Rifaximin-Mediated Changes to the Epithelial Cell Proteome: 2-D Gel Analysis

Schrodt, Caroline A.; McHugh, Erin; Gawinowicz, Mary Ann; DuPont, Herbert L.; Brown, Eric L.

doi:10.1371/journal.pone.0068550

Cited by 19 publications

(13 citation statements)

References 46 publications

(54 reference statements)

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“…21 Rifaximin and rifamycin SV have been shown to affect epithelial cell physiology, induce changes in bacterial attachment/internalization, and reduce inflammatory cytokine release. 11,12,20,22,23 These factors may all reduce pathogen virulence and contribute to clinical improvements at time points when the pathogen can still be detected in the stools. If bactericidal effects alone explained the clinical response we would have expected efficient eradication of the pathogens from the gut lumen.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

DuPont¹,

Petersen²,

Zhao

et al. 2014

J Travel Med

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Background. Rifamycin SV is under development for treatment of travelers' diarrhea (TD) in a new oral formulation, Rifamycin SV MMX ® (RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug. Methods. This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo (n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool (TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration (MIC), and adverse events (AEs). Results. TLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections (p = 0.0035) with nonsignificant activity against invasive bacteria (p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance (p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%). Conclusions. RIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon.

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Section: Discussionmentioning

confidence: 99%

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

DuPont¹,

Petersen²,

Zhao

et al. 2014

J Travel Med

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“…Although one may hypothesise that rifaximin exerts its effect by altering the composition of the gut microbiota, data have shown only modest changes in the components of the gut microbiome in patients with cirrhosis and hepatic encephalopathy after rifaximin treatment . Additionally, preclinical studies have indicated that the efficacy of rifaximin may be attributable to its beneficial effects on host cell physiology and bacterial gene expression …”

Section: Treatments For Nafld That Target Gut Microbiotamentioning

confidence: 99%

Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications

Jayakumar

Loomba

2019

Aliment Pharmacol Ther

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Summary Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent disorder associated with obesity and diabetes. Few treatment options are effective for patients with NAFLD, but connections between the gut microbiome and NAFLD and NAFLD‐associated conditions suggest that modulation of the gut microbiota could be a novel therapeutic option. Aim To examine the effect of the gut microbiota on pathophysiologic causes of NAFLD and assess the potential of microbiota‐targeting therapies for NAFLD. Methods A PubMed search of the literature was performed; relevant articles were included. Results The composition of bacteria in the gastrointestinal tract can enhance fat deposition, modulate energy metabolism and alter inflammatory processes. Emerging evidence suggests a role for the gut microbiome in obesity and metabolic syndrome. NAFLD is often considered the hepatic manifestation of metabolic syndrome, and there has been tremendous progress in understanding the association of gut microbiome composition with NAFLD disease severity. We discuss the role of the gut microbiome in NAFLD pathophysiology and whether the microbiome composition can differentiate the two categories of NAFLD: nonalcoholic fatty liver (NAFL, the non‐progressive form) vs nonalcoholic steatohepatitis (NASH, the progressive form). The association between gut microbiome and fibrosis progression in NAFLD is also discussed. Finally, we review whether modulation of the gut microbiome plays a role in improving treatment outcomes for patients with NAFLD. Conclusions Multiple pathophysiologic pathways connect the gut microbiome with the pathophysiology of NAFLD. Therefore, therapeutics that effectively target the gut microbiome may be beneficial for the treatment of patients with NAFLD.

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“…Interestingly, rifaximin, that is used to treat diarrhea and ulcerative colitis by blocking bacterial adherence to gut epithelial cells, upregulates fascin-1 protein, suggesting that fascin-1 might have a cytoprotective role in the context of inflammation [51].…”

Section: Mortality Lymph Node Invasion Distant Metastasismentioning

confidence: 99%

Fascin-1 as a biomarker and prospective therapeutic target in colorectal cancer

Adams

2014

Expert Review of Molecular Diagnostics

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Fascin-1 is a filamentous actin-binding protein that crosslinks actin microfilaments into tight, parallel bundles. These bundles are important for the extension of microspikes, filopodia and invadopodia from cell surfaces and for the functionality of these protrusions in cell migration and/or dynamic sensing of the local microenvironment. Fascin-1 is absent in normal colonic epithelium, but its upregulation in colorectal adenomas and adenocarcinomas and its correlation with an aggressive clinical course has piqued the interest of many laboratories with research interests in cancer metastasis. This report summarizes current knowledge of the molecular interactions of fascin-1 in relation to its activities and mechanisms of upregulation in colorectal carcinoma cells. The status and key questions surrounding investigations of fascin-1 as a novel, early prognostic biomarker in colorectal cancer are discussed. Ongoing pre-clinical research into new migration inhibitory and anti-metastatic compounds that alter the actin cytoskeleton, and the goal of targeting fascin-1, is also discussed.

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Rifaximin-Mediated Changes to the Epithelial Cell Proteome: 2-D Gel Analysis

Cited by 19 publications

References 46 publications

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications

Fascin-1 as a biomarker and prospective therapeutic target in colorectal cancer

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