Effects of VSL#3 on intestinal barrier function. VSL#3 acts on the four components of the intestinal barrier: The mechanical barrier, biological barrier, chemical barrier, and immune barrier. In terms of the mechanical barrier, VSL#3 can increase occludin and zonula occludens-1 and decrease claudin-2 in order to improve tight junction protein function, and the effect is achieved by increasing the activity of T-cell protein tyrosine phosphatase, which is able to decrease T-cell protein tyrosine phosphatase-dependent interferon-γ signaling and increase transepithelial electrical resistance[-]. VSL#3 can increase transepithelial electrical resistance by activating the mitogen-activated protein kinase p42/44 and p38 pathway[]. In terms of the biological barrier, VSL#3 can increase the amount of intestinal commensal bacteria and decrease the amount of fungi[]. In terms of the chemical barrier, VSL#3 can increase MUC2, MUC3 and MUC5AC gene expression to regulate mucus secretion[]. In terms of the immune barrier, VSL#3 can inhibit the proinflammatory nuclear factor-κB (NF-κB) pathway, such as inducing heat shock protein (HSP) and reducing monocyte chemoattractant protein-1 (MCP-1). The action mechanism is via the early inhibition of proteasome by producing soluble factors[]. VSL#3 also up-regulates the peroxisome proliferator-activated receptor α (PPARα) signaling pathway to antagonize the NF-κB pathway[]. An appropriate dose of VSL#3 can induce the maturation of dendrite cells (DC)[,], and VSL#3 can inhibit interferon-inducible protein-10 (IP-10) in intestinal epithelial cells (IEC)[-] and the lipopolysaccharide (LPS)-induced expression of chemokines (CXCL9, CXCL10, CCL2, CCL7, and CCL8) by inhibiting STAT-1 phosphorylation[]. VSL#3 is also able to decrease interleukin (IL)-12 (p40) production induced by LPS[]. Moreover, VSL#3 can induce IL-10 produced by DC and decrease the influx of innate immune cells (CD11b+) and adaptive immune cells (CD4+/CD8+)[,]. The down-regulation of the signaling pathway of Toll-like receptors (TLR) by VSL#3 also has benefits for the intestinal immune barrier[]. IEC: Intestinal epithelial cells; ZO-1: Zonula occludens-1; TCPTP: T-cell protein tyrosine phosphatase; IFN-γ: Interferon-γ; TER: Transepithelial electrical resistance; MAPK: Mitogen-activated protein kinase; GALT: Gut-associated lymphoid tissue; IEL: Intraepithelial lymphocytes; LPL: Lamina propria lymphocytes; sIgA: secreted immunoglobulin A; NF-κB: Nuclear factor-κB; IL: Interleukin; MCP-1: Monocyte chemoattractant protein-1; HSP: Heat shock protein; PPARα: Peroxisome proliferator-activated receptor α; IP-10: Interferon-inducible protein-10; DC: Dendrite cells; LPS: Lipopolysaccharide; TLR: Toll-like receptors.Effects of VSL#3 on mechanical barrier function, The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:1202–1209, 1209.e1. doi: 10.1016/j.cgh.2009.07.016., Tursi A, Brandimarte G, Papa A, et al. Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2010;105:2218–2227..