Biomedical subjects

C Pothoulakis

Publications and source records attributed to C Pothoulakis.

At least 19 recordsLinked to original sources

PubMed1998

Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.

Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.

Animals↗

PubMed1998

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury.

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R-/- mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R-/- animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.

Acute Disease↗

PubMed1998

Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice.

BACKGROUND & AIMS: The pathogenesis of Clostridium difficile toxin A-induced intestinal inflammation is not completely understood. The aim of this study was to define the contribution of mast cells to the fluid secretion and neutrophil infiltration associated with toxin A-induced enteritis. METHODS: Fluid secretion and neutrophil infiltration in toxin A- or buffer-challenged ileal loops were assessed in normal, mast cell-deficient, and mast cell-deficient KitW/KitW-v mice that had undergone selective repair of their mast cell deficiency. The effect of a specific substance P-receptor antagonist was also studied. RESULTS: Intestinal fluid secretion and neutrophil recruitment were significantly diminished in mast cell-deficient KitW/KitW-v and mast cell-deficient MgfSl/MgfSl-d mice compared with the respective normal mice. Mast cell-reconstituted KitW/KitW-v mice showed responses similar to the normal congenic mice. Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice. CONCLUSIONS: C. difficile toxin A elicits intestinal fluid secretion and neutrophil infiltration by both mast cell-dependent and -independent pathways, and substance P participates in both pathways.

Animals↗

PubMed1998

CGRP upregulation in dorsal root ganglia and ileal mucosa during Clostridium difficile toxin A-induced enteritis.

We have previously reported that pretreatment of rats with capsaicin (an agent that ablates sensory neurons) or CP-96345 (a substance P receptor antagonist) dramatically inhibits fluid secretion and intestinal inflammation in ileal loops exposed to Clostridium difficile toxin A. The aim of this study was to determine whether calcitonin gene-related peptide (CGRP), a neuropeptide also found in sensory afferent neurons, participates in the enterotoxic effects of toxin A. Administration of toxin A was also found to increase CGRP content in dorsal root ganglia and ileal mucosa 60 min after toxin exposure. Furthermore, immunohistochemical studies demonstrated increased neuronal staining for CGRP 2 h after toxin A treatment. Pretreatment of rats with CGRP-(8-37), a specific CGRP antagonist, before instillation of toxin A into ileal loops significantly inhibited toxin-mediated fluid secretion (by 48%), mannitol permeability (by 83%), and histological damage. We conclude that CGRP, like substance P, contributes to the secretory and inflammatory effects of toxin A via increased production of this peptide from intestinal nerves, including primary sensory afferent neurons.

Animals↗

PubMed1997

Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats.

Previously we reported that pretreatment of rats with the substance P (SP) antagonist CP-96,345 inhibits the enterotoxic responses following administration of toxin A from Clostridium difficile into ileal loops, indicating that SP participates in the intestinal responses to this toxin. We now report that injection of toxin A into rat ileum causes a rapid increase in SP content in lumbar dorsal root ganglia (DRG) and mucosal scrapings 30-60 min after toxin A administration. Toxin A-mediated fluid secretion, mannitol permeability, and ileal histologic damage is significantly increased only after 2 hr. Toxin A also causes an increase in the abundance of SP mRNA in lumbar DRG and ileal mucosa as measured by reverse transcription-PCR. Lamina propria macrophages (LPMs) obtained from toxin A-injected loops release greater amounts of tumor necrosis factor alpha (TNFalpha) and SP as compared with LPMs isolated from buffer-injected loops (P < 0.01). Pretreatment of rats with the SP antagonist CP-96,345 inhibits toxin A-mediated TNFalpha release from isolated LPMs, whereas an inactive enantiomer (CP-96,344) of the SP antagonist has no effect. LPMs obtained from toxin A-injected ileal loops incubated in vitro with SP (10(-8) to 10(-9) M) show enhanced TNFalpha secretion, whereas LPMs isolated from buffer-injected loops do not respond to SP. In addition, LPMs obtained from toxin A-injected ileal loops incubated in vitro with CP-96,345 showed a diminished TNFalpha release. Our results indicate that activated LPMs secrete SP during toxin A enteritis that can lead to secretion of cytokines, suggesting an autocrine/paracrine regulation of cytokine secretion by SP from LPMs during intestinal inflammation.

Animals↗

PubMed1997

Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract.

