Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition

Background and Purpose Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine us...

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Veröffentlicht in:British journal of pharmacology 2023-06, Vol.180 (12), p.1582-1596
Hauptverfasser: Ghosh, Nillu, Kesh, Kousik, Singh, Praveen Kumar, Sharma, Umakant, Chupikova, Irina, Ramakrishnan, Sundaram, Roy, Sabita
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container_end_page 1596
container_issue 12
container_start_page 1582
container_title British journal of pharmacology
container_volume 180
creator Ghosh, Nillu
Kesh, Kousik
Singh, Praveen Kumar
Sharma, Umakant
Chupikova, Irina
Ramakrishnan, Sundaram
Roy, Sabita
description Background and Purpose Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine‐mediated gastric inflammation. Experimental Approach Mice were implanted with 25 mg slow‐release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ‐free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. Key Results Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine‐mediated gastric pathology was significantly attenuated in germ‐free mice, and reconstitution of morphine gastric microbiome in germ‐free mice resulted gastric inflammation. In addition, morphine‐mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine‐induced gastric dysbiosis and preventing inflammation. Conclusion and Implications This study attributes morphine‐induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine‐associated pathophysiology. Morphine treatment increases gastric acid secretion which causes dysbiosis of gastric microbiome. The dysbiotic gastric microbiome induces gastric inflammation through TLR2‐mediated signaling. Omeprazole prevents morphine‐induced gastric damage by regulating gastric acid secretion and restoring normal gastric microbiota.
doi_str_mv 10.1111/bph.16025
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Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine‐mediated gastric inflammation. Experimental Approach Mice were implanted with 25 mg slow‐release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ‐free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. Key Results Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine‐mediated gastric pathology was significantly attenuated in germ‐free mice, and reconstitution of morphine gastric microbiome in germ‐free mice resulted gastric inflammation. In addition, morphine‐mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine‐induced gastric dysbiosis and preventing inflammation. Conclusion and Implications This study attributes morphine‐induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine‐associated pathophysiology. Morphine treatment increases gastric acid secretion which causes dysbiosis of gastric microbiome. The dysbiotic gastric microbiome induces gastric inflammation through TLR2‐mediated signaling. Omeprazole prevents morphine‐induced gastric damage by regulating gastric acid secretion and restoring normal gastric microbiota.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.16025</identifier><identifier>PMID: 36585367</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Acidity ; Analgesics, Opioid - pharmacology ; Animals ; Apoptosis ; Dysbacteriosis ; Dysbiosis - chemically induced ; gastric inflammation ; Gastric juice ; gastric microbiome ; Gastric mucosa ; germ‐free mice ; Inflammation ; Inflammation - drug therapy ; Mice ; Microbiomes ; Morphine ; Morphine - pharmacology ; Omeprazole ; Omeprazole - pharmacology ; opioid ; Opioids ; Pathology ; proton pump inhibition ; Proton pump inhibitors ; Proton Pump Inhibitors - adverse effects ; TLR2 protein ; Toll-Like Receptor 2 ; Toll-like receptors</subject><ispartof>British journal of pharmacology, 2023-06, Vol.180 (12), p.1582-1596</ispartof><rights>2022 British Pharmacological Society.</rights><rights>2023 The British Pharmacological Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3535-646feb38bb113de1d711afb0d9bb4f553f5965a33e155f3d7c86622d7b7f20873</citedby><cites>FETCH-LOGICAL-c3535-646feb38bb113de1d711afb0d9bb4f553f5965a33e155f3d7c86622d7b7f20873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbph.16025$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbph.16025$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36585367$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghosh, Nillu</creatorcontrib><creatorcontrib>Kesh, Kousik</creatorcontrib><creatorcontrib>Singh, Praveen Kumar</creatorcontrib><creatorcontrib>Sharma, Umakant</creatorcontrib><creatorcontrib>Chupikova, Irina</creatorcontrib><creatorcontrib>Ramakrishnan, Sundaram</creatorcontrib><creatorcontrib>Roy, Sabita</creatorcontrib><title>Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and Purpose Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine‐mediated gastric inflammation. Experimental Approach Mice were implanted with 25 mg slow‐release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ‐free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. Key Results Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine‐mediated gastric pathology was significantly attenuated in germ‐free mice, and reconstitution of morphine gastric microbiome in germ‐free mice resulted gastric inflammation. In addition, morphine‐mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine‐induced gastric dysbiosis and preventing inflammation. Conclusion and Implications This study attributes morphine‐induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine‐associated pathophysiology. Morphine treatment increases gastric acid secretion which causes dysbiosis of gastric microbiome. The dysbiotic gastric microbiome induces gastric inflammation through TLR2‐mediated signaling. Omeprazole prevents morphine‐induced gastric damage by regulating gastric acid secretion and restoring normal gastric microbiota.