A Low Dose of Fermented Soy Germ Alleviates Gut Barrier Injury, Hyperalgesia and Faecal Protease Activity in a Rat Model of Inflammatory Bowel Disease

Lara Moussa,Viorica Braniste,Vassilia Théodorou,Valérie Bacquié,Corinne Lencina,Mathilde Lévêque,Eric Houdeau,Christel Salvador-Cartier,Valérie Bézirard,Sandrine Ménard

doi:10.1371/journal.pone.0049547

Abstract

Pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF), IL-1β and TNF-α predominate in inflammatory bowel diseases (IBD) and TNBS colitis. Increased levels of serine proteases activating protease-activated receptor 2 (PAR-2) are found in the lumen and colonic tissue of IBD patients. PAR-2 activity and pro-inflammatory cytokines impair epithelial barrier, facilitating the uptake of luminal aggressors that perpetuate inflammation and visceral pain. Soy extracts contain phytoestrogens (isoflavones) and serine protease inhibitors namely Bowman-Birk Inhibitors (BBI). Since estrogens exhibit anti-inflammatory and epithelial barrier enhancing properties, and that a BBI concentrate improves ulcerative colitis, we aimed to evaluate if a fermented soy germ extract (FSG) with standardized isoflavone profile and stable BBI content exert cumulative or synergistic protection based on protease inhibition and estrogen receptor (ER)-ligand activity in colitic rats. Female rats received orally for 15 d either vehicle or FSG with or without an ER antagonist ICI 182.780 before TNBS intracolonic instillation. Macroscopic and microscopic damages, myeloperoxidase activity, cytokine levels, intestinal paracellular permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression were assessed 24 h, 3 d and 5 d post-TNBS. FSG treatment improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points. All FSG effects were reversed by the ICI 182.780 except the decrease in faecal proteolytic activity and PAR-2 expression. In conclusion, the anti-inflammatory properties of FSG treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.

Highlights

Inflammatory bowel diseases (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), are chronic and relapsing inflammatory conditions characterized by an abnormal immune response to microbiota, impaired epithelial barrier function, tissue damage, and abdominal pain [1,2,3]
TNBS administration resulted in colon inflammation associated with hyperemia, ulceration and bowel wall thickening, leading to a significant increase (p,0.01) in macroscopic damage score (MDS) 24 h, 3 d and 5 d after colitis induction compared with non colitic animals (Figure 1A)
We show that an oral treatment with a fermented soy germ ingredient (FSG) reduces inflammatory response, intestinal permeability and visceral hypersensitivity in a rat model of colitis through two distinct pathways

Summary

Introduction

Inflammatory bowel diseases (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), are chronic and relapsing inflammatory conditions characterized by an abnormal immune response to microbiota, impaired epithelial barrier function, tissue damage, and abdominal pain [1,2,3] In both disorders, mucosal immune cells produce large amounts of chemokines and cytokines, including macrophage migration inhibitory factor (MIF), IL-1b and TNF-a, both orchestrating the immuno-inflammatory process leading to epithelial barrier defect, tissue damage [3]. The levels of potential activators of PAR-2 such as serine-proteases are increased in the colonic tissue of IBD patients [4,5,6] Both PAR-2 activity and proinflammatory cytokines impair epithelial barrier by decreasing tight junction (TJ) protein expression [3,4], facilitate the entry of luminal aggressors perpetuating inflammation and pain [7]

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