To be therapeutically active, oral hyperimmune bovine immunoglobulin concentrate (BIC) must survive its passage through the intestinal tract. This led us to study the gastrointestinal stability of orally administered BIC directed against Clostridium difficile toxins (BIC-C. difficile). BIC-C. difficile was stable at neutral pH in vitro but was degraded at low pH, particularly in the presence of pepsin. Healthy volunteers (n = 6) took BIC-C. difficile (45 or 8 g) as a single oral dose. Total bovine immunoglobulin G (IgG) and specific anti-C. difficile IgG were measured in the stool. BIC was given under the following conditions: in the fasting state, in the fed state, with antacid, during omeprazole therapy, or in enteric capsules (released at pH > 6). The mean fecal bovine IgG content of 3-day stool collections was similar in the fasting (536 mg; 3.8% of the ingested dose of BIC), fed (221 mg; 1.6%), and antacid (381 mg; 2.7%) groups. Omeprazole therapy was associated with increased fecal bovine IgG levels (1253 mg; 8.8%), but this difference did not reach statistical significance (P = 0.07). Administration of 8 g of BIC-C. difficile in enteric capsules resulted in substantially higher fecal bovine IgG levels (1,124 mg; 32.7% of the oral dose) than those obtained after administration of nonencapsulated BIC (22 MG; 0.6%; P = 0.004). An inverse relationship was noted between intestinal transit time and fecal bovine IgG content (R = 0.83; P = 0.04 [data from omeprazole group]). Filtrates of stool samples collected after oral administration of BIC-C. difficile neutralized the cytotoxicity of C. difficile toxins A and B, whereas control stool filtrates did not. Bovine colostral IgG undergoes partial degradation in the intestinal tract. Exposure to acidic gastric secretions and prolonged colonic transit may both contribute to IgG degradation. Nonetheless, humans taking BIC-C. difficile orally have neutralizing antitoxin activity in their stool.

Administration, Oral↗

PubMed1997

Intravenous immunoglobulin therapy for severe Clostridium difficile colitis.

BACKGROUND: Many individuals have serum antibodies against Clostridium difficile toxins. Those with an impaired antitoxin response may be susceptible to recurrent, prolonged, or severe C difficile diarrhoea and colitis. AIMS: To examine whether treatment with intravenous immunoglobulin might be effective in patients with severe pseudomembranous colitis unresponsive to standard antimicrobial therapy. PATIENTS: Two patients with pseudomembranous colitis not responding to metronidazole and vancomycin were given normal pooled human immunoglobulin intravenously (200-300 mg/kg). METHODS: Antibodies against C difficile toxins were measured in nine immunoglobulin preparations by ELISA and by cytotoxin neutralisation assay. RESULTS: Both patients responded quickly as shown by resolution of diarrhoea, abdominal tenderness, and distension. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B by ELISA and neutralised the cytotoxic activity of C difficile toxins in vitro at IgG concentrations of 0.4-1.6 mg/ml. CONCLUSION: Passive immunotherapy with intravenous immunoglobulin may be a useful addition to antibiotic therapy for severe, refractory C difficile colitis. IgG antitoxin is present in standard immunoglobulin preparations and C difficile toxin neutralising activity is evident at IgG concentrations which are readily achieved in the serum by intravenous immunoglobulin administration.

Antibodies↗

PubMed1997

IL-11 inhibits Clostridium difficile toxin A enterotoxicity in rat ileum.

Interleukin-11 (IL-11) is a stromal cell-derived cytokine with several biological activities against hematopoietic cells. Recent results indicated that IL-11 reduced mucosal damage in animal models of colitis. This study aimed to explore the action of recombinant human IL-11 (rhIL-11) on the intestinal effects of Clostridium difficile toxin A, an inflammatory enterotoxin, and cholera toxin, a noninflammatory enterotoxin in rat ileum. We administered rhIL-11 subcutaneously to rats before injection of toxin A into ileal loops and measured fluid secretion, epithelial permeability to mannitol, histopathological damage, and release of rat mast cell protease II (RMCP II) from intestinal mast cells and of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) from lamina propria macrophages. rhIL-11 (50-1,000 micrograms/kg) inhibited toxin A but not cholera toxin-mediated secretion and permeability in a dose-dependent fashion and reduced toxin A-induced epithelial cell damage. Rats treated with rhIL-11 also showed reduced RMCP II, TNF-alpha, and MIP-2 release in response to toxin A. Exposure of rat peripheral monocytes in vitro to rhIL-11 (1 microgram/ml) inhibited lipopolysaccharide and toxin A-mediated increases in TNF-alpha mRNA and protein levels. We conclude that rhIL-11 blocks the intestinal effects of C. difficile toxin A, possibly by inhibiting release of inflammatory mediators from mucosal mast cells and intestinal macrophages.

