Identification of omega-3 oxylipins in human milk-derived extracellular vesicles with pro-resolutive actions in gastrointestinal inflammation

Front Immunol. 2023 Nov 20:14:1293737. doi: 10.3389/fimmu.2023.1293737. eCollection 2023.

Abstract

Introduction: Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. Identifying these molecules and their biological effects has potential for the treatment of intestinal disorders in PIs and could contribute to the development of HM-based fortified formulas.

Methods: We isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and in a murine model of inflammatory bowel disease (IBD).

Results: HM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA (ω3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both ω3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis.

Discussion: Incorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.

Keywords: human milk (HM); inflammatory bowel disease (IBD); necrotizing enterocolitis (NEC); oxylipins; small extracellular vesicles (sEVs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Fatty Acids, Omega-3*
  • Fibrosis
  • Humans
  • Infant
  • Infant, Newborn
  • Inflammation
  • Inflammatory Bowel Diseases*
  • Mice
  • Milk, Human
  • Oxylipins

Substances

  • Oxylipins
  • Fatty Acids, Omega-3
  • Anti-Inflammatory Agents

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by grants from the Instituto de Salud Carlos III, Spain (PI22/00230, FI21/00193, CD19/00176, and CPII21/00003), co-funded by FEDER “una manera de hacer Europa”; and from Agencia Valenciana de Innovación (INNVA1/2021/29, INNVA2/2022/1 and UCIE 22-24); and grant CNS2022-135398 funded by MCIN/AEI/10.13039/501100011033 and, as appropriate, by “European Union NextGenerationEU/PRTR. It was also supported by grant ACIF/2020/352 to EA-P from the Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital and co-financed by the European Union through the Operational Program of the European Regional Development Fund (FEDER) of the Valencian Community 2014-2020.