</description><subject>Acidity</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Dysbacteriosis</subject><subject>Dysbiosis - chemically induced</subject><subject>gastric inflammation</subject><subject>Gastric juice</subject><subject>gastric microbiome</subject><subject>Gastric mucosa</subject><subject>germ‐free mice</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Mice</subject><subject>Microbiomes</subject><subject>Morphine</subject><subject>Morphine - pharmacology</subject><subject>Omeprazole</subject><subject>Omeprazole - pharmacology</subject><subject>opioid</subject><subject>Opioids</subject><subject>Pathology</subject><subject>proton pump inhibition</subject><subject>Proton pump inhibitors</subject><subject>Proton Pump Inhibitors - adverse effects</subject><subject>TLR2 protein</subject><subject>Toll-Like Receptor 2</subject><subject>Toll-like receptors</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kbtOHDEUhi0UFBaSgheILNFAMWCP15ctAUGItFEQIvXIHts7B80t9hi0z5EXjidLKJByGhfn-z_Z_hE6puSc5rkwY3NOBSn5HlrQpRQFZ4p-QAtCiCwoVeoAHcb4REheSv4RHTDBFWdCLtDv70MYG-gdTtFh6G2qXcQbHacANe6gDoMB3WK7jQaGCBHbAM_Qb94Y6H2ru05PMPR4asKQNg1-XD-UOMKm1207wy8N1A3OaT1Nrk96chabLR7DMOXUmLoxexowMFs-oX2v2-g-v55H6OftzeP1XbH-8fXb9eW6qBlnvBBL4Z1hyhhKmXXUSkq1N8SujFl6zpnnK8E1Y45y7pmVtRKiLK000pdESXaETnfefI1fycWp6iDWrm1174YUq1Ly1UqUXC0zevIOfRpSyK_LlJo7YLKchWc7Kv9ajMH5agzQ6bCtKKlmqspNVX-byuyXV2MynbNv5L9qMnCxA16gddv_m6qr-7ud8g9d95-2</recordid><startdate>202306</startdate><enddate>202306</enddate><creator>Ghosh, Nillu</creator><creator>Kesh, Kousik</creator><creator>Singh, Praveen Kumar</creator><creator>Sharma, Umakant</creator><creator>Chupikova, Irina</creator><creator>Ramakrishnan, Sundaram</creator><creator>Roy, Sabita</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>202306</creationdate><title>Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition</title><author>Ghosh, Nillu ; Kesh, Kousik ; Singh, Praveen Kumar ; Sharma, Umakant ; Chupikova, Irina ; Ramakrishnan, Sundaram ; Roy, Sabita</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3535-646feb38bb113de1d711afb0d9bb4f553f5965a33e155f3d7c86622d7b7f20873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Acidity</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Dysbacteriosis</topic><topic>Dysbiosis - chemically induced</topic><topic>gastric inflammation</topic><topic>Gastric juice</topic><topic>gastric microbiome</topic><topic>Gastric mucosa</topic><topic>germ‐free mice</topic><topic>Inflammation</topic><topic>Inflammation - drug therapy</topic><topic>Mice</topic><topic>Microbiomes</topic><topic>Morphine</topic><topic>Morphine - pharmacology</topic><topic>Omeprazole</topic><topic>Omeprazole - pharmacology</topic><topic>opioid</topic><topic>Opioids</topic><topic>Pathology</topic><topic>proton pump inhibition</topic><topic>Proton pump inhibitors</topic><topic>Proton Pump Inhibitors - adverse effects</topic><topic>TLR2 protein</topic><topic>Toll-Like Receptor 2</topic><topic>Toll-like receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghosh, Nillu</creatorcontrib><creatorcontrib>Kesh, Kousik</creatorcontrib><creatorcontrib>Singh, Praveen Kumar</creatorcontrib><creatorcontrib>Sharma, Umakant</creatorcontrib><creatorcontrib>Chupikova, Irina</creatorcontrib><creatorcontrib>Ramakrishnan, Sundaram</creatorcontrib><creatorcontrib>Roy, Sabita</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; 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however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine‐mediated gastric inflammation. Experimental Approach Mice were implanted with 25 mg slow‐release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ‐free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. Key Results Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine‐mediated gastric pathology was significantly attenuated in germ‐free mice, and reconstitution of morphine gastric microbiome in germ‐free mice resulted gastric inflammation. In addition, morphine‐mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine‐induced gastric dysbiosis and preventing inflammation. Conclusion and Implications This study attributes morphine‐induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine‐associated pathophysiology. Morphine treatment increases gastric acid secretion which causes dysbiosis of gastric microbiome. The dysbiotic gastric microbiome induces gastric inflammation through TLR2‐mediated signaling. Omeprazole prevents morphine‐induced gastric damage by regulating gastric acid secretion and restoring normal gastric microbiota.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>36585367</pmid><doi>10.1111/bph.16025</doi><tpages>15</tpages></addata></record>
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subjects Acidity
Analgesics, Opioid - pharmacology
Animals
Apoptosis
Dysbacteriosis
Dysbiosis - chemically induced
gastric inflammation
Gastric juice
gastric microbiome
Gastric mucosa
germ‐free mice
Inflammation
Inflammation - drug therapy
Mice
Microbiomes
Morphine
Morphine - pharmacology
Omeprazole
Omeprazole - pharmacology
opioid
Opioids
Pathology
proton pump inhibition
Proton pump inhibitors
Proton Pump Inhibitors - adverse effects
TLR2 protein
Toll-Like Receptor 2
Toll-like receptors
title Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition
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