Animals↗

PubMed1997

Epidermal growth factor attenuates Clostridium difficile toxin A- and B-induced damage of human colonic mucosa.

Epidermal growth factor (EGF) exhibits a cytoprotective effect on gastrointestinal epithelia via a receptor-mediated mechanism. We investigated the effect of EGF on Clostridium difficile toxin A (TxA)- and toxin B (TxB)-induced damage of human colon. Ussing-chambered colonic mucosa was exposed serosally to EGF before and during luminal exposure to TxA and TxB. Resistance was calculated from potential difference and short-circuit current. Epithelial damage was assessed by light microscopy and alteration of F-actin by fluoresceinated phalloidin. Luminal exposure of colonic strips to TxA and TxB caused a time- and dose-dependent decrease in electrical resistance, necrosis and dehiscence of colonocytes, and disruption and condensation of enterocyte F-actin. These effects were inhibited by prior, but not simultaneous, serosal application of EGF (20 nM). Administration of the tyrosine kinase inhibitor genistein (10(-6) M) inhibited the protective effects of EGF. We conclude that EGF protects against TxA and TxB probably by stabilizing the cytoskeleton, the main target of these toxins.

Actins↗

PubMed1997

IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes.

Neutrophil infiltration is central to the pathogenesis of Clostridium difficile toxin A-induced enterocolitis. This study examines whether monocyte activation by C. difficile toxins is instrumental in initiating neutrophil activation and recruitment. Human monocytes were exposed to low concentrations of highly purified C. difficile toxins, and the conditioned media were harvested for cytokine and functional assays. Monocytes exposed to C. difficile toxin A (10(-10) M) or toxin B (10(-12) M) released 100 and 20 times basal levels, respectively, of the neutrophil chemoattractant interleukin-8 (IL-8). Reverse transcriptase-polymerase chain reaction demonstrated a marked increase in IL-8 mRNA expression by monocytes 3 h after toxin exposure. Conditioned media from toxin A- and toxin B-treated monocytes stimulated neutrophil migration (324 and 245% of control, respectively). This effect was completely blocked by IL-8 antiserum. These media also upregulated neutrophil CD11b/CD18 and endothelial cell intercellular adhesion molecule-1 expression. C. difficile toxins, at low concentrations, potently activate monocytes to release factors, including IL-8, that facilitate neutrophil extravasation and tissue infiltration. Our findings indicate a major role for toxin-mediated monocyte and macrophage activation in C. difficile colitis.

Bacterial Proteins↗

PubMed1996

A neurotensin antagonist, SR 48692, inhibits colonic responses to immobilization stress in rats.

We previously reported that short-term immobilization stress of rats causes increased colonic mucin release, goblet cell depletion, prostaglandin E2 secretion, and colonic mast cell activation, as well as increased colonic motility. The purpose of this study was to investigate whether neurotensin (NT), a peptide expressed in both brain and digestive tract, participates in these responses. Rats were pretreated with SR 48692 (1 mg/kg, i.p.), an NT antagonist, 15 min before immobilization (30 min). The administration of the antagonist significantly inhibited stress-mediated secretion of colonic mucin, prostaglandin E2, and a product of rat mast cells, rat mast cell protease II (P < 0.05), but did not alter the increase in fecal pellet output caused by immobilization stress. Immobilization stress also resulted in a quantifiable decrease in the abundance of NT receptor mRNA in rat colon compared with that in colonic tissues from nonimmobilized rats as measured by densitometric analysis of in situ hybridization studies (P < 0.03). We conclude that the peptide NT is involved in colonic goblet cell release and mucosal mast cell activation after immobilization stress.

Animals↗

PubMed1996

Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A.

The intestinal effects of Clostridium difficile toxin A are inidated by toxin binding to luminal enterocyte receptors. We reported previously that the rabbit ileal brush border (BB) receptor is a glycoprotein with an alpha-d-galactose containing trisaccharide in the toxin-binding domain (1991. J. Clin. Invest. 88:119-125). In this study we characterized the rabbit ileal BB receptor for this toxin. Purified toxin receptor peptides of 19 and 24 amino acids showed 100% homology with rabbit sucrase-isomaltase (SI). Guinea pig receptor antiserum reacted in Western blots with rabbit SI and with the purified toxin receptor. Antireceptor IgG blocked in vitro binding of toxin A to rabbit ileal villus cell BB. Furthermore, anti-SI IgG inhibited toxin A-induced secretion (by 78.1%, P < 0.01), intestinal permeability (by 80.8%, P < 0.01), and histologic injury (P < 0.01) in rabbit ileal loops in vivo. Chinese hamster ovary cells transfected with SI cDNA showed increased intracellular calcium increase in response to native toxin (holotoxin) or to a recombinant 873-amino acid peptide representing the receptor binding domain of toxin A. These data suggest that toxin A binds specifically to carbohydrate domains on rabbit ileal SI, and that such binding is relevant to signal transduction mechanisms that mediate in vitro and in vivo toxicity.

