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Proton pump inhibitors promote non-steroidal anti-inflammatory drug-induced enteropathy via microbiota. Murine models demonstrate that proton pump inhibitor (PPI) treatment, in addition to non-steroidal anti-inflammatory drugs (NSAIDs) therapy, brings about an exacerbation of mucosal damage in the small intestine. PPIs cause a bacterial imbalance, such as the reduction (↓) of Actinobacteria and Bifidobacteria spp., which is responsible for the mucosal damage. Specifically, PPIs increase the expression of bacteria with beta-glucuronidases activity and the consequent spreading of NSAIDs into enterohepatic circulation; ultimately, bile cytotoxicity then causes ulcerative intestinal lesions. The co-administration of Bifidobacteria-enriched suspension restores the gut microbiota and reduces mucosal damage. Germ-free mice are less susceptible to NSAIDs' harmful effects and they develop NSAID-induced enteropathy through microbiota transfer. PPI: Proton pump inhibitor; NSAID: Non-steroidal anti-inflammatory drugs.
Source publication
Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the lon...
Context in source publication
Context 1
... have also been reported to exacerbate the mucosal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) in the distal portion of the small bowel to the ligament of Treitz [95,96] , which stands in contrast to the protective effects of PPIs on NSAIDs-induced upper GI mucosal injury [97] . Even if the exact mechanism by which it occurs is not clear, bacterial imbalance can play an important role and, as such, has been investigated in a number of studies conducted in murine models (Figure 2). In rats, a PPI-driven significant reduction of Actinobacteria and Bifidobacteria spp. in the jejunum was shown to exacerbate NSAID-induced enteropathy [98] . ...
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Background
Type I gastric neuroendocrine tumors (gNETs) arise from hypergastrinemia in patients with autoimmune chronic atrophic gastritis. According to the classical model, the gastric H+/K+ ATPase was the causative autoantigen recognized by CD4+ T cells in chronic autoimmune scenario that secretes IL-17 and correlates with parietal cell (PC) atro...
Citations
... Such changes may weaken the ability of the gut to resist infections, exacerbate inflammation, and eventually predispose an individual to gastrointestinal disorders. 39,66 Long-term PPI use may cause achlorhydria in some cases, which may promote the migration of oral bacteria into the lower gut, increasing the chances of infections. 40,66 In cirrhotic patients, PPI therapy has been linked to disruptions in the gut microbiome, spontaneous bacterial peritonitis, and hepatic encephalopathy. ...
... 39,66 Long-term PPI use may cause achlorhydria in some cases, which may promote the migration of oral bacteria into the lower gut, increasing the chances of infections. 40,66 In cirrhotic patients, PPI therapy has been linked to disruptions in the gut microbiome, spontaneous bacterial peritonitis, and hepatic encephalopathy. Identification of specific species, such as Streptococcus salivarius, Veillonella parvula, and the Streptococcus genus, were indicative of PPI-associated dysbiosis, intestinal inflammation, and severe liver disease. ...
... Upper GI comorbidities and the use of PPIs are associated with disruption of the gut microbiome [16]. Moreover, reduced gut microbial diversity has been observed in patients with CLL and is thought to contribute to disease development and/or be a manifestation of the underlying immune dysfunction [17]. ...
In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients.
... There have been multiple studies that found individuals using PPIs who had a significant increase in various bacterial genera, including, Enterococcus, Streptococcus, Staphylococcus, and Rothia; as well as, the species such as Lactobacillus salivarius and a potentially pathogenic species of Escherichia coli (127). Another study by Bruno et al. also found that PPIs can lead to dysbiosis throughout various segments of the GI tract with increased Enterobacteriaceae, Enterococcaceae, and Lactobacillaceae while there was a decrease in Ruminococcaceae and Bifidobacteriaceae in the colon (128). It is suspected that individuals who are on long-term PPI use can be at risk for enteric infection through dysbiosis which can lead to irritable bowel syndrome (IBS) development (129). ...
All microorganisms like bacteria, viruses and fungi that reside within a host environment are considered a microbiome. The number of bacteria almost equal that of human cells, however, the genome of these bacteria may be almost 100 times larger than the human genome. Every aspect of the physiology and health can be influenced by the microbiome living in various parts of our body. Any imbalance in the microbiome composition or function is seen as dysbiosis. Different types of dysbiosis are seen and the corresponding symptoms depend on the site of microbial imbalance. The contribution of the intestinal and extra-intestinal microbiota to influence systemic activities is through interplay between different axes. Whole body dysbiosis is a complex process involving gut microbiome and non-gut related microbiome. It is still at the stage of infancy and has not yet been fully understood. Dysbiosis can be influenced by genetic factors, lifestyle habits, diet including ultra-processed foods and food additives, as well as medications. Dysbiosis has been associated with many systemic diseases and cannot be diagnosed through standard blood tests or investigations. Microbiota derived metabolites can be analyzed and can be useful in the management of dysbiosis. Whole body dysbiosis can be addressed by altering lifestyle factors, proper diet and microbial modulation. The effect of these interventions in humans depends on the beneficial microbiome alteration mostly based on animal studies with evolving evidence from human studies. There is tremendous potential for the human microbiome in the diagnosis, treatment, and prognosis of diseases, as well as, for the monitoring of health and disease in humans. Whole body system-based approach to the diagnosis of dysbiosis is better than a pure taxonomic approach. Whole body dysbiosis could be a new therapeutic target in the management of various health conditions.
