# Probiotic Molecules That Inhib Inflammatory Diseases
## 3 Secreted Molecules  
_A. Proteins._ Numerous extracellular and secreted bacterial proteins are known to diminish inflammation. These include serpin from _Bifidobacterium longum_, which inhibits eukaryotic elastase-like serine proteases that are dysregulated in inflammatory disorders, such as celiac disease [28; 29], and p40 and p75, molecules from _Lactobacillus casei_ BL23 that _in vitro_ protect from disruption of epithelial cell tight junctions induced by hydrogen peroxide in a PKC and MAP kinase-dependent manner [39]. A p40 secreted molecule from \(L\). _rhammosus GG_ activated EGFR _in vitro_ and, after oral administration, prevented DSS-induced intestinal epithelial damage in mice [40; 41]. Moreover, _L. casei_ secretes lactoeptin, which hydrolyzes the pro-inflammatory chemokine IP-10, and its i.p. administration leads to reduced lymphocyte recruitment in an ileitis murine model [38]. Another extracellular molecule that moderates the immune response is flagellin from _Escherichia coli_ Nissle 1917, which induces the release of the antimicrobial peptide \(\beta\)-defensin 2 in epithelial cells _in vitro_[36]. Other secreted probiotic proteins that can modulate immune responses are summarized in Table 1. These examples illustrate the potential of using extracellular and secreted peptides from probiotics for therapeutic treatments of immune-mediated diseases. _B. Exopolysaccharide._ Many probiotics secrete polysaccharides that have anti-inflammatory properties, which can reduce the production of pro-inflammatory cytokines, increase anti-inflammatory cytokines, enhance the intestinal epithelial barrier, and inhibit T cell-dependent immune responses. These polysaccharides are usually obtained by alcohol precipitation from culture supernatants, and the solubilized precipitate is designated as exopolysaccharide (EPS). As discussed below, EPS molecules of different origins vary widely in the anti-inflammatory effects and the mechanism of protection. Although the term \"EPS\" is used for all of these samples, the composition and structure of them are generally not known. Likely, EPS from different microorganisms have different compositions and structures, leading to diverse functions and mechanisms of immune regulation. A defined classification of EPS from different organisms will require the structure and structure/function relationship of these polysaccharides. In this review, we distinguish the EPS preparations by using superscripts to symbolize the bacterium from which a specific EPS is isolated, e.g., EPS\({}^{\text{Bb}}\) from _Bacillus subtilis_. Using bacterial mutants, EPS\({}^{\text{Bb}}\) from _Bifidobacterium breve_ has been implicated in reducing colitis during _Citrobacter roedentium_ infection in mice [24] and in reducing rates of epithelial cell shedding [26]. Oral administration of EPS\({}^{\text{Bb}}\) from _B. breve_ has also been shown to enhance the intestinal barrier integrity, thereby preventing allergen infiltration and food allergy [27]. Another species of _Bifidobacterium_, the non-aggregating strain IF1-03 _B. adolescents_, protects from colitis by inducing IL-10 production, activating dendritic cells (DCs) and macrophages, and increasing the ratio of Treg/Th17 cells in mice [23]. Based on data from a bacterial mutant, EPS\({}^{\text{BI}}\) from still another _Bifidobacterium_ species, _B. Longum_ 35624, dampens pro-inflammatory cytokines and reduces inflammatory symptoms in the T cell transfer colitis model [30], and in an allergy model, EPS\({}^{\text{BI}}\) stimulates the release of IL-10 in a TLR2-dependent manner that reduces recruitment of eosinophils to the lungs [31]. For _Lactobacillus_, numerous immunomodulatory effects of EPS\({}^{\text{Lh}}\) have been identified and are reviewed in [PERSON] et al. [66]. Oral administration of EPS\({}^{\text{Lh}}\) isolated from \(L\). _helveticus_ KLDS1.8701 reduces intestinal inflammation and improves mucosal barrier function in a colitis model [44], whereas EPS\({}^{\text{Lr}}\) from \(L\).