Amino Acid Sequence↗

PubMed1996

A human antibody binds to alpha-galactose receptors and mimics the effects of Clostridium difficile toxin A in rat colon.

BACKGROUND & AIMS: Nearly all human sera contain an immunoglobulin G antibody (antigalactose) that binds the trisaccharide Gal alpha 1-3Gal beta 1-4GlcNAc expressed on cells from most mammals but not humans. Because the Clostridium difficile toxin A receptor in rodents contains this trisaccharide, the aim of this study was to examine whether antigalactose could mimic the enterotoxic effects of toxin A and bind to receptors containing this trisaccharide. METHODS: Fluid secretion, [3H]-mannitol permeability, and release of rat mast cell protease II and prostaglandin E2 were measured after luminal exposure of rat colon to either purified human anti-galactose, control immunoglobulin G, toxin A, or buffer. RESULTS: Toxin A (5 micrograms) and antigalactose (250 micrograms) but not control immunoglobulin (250 micrograms) stimulated colonic fluid secretion and caused increased mannitol permeability and rat mast cell protease II release. Antigalactose and toxin A and, to a lesser degree, control immunoglobulin G also stimulated release of prostaglandin E2, but only toxin A produced acute inflammation of rat colonic mucosa. Antigalactose and toxin A bound specifically to a single class of colonic brush border receptors with dissociation constants of 10(-6) mol/L and 5.4 x 10(-8) mol/L, respectively. CONCLUSIONS: Fluid secretion, increased permeability, and mast cell activation occur in rat colon when toxin A or human antigalactose immunoglobulin G bind to receptors bearing the trisaccharide Gal alpha 1-3Gal beta 1-4GlcNAc.

Animals↗

PubMed1996

Nitric oxide inhibits rat intestinal secretion by Clostridium difficile toxin A but not Vibrio cholerae enterotoxin.

BACKGROUND & AIMS: Intestinal inflammation is associated with increased synthesis of nitric oxide, whereas inhibition of NO synthase (NOS) reduces experimental chronic intestinal inflammation. The aim of this study was to test the effects of NO blockers and donors on acute intestinal inflammation induced by Clostridium difficile toxin A in rat ileum. METHODS: Rats received NOS inhibitors or NO donors before measurement of toxin-mediated ileal secretion and permeability changes. Mucosal mast cell and neutrophil activity were measured by release of rat mast cell protease II and myeloperoxidase activity, respectively. RESULTS: NOS inhibitors augmented but an NO donor inhibited toxin A-mediated ileal secretion and permeability when given before but not after toxin administration. Neither an NOS inhibitor nor an NO donor had any effect on cholera toxin-mediated secretion. Mast cell degranulation and neutrophil infiltration occurred after injection of toxin A or an NOS inhibitor, whereas the NO donor blocked both toxin A effects. CONCLUSIONS: NOS inhibitors augmented and an NO donor blocked the intestinal effects of toxin A but not of cholera toxin. NO protects against toxin A by inhibition of intestinal mast cells and neutrophils, which are activated by toxin A, but not by cholera toxin.

Acetylcysteine↗

PubMed1996

A receptor decoy inhibits the enterotoxic effects of Clostridium difficile toxin A in rat ileum.

BACKGROUND & AIMS: Clostridium difficile toxin A causes secretion and intestinal inflammation in rodents by binding to a specific trisaccharide Gal alpha 1-3Gal beta 1-4 GlcNAc on enterocyte receptors. The purpose of this study was to explore the ability of Synsorb 90 (Synsorb Biotech Inc., Calgary, Alberta, Canada), and inert support carrying this trisaccharide, to bind toxin A in vitro and to inhibit its enterotoxic effects in vivo. METHODS: Binding of [3H]toxin A to Synsorb 90, Synsorb 83 (beta-mannose attached), and Chromosorb P (inert support with no sugar attached) (Synsorb Biotech Inc.) was measured. The inhibitory effects of these compounds on toxin A-mediated fluid secretion, mannitol permeability, and histological damage were measured in ileal loops in vivo. RESULTS: Toxin A showed specific binding to Synsorb 90, bearing the specific trisaccharide that binds toxin A, but not to Synsorb 83 or to Chromosorb P. Pretreatment of rats with Synsorb 90 by gavage (200 mg/kg body wt), but no Synsorb 83 or Chromosorb P at the same doses, dramatically reduced toxin A-associated fluid secretion and permeability. CONCLUSIONS: An immobilized toxin A receptor sequesters toxin A in the intestinal lumen and inhibits its effects of ileal mucosa. These results suggest a potential use for this agent in treating patients with C. difficile colitis.

