Molecular Mechanism and Clinical Effects of Probiotics in the Management of Cow's Milk Protein Allergy

Abstract

Cow's milk protein allergy (CMPA) is the most common food allergy (FA) in infancy, affecting approximately 2% of children under 4 years of age. According to recent studies, the increasing prevalence of FAs can be associated with changes in composition and function of gut microbiota or "dysbiosis". Gut microbiota regulation, mediated by probiotics, may modulate the systemic inflammatory and immune responses, influencing the development of allergies, with possible clinical benefits. This narrative review collects the actual evidence of probiotics' efficacy in the management of pediatric CMPA, with a specific focus on the molecular mechanisms of action. Most studies included in this review have shown a beneficial effect of probiotics in CMPA patients, especially in terms of achieving tolerance and improving symptoms.

Keywords: children; cow’s milk protein allergy (CMPA); microbiota; pediatric; probiotics.

Figure 1

Created with BioRender.com. In susceptible subjects, lack of integrity of the intestinal barrier permits the passage of allergens into sub-epithelial space and the release of proinflammatory cytokines IL-25, IL-33, and TSLP. DCs, under the stimuli of these cytokines, migrate to the draining lymphnode, and present antigens to naive T cells, promoting the type 2 immune response. The activated T cells differentiate into Th2 cells, which are involved in tissue inflammation and interaction with B cells, and into Tfh13 cells, which produce IL-4 and IL-13 in order to elicit B cell isotype class switching to high affinity IgEs. The Tfr cells seem to both suppress and enhance antigen-specific IgEs production by producing neuritin and through IL-10 stimulation, respectively. IgEs bind to the surface of mast cells and basophils through the high affinity IgE receptor Fc epsilon receptor I (FcεR1). The successive exposures to allergens cause the degranulation of sensitized mast cells and basophils, thanks to the binding of IgE to FcεR1 receptors, leading to the release of preformed and de novo synthesized proinflammatory mediators, i.e., leukotrienes, histamine, prostaglandins, and others. CD4: cluster of differentiation 4; CD40: cluster of differentiation 40; CD40L: CD40 ligand; FcεR1: Fc epsilon receptor I; GC: germinal center; IgE: immunoglobulin E; IL: interleukin; MHC-II: major histocompatibility complex class II; TCR: T-cell receptor; Tfh: T follicular helper cells; Tfr: T follicular regulatory cells; Th2: T helper type 2; TSLP: thymic stromal lymphopoietin.

Figure 2

Created with BioRender.com. Dietary fibers are carbohydrates that are not digestible in the small intestines of mammals. Human intestinal lumen is rich in different types of microorganisms, better known as gut microbiota. Dietary fiber fermentation by intestinal microorganisms produces SCFA (acetate, butyrate, propionate). SCFAs bind specific G protein-coupled receptors (GPRs) on the IECs surfaces called Gpr41, Gpr43, and Gpr109a. Recent studies demonstrated the role of these receptors in regulating inflammation, GI functions, allergies, adipogenesis, the central nervous system, and cardiovascular health. Butyrate stimulates DCs to produce IL-10 and RA, which are responsible for the conversion of naive T cells into Treg, suppressing the Th17 response. Treg cells produce IL-10, which has a role in the suppression of intestinal inflammation, and it is required for the induction and maintenance of Treg cells. Gpr43 signaling induces K+ flux, which is responsible for the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, resulting in IL-18 maturation; Gpr109a signaling inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation in colonic epithelium and stimulates the IL-18 transcription. Gpr43 activation inhibits neutrophils chemiotaxis, downregulating chemotactic receptors. DC: dendritic cells; Gpr43: G protein-coupled receptor 43; Gpr109a: G protein-coupled receptor 109a; IL: interleukin; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR family pyrin domain containing 3 (NLRP3) inflammasome; SCFA: small chain fatty acids; Th17: T helper type 17; Treg: regulatory T cell.

Figure 3

Created with BioRender.com. Probiotics have beneficial effects on FAs through different mechanisms. They increase mucin expression in intestinal cells, and straighten mucus layers and phosphorylate cytoskeletal tight junctional proteins, leading to the enhancement of the barrier function. Immunological functions of probiotics include development of GALT, increased mucosal IgA production, suppression of proinflammatory responses, and activation of anti-inflammatory cytokines like IL-10. Antimicrobial activities of probiotics include decreasing luminal pH and secreting bacteriocins and β-defensins, which are antibacterial substances; these functions lead to the blockage of pathogenic bacteria adherence and translocation. Probiotics compete with pathogenic bacteria for epithelial cell binding sites. DC: dendritic cells; IgA: immunoglobulin A; IL: interleukin; Th-1: T helper type 1; Treg: regulatory T cell.