... In a recent scientific advancement, the importance of the intestinal microbiota in influencing these associations has been brought to the forefront. The relationship between microbiota and the gut-brain axis appears bidirectional, as neurological, endocrine, immune, and humoral connections transmit signals from the brain to the gut microbiota and vice versa [41]. Studies have indicated that PPIs have the potential to induce neurodegenerative disorders, such as dementia, through their impact on the brain-microbiota axis [42]. ...
Dementia, an international health issue distinguished by the impairment of daily functioning due to cognitive decline, currently affects more than 55 million people worldwide, with the majority residing in low-income and middle-income countries. Globally, dementia entails significant economic burdens in 2019, amounting to a cost of 1.3 trillion US dollars. Informal care-givers devote considerable hours to providing care for those affected. Dementia imposes a greater caregiving and disability-adjusted life-year burden on women. A recent study has established a correlation between prolonged Proton Pump Inhibitor (PPI) usage and dementia, in addition to other neurodegenerative conditions. PPIs are frequently prescribed to treat peptic ulcers and GERD (gastroesophageal reflux disease) by decreasing stomach acid secretion. They alleviate acid-related symptoms through the inhibition of acid-secreting H +-K + ATPase. In a number of observational studies, cognitive decline and dementia in the elderly have been linked to the use of PPIs. The precise mechanism underlying this relationship is unknown. These drugs might also alter the pH of brain cells, resulting in the accumulation of amyloid-beta (Aβ) peptides and the development of Alzheimer's disease (AD). Despite the compelling evidence supporting the association of PPIs with dementia, the results of studies remain inconsistent. The absence of a correlation between PPI use and cognitive decline in some studies emphasizes the need for additional research. Chronic PPI use can conceal underlying conditions, including cancer, celiac disease, vitamin B12 deficiency, and renal injury, highlighting dementia risk and the need for further investigations on cognitive health.
... 104 PPI use is associated with variation in the gut microbiome, development of dysbiosis, a change in microbial composition, and a decrease in commensal bacteria abundance. [105][106][107] Interestingly, the abundance of the genus Faecalibacterium, which has evidence of association with TAC pharmacokinetics, is significantly decreased with the use of PPI. 108,109 Due to the effects of PPI on the gut microbiome coupled with the evidence that TAC metabolism is susceptible to bacteria, studies are needed to assess a potential DMDI. ...
... PPI use changes the gut microbiome composition in the stomach, small bowel, and colon and reduces gut diversity. [105][106][107]152 Use of PPI results in small intestine overgrowth of Streptococcus, Staphylococcus, Escherichia, and Klebsiella and anaerobic bacteria such as Bacteroides, Lactobacillus, Veillonella, and Clostridium. 106 It is possible that PPI-related changes in the gut microbiome, particularly Bacteroides, contribute to MMF-PPI interactions. ...
... [105][106][107]152 Use of PPI results in small intestine overgrowth of Streptococcus, Staphylococcus, Escherichia, and Klebsiella and anaerobic bacteria such as Bacteroides, Lactobacillus, Veillonella, and Clostridium. 106 It is possible that PPI-related changes in the gut microbiome, particularly Bacteroides, contribute to MMF-PPI interactions. ...
The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug–microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.
... Final collection and analysis of the stool and sputum microbiome is currently underway. Patients with active GI disease, diarrhea, and/or abdominal pain may be on acid suppressants or other treatments, which are associated with a reduction in microbial diversity and an increase in the oral bacteria in the feces [30], thus, including these patients may have been a limitation within the study. ...
Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.
... Rodent studies show that translocation of oral pathobionts can lead to gut inflammation (Kitamoto et al., 2020). Drugs, such as proton pump inhibitors (PPI), that lower the gastric acidity has been shown to increase the gut colonization by oral bacteria (Atarashi et al., 2017;Bruno et al., 2019). Unfortunately, there is no information about the PPI usage in our cohort, which is a study limitation. ...