Animals↗

PubMed1996

Pathogenesis of Clostridium difficile-associated diarrhoea.

Clostridium difficile is now regarded as a major enteric pathogen in hospitals and nursing-home facilities. The pathophysiology of this pathogen involves alterations of the indigenous colonic flora by antibiotics, ingestion of spores and colonization by C. difficile, followed by release of its toxins. Although most of the research on the intestinal effects of C. difficile had been focused on its enterotoxin or toxin A, recent results indicate that toxin B, the cytotoxin of C. difficile, is also active in human colon. The cloning and sequencing of the toxin A and toxin B gene and the identification of the GTP-binding protein Rho as their intracellular target represent major advances in our understanding of the mode of action of these toxins. An important characteristic of C. difficile infection is the dramatic inflammation seen in pseudomembranous colitis. Recent studies indicate that an interplay between lamina propria neuroimmune cells and intestinal epithelial cells may be central in pathogenesis of this toxin-mediated inflammatory response.

Bacterial Toxins↗

PubMed1996

Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins.

Clostridium difficile diarrhea and colitis result from the actions of bacterial exotoxins on the colonic mucosa. This study examined the ability of hyperimmune bovine colostral antibodies to neutralize the biological effects of these toxins. Anti-C. difficile bovine immunoglobulin concentrate was prepared from the colostral milk of Holstein cows previously immunized with C. difficile toxoids. The anti-C. difficile bovine immunoglobulin concentrate contained high levels of bovine immunoglobulin G specific for C. difficile toxins A and B, as evaluated by enzyme-linked immunosorbent assay. Anti-C. difficile bovine immunoglobulin concentrate neutralized the cytotoxic effects of purified toxin A and toxin B on cultured human fibroblasts, whereas control bovine immunoglobulin concentrate had little toxin-neutralizing activity. Anti-C. difficile bovine immunoglobulin concentrate also blocked the binding of toxin A to its enterocyte receptor and inhibited the enterotoxic effects of C. difficile toxins on the rat ileum, as measured by an increased rat ileal loop weight/length ratio (63% inhibition; P < 0.01), increased mannitol permeability (92% inhibition; P < 0.01), and histologic grading of enteritis (P < 0.01 versus nonimmune bovine immunoglobulin concentrate). Thus, anti-C. difficile bovine immunoglobulin concentrate neutralizes the cytotoxic effects of C. difficile toxins in vitro and inhibits their enterotoxic effects in vivo. This agent may be clinically useful in the prevention and treatment of C. difficile diarrhea and colitis.

Animals↗

PubMed1996

Saccharomyces boulardii protease inhibits Clostridium difficile toxin A effects in the rat ileum.

Saccharomyces boulardii, a nonpathogenic yeast, is effective in treating some patients with Clostridium difficile diarrhea and colitis. We have previously reported that S. boulardii inhibits rat ileal secretion in response to C. difficile toxin A possibly by releasing a protease that digests the intestinal receptor for this toxin (C. Pothoulakis, C. P. Kelly, M. A. Joshi, N. Gao, C. J. O'Keane, I. Castagliuolo, and J. T. LaMont, Gastroenterology 104: 1108-1115, 1993). The aim of this study was to purify and characterize this protease. S. boulardii protease was partially purified by gel filtration on Sephadex G-50 and octyl-Sepharose. The effect of S. boulardii protease on rat ileal secretion, epithelial permeability, and morphology in response to toxin A was examined in rat ileal loops in vivo. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified S. boulardii protease revealed a major band at 54 kDa. Pretreatment of rat ileal brush border (BB) membranes with partially purified protease reduced specific toxin A receptor binding (by 26%). Partially purified protease digested the toxin A molecule and significantly reduced its binding to BB membranes in vitro (by 42%). Preincubation of toxin A with S. boulardii protease inhibited ileal secretion (46% inhibition, P < 0.01), mannitol permeability (74% inhibition, P < 0.01), and histologic damage caused by toxin A. Thus, S. boulardii protease inhibits the intestinal effects of C. difficile toxin A by proteolysis of the toxin and inhibition of toxin A binding to its BB receptor. Our results may be relevant to the mechanism by which S. boulardii exerts its protective effects in C. difficile infection in humans.

Animals↗