The re-emerging role of linoleic acid in paediatric asthma

Abstract

Asthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.

FIGURE 1

Pathway of linoleic and α-linolenic acid metabolism. a) Linoleic acid is an 18-carbon fatty acid (octadecanoid) and its dietary sources include plant oils along with other n-6 polyunsaturated fatty acids (PUFAs). Linoleic acid and its metabolites including 13-hydroxy-octadecadienoic acid (13-HODE), 13-HpODE (13-hydroperoxy-octadecadienoic acid) and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) have been implicated in paediatric asthma. b) α-Linoleic acid (ALA) is also an octadecanoid. Its dietary sources include seed oils and fish along with other n-3 PUFAs. ALA and its metabolites along with other n-3 PUFAs may have a beneficial effect in preventing paediatric asthma. COX: cyclo-oxygenase; LOX: lipoxygenase.

FIGURE 2

Impact of maternal diet on the infant microbiome. The human microbiome is thought to impact an infant's immune development during a critical period in early life. It is during this period when maternal dietary intake of n-3/n-6 polyunsaturated fatty acids (PUFAs), transferred in breastmilk, may affect asthma development. Levan et al. [7] demonstrated that neonates who produced specific bacterial epoxide hydrolases that convert 12,13-EpOME to 12,13-DiHOME demonstrated a significantly increased probability of developing childhood allergies, eczema and asthma. In a mouse model, intra-abdominal injection of 12,13-DiHOME led to increased peribronchial and perivascular inflammation. Administration of 12,13-DiHOME to human dendritic cells resulted in reduced anti-inflammatory cytokine secretion and reduction of the number of T-regulatory (Treg) cells. Ig: immunoglobulin; IL: interleukin. Figure created using BioRender.com.

FIGURE 3

Allergic airway remodelling and sensitisation. a) The role of linoleic acid metabolite 13-hydroxy-octadecadienoic acid (13-HODE) in asthma has largely been based on animal and cell models. Hypothesised mechanisms include induction of airway remodelling due to mitochondrial dysfunction and decreased response to steroid treatment due to decreased expression of glucocorticoid receptor α. b) Administration of cis-9, trans-11, conjugated linoleic acid (c9,t11-CLA), found in dairy products and as a bacterial pathway product, led to a significant reduction of immunoglobulin (Ig)E levels and airway responsiveness in a mouse model and decreased interleukin (IL)-6 and IL-8 production when administered to human bronchial epithelial cells. ICAM: intercellular adhesion molecule 1. Figure created using BioRender.com.