA-producing bacterial taxa such as Lactobacillus, Roseburia, and Sutterella [3]. Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome It is not known whether this effect is associated with increased PUFA concentrations in the gut. Objectives: We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Conclusions: Oral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy.

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