Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.

Dietary intervention using nondigestible oligosaccharides, short-chain galacto-oligosaccharides (scGOS)/long-chain fructo-oligosaccharides (lcFOS), in combination with Bifidobacterium breve M-16V prevents allergic disease involving galectin-9. In addition, apical TLR9 signaling contributes to intestinal homeostasis. We studied the contribution of galectin-9 secreted by intestinal epithelial cells (IEC; HT-29 and T84) in Th1 and regulatory T-cell (Treg) polarization in vitro. IEC were grown in transwell filters, cocultured with CD3/CD28-activated human peripheral blood mononuclear cells (PBMC) and apically exposed to genomic DNA derived from B. breve M-16V or synthetic TLR9 ligand in the absence or presence of scGOS/lcFOS. Cytokine production and T-cell phenotype were determined and galectin expression by IEC was assessed. Galectin-9 was neutralized using lactose or a TIM-3-Fc fusion protein. IEC exposed to DNA from B. breve M-16V or TLR9 ligand in the presence of scGOS/lcFOS enhanced IFN-γ secretion by PBMC and increased the percentage of Th1 and Treg cells. Expression and secretion of galectin-9 by IEC was increased and neutralization of galectin-9 prevented the induction of IFN-γ secretion and also suppressed the production of IL-10 by PBMC. Furthermore, we show that galectin-9 induces Treg and Th1 polarization through interaction with antigen-presenting cells. Our findings show that galectin-9 secreted by IEC apically exposed to TLR9 ligand in the presence of scGOS/lcFOS is involved in Th1 and Treg polarization and may be a promising target to prevent or treat allergic disease.

N-3 long chain polyunsaturated fatty acids (LCPUFAs) are considered to possess protective properties for human health by impacting on immunological reactions. An “inflammation-suppressive” effect appears to be the common denominator of the beneficial effects of most of these dietary components which may protect against the development of chronic immune disorders such as (food) allergy. LCPUFAs, especially n-3 LCPUFAs, have been shown to interact with both the sensitization as well as the effector phase in food allergy in pre-clinical models. In this review, we explore the anti-allergic properties of LCPUFAs by providing an overview of clinical, in vivo and in vitro studies. Furthermore, we discuss the susceptibility of LCPUFAs to lipid oxidation and possible strategies to support the efficacy of LCPUFAs in reducing the allergy risk by using additional components with anti-oxidative and anti-inflammatory capacities such as the flavonoid quercetin. Finally, we propose new strategies to prevent (food) allergy using combinations of LCPUFAs and additional nutrients in diets or supplements, and postulate to investigate the use of LCPUFAs in allergic symptom relief.