... 55 Nevertheless, findings were often based on a limited number of relatively small studies that often looked at genus level and not specific species, as in a similar overview paper on PPIs. 56 This systematic review has highlighted the consistent changes of quinolone and metronidazole on the microbiome, two classes also showing high CDI risks in the present study. ...
... Previous studies described that nitrofurans and tetracyclines may reduce the number of Clostridia class. 55,56 PPIs have been associated with an important disruption of the gut microbiome, on a population level potentially bigger than Moreels et al. ...
... [59][60][61][62]64 PPIs were associated in particular with a decreased abundance of Ruminococcocea and increased Enterobacteriaceae, Enterococcoceae and Lactobacillaceae, creating a pro-inflammatory environment. 35,56,65 An increase in the Clostridiaceae family was related to PPI use in the oesophagus and small intestine but not in the colon. 56 Combined administration of different antibiotic classes may also result in interactions and potential bigger disruptions of the microbiome, as the spectrum of antibacterial activity broadens. ...
Background
Antibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear.
Objectives
To assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence.
Methods
Population-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.
Results
Compared 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.
Conclusion
Recent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.
... Regarding CDI pathogenesis, the gut microbiota plays an important role. Several risk factors of CDI include old age, diet, hospitalization, antibiotics, and proton pump inhibitor treatment [20,[23][24][25][26], which could alter the gut microbiota composition. Bifidobacteria species are dominant in infants and their proportion decreases with age [27]. ...
... One of the several mechanisms by which the decreased gut microbial diversity contributes to CDI pathogenesis is due to weakened colonization resistance against C. difficile [34,35]. CDI is a hospital-associated infection because of the use of antibiotics and proton pump inhibitors and the potential transfer of C. difficile spores [23,34,36]. Antibiotics and proton pump inhibitors modulate and reduce the diversity of the gut microbiota. ...
Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and fecal microbiota transplantation, which contribute to recurrent CDIs and potential risks. Therefore, there is an ongoing need to develop new preventative treatment strategies for CDI. Notably, gut microbiota dysbiosis is the primary risk factor for CDI and provides a promising target for developing novel CDI therapy approaches. Along with gut microbiota dysbiosis, a reduction in important gut metabolites like secondary bile acids and short-chain fatty acids (SCFAs) were also seen in patients suffering from CDI. In this review study, we investigated the roles and mechanisms of gut microbiota and gut microbiota-derived gut metabolites, especially secondary bile acids and SCFAs in CDI pathogenesis. Moreover, specific signatures of gut microbiota and gut metabolites, as well as different factors that can modulate the gut microbiota, were also discussed, indicating that gut microbiota modulators like probiotics and prebiotics can be a potential therapeutic strategy for CDI as they can help restore gut microbiota and produce gut metabolites necessary for a healthy gut. The understanding of the associations between gut microbiota–gut metabolites and CDI will allow for developing precise and sustainable approaches, distinct from antibiotics and fecal transplant, for mitigating CDI and other gut microbiota dysbiosis-related diseases.
... 28 PPIs also affect the gut microbiome by changing the pH of the stomach, delaying gastric emptying, and inducing the positive and negative selection of specific bacterial species in the gut. 29,30 However, the microbiome regulates the local immune response at the intestinal interface, and the F I G U R E 3 Developed nomogram. This nomogram was developed with metastases of the lung, metastases in at least three organ sites, use of antibiotics, and use of PPIs. ...
Background
Immune‐related pneumonitis is a rare and potentially fatal adverse event associated with sintilimab. We aimed to develop and validate a nomogram for predicting the risk of immune‐related pneumonitis in patients treated with sintilimab.
Methods
The least absolute shrinkage and selection operator (LASSO) regression was used to determine risk factors. Multivariable logistic regression was used to establish a prediction model. Its clinical validity was evaluated using calibration, discrimination, decision, and clinical impact curves. Internal validation was performed against the validation set and complete dataset.
Results
The study included 632 patients; 59 were diagnosed with immune‐related pneumonitis. LASSO regression analysis identified that the risk factors for immune‐related pneumonitis were pulmonary metastases (odds ratio [OR], 4.015; 95% confidence interval [CI]: 1.725–9.340) and metastases at >3 sites (OR, 2.687; 95% CI: 1.151–6.269). The use of combined antibiotics (OR, 0.247; 95% CI: 0.083–0.738) and proton pump inhibitors (OR, 0.420; 95% CI: 0.211–0.837) were protective factors. The decision and clinical impact curves showed that the nomogram had clinical value for patients treated with sintilimab.
Conclusions
We have developed and validated a practical nomogram model of sintilimab‐associated immune‐related pneumonitis, which provides clinical value for determining the risk of immune‐related pneumonitis and facilitating the safe administration of sintilimab therapy.
