## 6 Overview on Mast Cells
### Probiotics and Microbiota-Derived Molecules  
The beneficial impact of probiotics or even prebiotics or symbiotics on HPA and MCs was reported [109]. In particular, evidence indicates that the administration of a probiotic combined formulation of _Lactobacillus helveticus_ and _Bifidobacterium longum_ attenuates HPA axis activity and the autonomic nervous system (ANS), with a decrease in plasma cortisol and catecholamine levels [38]. _L. rhamn_ reduces hippocampal expression of the GABA receptor gene, suggesting a modulation of the balance of inhibition/excitation to control responses to stress, anxiety, and depression [130]. Several preclinical studies demonstrated the potential beneficial effects of _Lactobacillus_ and _Bifidobacteria_ species on the intestinal mucosal barrier. For example, _L helveticus_ and _B. longum_ restore the TJ integrity and the protection of the intestinal barrier [38]. _L. rhamn_s and _B. breve_ increase the production of mucins, the induction and production of defensins (human-\(\beta\)-defensin-2), and the secretion of immunoglobulin A, as well as the reduction of mucosal permeability through action on epithelial TJs. _B. infants_ was able to reduce the systemic proinflammatory cytokine profile along with symptom improvement in patients with IBD [131]. The ENS represents the target of bacterial metabolites; one of the main products of bacterial metabolism constitutes SCFAs, which are able to stimulate the sympathetic nervous system and mucosal 5-HT release. SCFAs are produced via the fermentation of complex carbohydrates by bacteria. In particular, propionate and acetate are produced by Bacteroides phylum, and butyrate is mainly produced by Firmicutes. SCFAs are critical for both enterocytes and colonocytes [132]. SCFAs exert their effects through the activation of membrane G-protein-coupled receptors (GPRs), including GPR41, GPR43, and GPR109, expressed on a wide range of cell types, such as intestinal epithelial cells, macrophages, and dendritic cells. In intestinal endocrine-L cells, GPR43 mediates the release of glucagon-like peptide 1 and peptide YY, suggesting a role in insulin resistance and obesity [133]. SCFA can directly control the immune response, sustaining an anti-inflammatory environment. Butyrate is a histone deacetylases inhibitor regulating epithelial cell gene expression and function through an epigenetic mechanism. In this manner, butyrate can induce regulatory T cell (Treg) differentiation, acting as an anti-inflammatory molecule [132; 134]. In addition, propionate and butyrate can modulate immune system cells, causing apoptosis of neutrophils and affecting cytokine production. SCFA propionic acid increases the number of regulatory T cells associated with an increase in remyelinization. It can protect BBB integrity from oxidative stress through the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Butyrate plays an immunomodulatory role in macrophages, leading to a reduction in inflammation. Diet-derived SCFAs are implicated in neuroinflammatory and neurodegenerative diseases [135]. It was reported that the combination of SCFAs with the probiotic _B. breve_ M-16V reduced MC degranulation without significantly reducing allergen-specific IgE levels. SCFAs also have an effect on MC activation. Sodium butyrate decreased the percentage of degranulated MCs and their inflammatory mediator content in weaned pigs. SCFAs are crucial in improving the barrier activity of intestinal epithelial cells, acting on TJs [136]. Sodium butyrate could improve intestinal barrier function and inflammatory mediator production through modulation of mitogen-activated protein kinase (MAPK) signaling pathways. In addition, sodium butyrate reduces the expression of MC-specific trypatase, TNF-\(\alpha\), and IL-6 messenger RNA (mRNA). A butyrate-producing probiotic (_Clostridium butylricum_) restored the intestinal epithelial barrier integrity through the regulation of tandem of pore domains in a weak inward rectifying K+ channel and by reducing the allergic response [137].