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Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

ABSTRACT: Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1? that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-? and IL-1? systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-? and IL-1? to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions.

SUBMITTER: Balza E

PROVIDER: S-EPMC4973356 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

Balza E E Piccioli P P Carta S S Lavieri R R Gattorno M M Semino C C Castellani P P Rubartelli A A

Cell death & disease 20160721

Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the ...[more]

PMID: 27441656

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Project description:BackgroundCurrently, few studies focus on the association between gut microbiota and systemic lupus erythematosus (SLE), and much less studies consider the effect of drug usage. Proton pump inhibitors (PPIs) are commonly used to treat drug-related gastrointestinal damage in SLE patients. Therefore, the purpose of this study is to examine the gut microbiota of SLE patients using PPIs.MethodsFecal samples from 20 SLE patients with PPIs (P-SLE), 20 SLE patients without PPIs (NP-SLE) and 17 healthy controls (HCs) were obtained. The structure of the bacterial community in the fecal samples was analyzed by 16S rRNA gene sequencing. Redundancy analysis (RDA) was performed to observe the relationship between clinical variables and microbiome composition in P-SLE and NP-SLE patients. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, functional capabilities of microbiota were estimated. Network analysis was performed to analyze the association of metabolic pathway alterations with altered gut microbiota in P-SLE and NP-SLE patients.ResultsP-SLE patients exhibited increased alpha-diversity and an altered composition of the gut microbiota compared with NP-SLE patients. The alpha-diversity of NP-SLE patients was significantly lower than HCs but also of P-SLE patients, whose alpha-diversity had become similar to HCs. Compared with NP-SLE patients, the relative abundances of Lactobacillus, Roseburia, Oxalobacter, and Desulfovibrio were increased, while those of Veillonella, Escherichia, Morganella, Pseudomonas and Stenotrophomonas were decreased in P-SLE patients. RDA indicated that PPI use was the only significant exploratory variable for the microbiome composition when comparing SLE patients. KEGG analysis showed that 16 metabolic pathways were significantly different between NP-SLE and P-SLE patients. These metabolic pathways were mainly associated with changes in Escherichia, Roseburia, Stenotrophomonas, Morganella and Alipipes as determined by the network analysis.ConclusionsPPI use is associated with an improved microbiome composition of SLE patients as it 1) increases alpha-diversity levels back to normal, 2) increases the abundance of various (beneficial) commensals, and 3) decreases the abundance of certain opportunistic pathogenic genera such as Escherichia. Validation studies with higher patient numbers are however recommended to explore these patterns in more detail.

Project description:BackgroundThe use of antibiotics (ATB) and proton-pump inhibitors (PPI) alters the composition and diversity of the gut microbiota, which can influence the immune system, consequently interfering with response to anti-PD1 immune checkpoint inhibitors (ICI). We assessed the impact of ATB and/or PPI use on the efficacy and safety of ICI.MethodsTwo hundred twelve patients treated with anti-PD1 ICI for non-small cell lung carcinoma, melanoma, upper airway & digestive tract carcinoma or renal cell carcinoma were retrospectively included. Patients having received ATB within 60 days before ICI initiation were included in the ATB+ group. Patients having received PPI within 30 days before ICI initiation were included in the PPI+ group. Four groups were thus considered: ATB-/PPI-, ATB+/PPI-, ATB-/PPI+, ATB+/PPI+. Response rate was assessed by RECIST v1.1. Overall survival (OS), progression-free survival (PFS) and adverse events, recorded using Common Terminology Criteria for Adverse Events Version 5, were compared using inverse probability of treatment weighting to account for selection bias.ResultsPFS at 6 months was 56.7 %, 95%CI (49.6%; 63.2%) and 47.2 %, 95%CI (39.8%;54.1%) at 12 months. OS was 81.6%, 95%CI (75.6%; 86.2%) at 6 months, and 69.4%, 95%CI (61.9%;75.7%) at 12 months. Compared to ATB-/PPI- group, PFS was lower for the ATB+/PPI- group [Hazard ratio (HR) 1.90, 95%CI (1.41;2.57)] and the ATB-/PPI+ group [HR 1.51, 95%CI (1.11;2.05)], and lowest in the ATB+/PPI+ group [HR 3.65, 95%CI (2.75;4.84)]. For OS, the use of ATB alone or PPI alone or in combination was a risk factor for death, with each increasing HR values by a similar magnitude, and the combination of ATB and PPI did not increase risk further. AEs were observed in 78 cases (36.8%) with no significant impact of ATB or PPI use.ConclusionsThis study reveals that ATB and/or PPI use can alter response to anti-PD1 ICI, and the prognosis of cancer patients. The microbiota mechanisms involved in the response to ICI should be investigated to optimize patient management.

Project description:Introduction: Proton pump inhibitors (PPIs) are commonly used to treat acid-related disorders. Their appropriate use depends on the correct indications from the clinician. Owing to the high incidence of use and misuse, PPIs have been identified as an essential pharmacological class for developing deprescribing recommendations. Therefore, assessing physicians' knowledge and practice regarding PPI usage is critical for paving the way toward targeted recommendations and efforts. Objective: This study aimed to assess Syrian physicians' perceptions of proton pump inhibitors adverse effects, their benefit in upper gastrointestinal bleeding (UGIB) prophylaxis, and how these perceptions are related to PPI prescription practice. Methods: A cross-sectional study was performed using a web-based questionnaire distributed among Syrian physicians in internal medicine between 28 November and 23 December 2022. The questionnaire assessed perceptions and experiences of PPIs, concerns about specific adverse effects, and their effectiveness for UGIB prophylaxis, in addition to the different scenarios used to determine the best practice for appropriate treatment to manage minimal, mild, moderate, and high-risk UGIB patients. Results: A total of 473 participants completed the questionnaire, with median age ±SD was (28.46 ± 4.58), and most participants (83.3%) were residents. Approximately half of the participants (45.5%) agreed that discussion assistance was provided to continue or terminate PPIs properly. Only 8.9% were very familiar with published evidence of PPI adverse effects. Bone weakening and vitamin B12 deficiency were the most frequently reported side effects (81.8% and 79.7%, respectively). However, dementia (0.4%) and mortality (1.9%) were the least reported adverse effects. More than half of the participants (64%) perceived using PPIs to prevent upper GI bleeding. Non-trainee physicians were less knowledgeable about appropriate GERD management than resident physicians (p < 0.001). Conclusion: The study showed a gap between Syrian physicians' perceptions and practices regarding PPI use, which necessitates spreading awareness of updated guidelines for PPI usage and their side effects.

Project description:BackgroundAntibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear.ObjectivesTo assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence.MethodsPopulation-based study including all 43 152 patients diagnosed with CDI in Sweden (2006-2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0-30 days) and preceding (31-180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs.ResultsCompared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48-17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83-15.93); ORPPI = 2.65 (2.54-2.76)]. Results were less pronounced for exposure during the preceding months. Dose-response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15-6.49); ORPPI = 1.65 (1.62-1.68) per prescription increase].Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23-1.38)] and preceding [ORAB = 1.23 (1.16-1.31); ORPPI = 1.12 (1.03-1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes.ConclusionRecent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.

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Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

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Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

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