Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii

Nadatani, Yuji; Watanabe, Toshio; Suda, Wataru; Nakata, Atsushi; Matsumoto, Yuji; Kosaka, Shogo; Higashimori, Akira; Otani, Koji; Hosomi, Shuhei; Tanaka, Fumio; Nagami, Yasuaki; Kamata, Noriko; Taira, Koichi; Yamagami, Hirokazu; Tanigawa, Tetsuya; Hattori, Masahira; Fujiwara, Yasuhiro

doi:10.1038/s41598-019-53559-7

Cited by 39 publications

(40 citation statements)

References 33 publications

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“…Indomethacin use may not reproduce identical mechanisms involved in EED etiology but enabled to display many EED features while LPS did not. Experimental models of enteropathy induced by chemical agents such as indomethacin are used in the analysis of pathological mechanisms of enteropathy 29,42 as well as the development of therapeutic agents 43 . Although NSAID-induced enteropathy models do not have the complexity of human EED, the present model can contribute to the study of the disease such as microbiota changes 29 or to the evaluation of nutritional intervention 44 .…”

Section: Discussionmentioning

confidence: 99%

Modeling undernutrition with enteropathy in mice

Salameh

Jarbeau

Morel³

et al. 2020

Sci Rep

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Undernutrition is a global health issue leading to 1 out 5 all deaths in children under 5 years. Undernutrition is often associated with environmental enteric dysfunction (EED), a syndrome associated with increased intestinal permeability and gut inflammation. We aimed to develop a novel murine model of undernutrition with these EED features. Post-weaning mice were fed with low-protein diet (LP) alone or combined with a gastrointestinal insult trigger (indomethacin or liposaccharides). Growth, intestinal permeability and inflammation were assessed. LP diet induced stunting and wasting in post-weaning mice but did not impact gut barrier. We therefore combined LP diet with a single administration of indomethacin or liposaccharides (LPS). Indomethacin increased fecal calprotectin production while LPS did not. To amplify indomethacin effects, we investigated its repeated administration in addition to LP diet and mice exhibited stunting and wasting with intestinal hyperpermeability and gut inflammation. The combination of 3-weeks LP diet with repeated oral indomethacin administration induced wasting, stunting and gut barrier dysfunction as observed in undernourished children with EED. As noninvasive methods for investigating gut function in undernourished children are scarce, the present pre-clinical model provides an affordable tool to attempt to elucidate pathophysiological processes involved in EED and to identify novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Modeling undernutrition with enteropathy in mice

Salameh

Jarbeau

Morel³

et al. 2020

Sci Rep

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“…However, complications of excessive gastric acid suppression, like dyspepsia, luminal dysbiosis, gastric microfloral imbalance, vitamin B12 deficiency, pernicious anemia, osteoarthritis, malabsorption of certain drugs active in the acidic microenvironment and even gastric parietal cell hyperplasia and gastric cancer staunchly warrant against rampant use of PPIs and histamine receptor blockers [104]. In fact, a recent study also indicated that PPIs can actually exacerbate indomethacin-induced small intestinal damage by detrimentally altering intestinal microbiome composition [135]. Hence, gastric acid is in no way a physiological evil and opting for antioxidant-based therapeutic strategy to prevent the gastric mucosa from NSAID-induced cytopathies is a rather safer approach than indiscriminate usage of acid suppressors.…”

Section: Risk To the Gastric Mucosal And Small Bowel Injuriesmentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

Bindu

Mazumder

Bandyopadhyay

2020

Biochemical Pharmacology

1,051

519

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Owing to the efficacy in reducing pain and inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most popularly used medicines confirming their position in the WHO's Model List of Essential Medicines. With escalating musculoskeletal complications, as evident from 2016 Global Burden of Disease data, NSAID usage is evidently unavoidable. Apart from analgesic, anti-inflammatory and antipyretic efficacies, NSAIDs are further documented to offer protection against diverse critical disorders including cancer and heart attacks. However, data from multiple placebo-controlled trials and meta-analyses studies alarmingly signify the adverse effects of NSAIDs in gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary complications. Although extensive research has elucidated the mechanisms underlying the clinical hazards of NSAIDs, no review has extensively collated the outcomes on various multiorgan toxicities of these drugs together. In this regard, the present review provides a comprehensive insight of the existing knowledge and recent developments on NSAID-induced organ damage. It precisely encompasses the current understanding of structure, classification and mode of action of NSAIDs while reiterating on the emerging instances of NSAID drug repurposing along with pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compromising the clinical benefits. The review does not intend to vilify these 'wonder drugs'; rather provides a careful understanding of their side-effects which would be beneficial in evaluating the risk-benefit threshold while rationally using NSAIDs at safer dose and duration.

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“…Vonoprazan, which belongs to a class of acid-inhibitory agents called potassium-competitive acid blockers, was approved in Japan in February 2015, and its superiority or non-inferiority to PPIs for the treatment of acid-related diseases has been demonstrated [45][46][47]. Although vonoprazan suppresses gastric acid secretion by a different mechanism from PPIs, a recent animal study reported that both rabeprazole and vonoprazan aggravated NSAIDs-induced small intestinal injury in mice by reducing the population of Lactobacillus johnsonii in the small intestine [48]. Thus, strong inhibitors of gastric acid secretion may commonly cause small intestinal dysbiosis and the resultant aggravation of NSAIDs-induced enteropathy.…”

Section: Risk Factors For Nsaids-induced Enteropathymentioning

confidence: 99%

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

2019

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Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal antiinflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-a and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1b into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step. Keywords Non-steroidal anti-inflammatory drug Á Lowdose aspirin Á Enteropathy Á Innate immunity Á Misoprostol Abbreviations NSAID Non-steroidal anti-inflammatory drug RA Rheumatoid arthritis

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Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii

Cited by 39 publications

References 33 publications

Modeling undernutrition with enteropathy in mice

Modeling undernutrition with enteropathy in mice

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

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