Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria

Yasutomi, Eiichiro; Hoshi, Namiko; Adachi, Soichiro; Otsuka, Takafumi; Kong, Lingling; Y, Ku; Yamairi, Haruka; Inoue, Jun; Ishida, Tatsuro; Watanabe, Daisuke; Ooi, Makoto; Yoshida, Masaru; Tsukimi, Tomoya; Fukuda, Shinji; Azuma, Takeshi

doi:10.1007/s10620-017-4905-3

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…The results of two mouse studies suggest that reduced bactericidal effect, due to increased stomach pH, may be the most important factor for increased enteric infection risk. Mice received PPIs 7 days prior to infection with the murine pathogen Citrobacter rodentium, which resulted in increased numbers of C. rodentium organisms in the cecum 1 h postinoculation compared to control mice (96). Similar results were observed in another study, where treatment of mice with PPIs led to increased colonization by vancomycin-resistant enterococci and Klebsiella pneumoniae (97).…”

Section: Proton Pump Inhibitorssupporting

confidence: 71%

Gut Microbiota and Colonization Resistance against Bacterial Enteric Infection

Ducarmon

Zwittink

Hornung

et al. 2019

Microbiol Mol Biol Rev

327

262

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SUMMARY The gut microbiome is critical in providing resistance against colonization by exogenous microorganisms. The mechanisms via which the gut microbiota provide colonization resistance (CR) have not been fully elucidated, but they include secretion of antimicrobial products, nutrient competition, support of gut barrier integrity, and bacteriophage deployment. However, bacterial enteric infections are an important cause of disease globally, indicating that microbiota-mediated CR can be disturbed and become ineffective. Changes in microbiota composition, and potential subsequent disruption of CR, can be caused by various drugs, such as antibiotics, proton pump inhibitors, antidiabetics, and antipsychotics, thereby providing opportunities for exogenous pathogens to colonize the gut and ultimately cause infection. In addition, the most prevalent bacterial enteropathogens, including Clostridioides difficile, Salmonella enterica serovar Typhimurium, enterohemorrhagic Escherichia coli, Shigella flexneri, Campylobacter jejuni, Vibrio cholerae, Yersinia enterocolitica, and Listeria monocytogenes, can employ a wide array of mechanisms to overcome colonization resistance. This review aims to summarize current knowledge on how the gut microbiota can mediate colonization resistance against bacterial enteric infection and on how bacterial enteropathogens can overcome this resistance.

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Section: Proton Pump Inhibitorssupporting

confidence: 71%

Gut Microbiota and Colonization Resistance against Bacterial Enteric Infection

Ducarmon

Zwittink

Hornung

et al. 2019

Microbiol Mol Biol Rev

327

262

View full text Add to dashboard Cite

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“…Upon ingestion of contaminated food or water, EPEC and EHEC initially enter the stomach. Acidity of the gastric fluid not only aids the host in digestion of food but also serves as a significant barrier to enteric infection (Pienaar, Singh, & Barnard, 2019;Yasutomi et al, 2018). EPEC has the ability to withstand and recover from exposure to simulated gastric fluid (Pienaar et al, 2019).…”

Section: The Physical Landscape and Ae Pathogensmentioning

confidence: 99%

“…However, during EHEC infection, 20-80% of ingested bacteria are estimated to die before reaching the small intestine (Takumi, de Jonge, & Havelaar, 2000). Neutralising the stomach acid of mice by treating the animals with proton pump inhibitor (PPI) lansoprazole before infection with C. rodentium, and thereby attenuating this barrier, increased murine susceptibility to C. rodentium by allowing more bacteria to survive and reach the infection site, resulting in colitis symptoms in response to a 10-fold lower infectious dose (Yasutomi et al, 2018). A retrospective human case-control study confirmed that patient exposure to PPIs is a significant risk factor for Enterobacteriaceae infection (Cunningham, Jones, Enki, & Tischhauser, 2018).…”

Section: The Physical Landscape and Ae Pathogensmentioning

confidence: 99%

Here, there, and everywhere: How pathogenicEscherichia colisense and respond to gastrointestinal biogeography

Woodward

Krekhno

2019

Cellular Microbiology

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Gastrointestinal (GI) pathogens enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC), and related mouse pathogen Citrobacter rodentium, are referred to as attaching and effacing (AE) pathogens for the lesions they form upon colonisation of the host epithelium. EPEC, EHEC, and C. rodentium are well known to use a type III secretion system to intimately attach to intestinal cells and secrete bacterial effectors to manipulate host cell processes. Less well known is the ability of AE pathogens to overcome significant physiological and microbial barriers and target specific gut niches for initial colonisation of the host epithelium. This review considers recent work highlighting the biogeography of the GI tract as it applies to colonisation by enteric pathogens, including environmental barriers to enteric infection, signals sensed by AE pathogens for navigation of the GI tract, and the tools AE pathogens use to respond to the changing host environment.

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“…As previously described by Yasutomi et al (11), mice were unfed for 2 d with no solid food but provided water up until 2 h prior to experiments. TM inh -23 (10 mg/kg), lansoprazole (10 mg/kg), or vehicle was administered intraperitoneally 6 h and 30 min prior to stomach excision.…”

Section: Gastric Fluid Phmentioning

confidence: 99%

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A

Çil¹,

Anderson²,

Yen³

et al. 2019

FASEB j.

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Interstitial cells of Cajal, which express the calcium‐activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2‐bromodifluoroacetylamino‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]thiophene‐3‐carboxylic acid o‐tolylamide (TMinh‐23) with 30 nM half‐maximal inhibitory concentration. Here, we tested the efficacy of TMinh‐23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh‐23 strongly inhibited spontaneous and carbachol‐stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh‐23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [99mTc]‐diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh‐23 by ∼60% at 20 min. Interestingly, there was little effect of TMinh‐23 on baseline whole‐gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TMinh‐23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.—Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A. FASEB J. 33, 11247–11257 (2019). http://www.fasebj.org

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Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria

Abstract: Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

Cited by 15 publications

References 47 publications

Gut Microbiota and Colonization Resistance against Bacterial Enteric Infection

Gut Microbiota and Colonization Resistance against Bacterial Enteric Infection

Here, there, and everywhere: How pathogenicEscherichia colisense and respond to gastrointestinal biogeography

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A

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