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Abstract

The relationship between analgesic use and gut microbiota alterations has garnered increasing attention. However, the causal link between these two factors remains to be elucidated. Given the prevalence of analgesic use and the significant role of gut microbiota in human health, clarifying this relationship is of great importance.

Existing observational studies are limited in their ability to establish causality between analgesic use and gut microbiota alterations. Therefore, there is a need for robust causal inference methods to explore this relationship and uncover the underlying mechanisms.

This study aims to investigate the causal associations between genetic susceptibility to four common analgesics (NSAIDs, salicylic acid, opioids, and anilides) and gut microbiota composition, as well as circulating metabolites, using a two-sample Mendelian randomization approach.

A two-sample Mendelian randomization was used to investigate the potential association between genetic susceptibility to four analgesic uses and gut microbiota composition, as well as circulating metabolites. Summary-level statistics of genome-wide association studies were obtained from primarily European ancestry cohorts, including 466,457 participants from the UK Biobank and 18,340 individuals from the MiBioGen consortium.

Only one suggestive causal association was found between NSAID use and elevated abundance of gut microbiota, namely group . In addition, salicylic use was correlated with an increased abundance of the family (=0.006) while it was negatively associated with the abundance of 8 microbiota traits, including genus , , , family , , phylum , class and order with value ranging from 0.009 to 0.043. No clear evidence was found between opioid and anilide use and gut microbiota alteration. Meanwhile, salicylic use was potentially causally associated with four metabolites, including acetoacetate, creatinine, omega-3 fatty acids and triglycerides in very large high-density lipoprotein, with values ranging from 0.005 to 0.046.

The results of this study offer powerful evidence that the long-term use of salicylic acid may substantially impact gut microbiota composition and circulating metabolites. Further investigations are needed to uncover the underlying mechanisms.

Funding
This study was supported by the:
  • Medical Science and Technology Foundation of Guangdong Province (Award A2024010)
    • Principal Award Recipient: LinLiling
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. The Microbiology Society waived the open access fees for this article.
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/content/journal/jmm/10.1099/jmm.0.002028
2025-06-12
2026-04-10

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References

  1. Álvarez J, Fernández Real JM, Guarner F, Gueimonde M, Rodríguez JM et al. Gut microbes and health. Gastroenterol Hepatol 2021; 44:519–535 [View Article] [PubMed]
    [Google Scholar]
  2. Myhrstad MCW, Tunsjø H, Charnock C, Telle-Hansen VH. Dietary fiber, gut microbiota, and metabolic regulation—current status in human randomized trials. Nutrients 2020; 12:859 [View Article] [PubMed]
    [Google Scholar]
  3. Sun MF, Shen YQ. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease. Ageing Res Rev 2018; 45:53–61 [View Article] [PubMed]
    [Google Scholar]
  4. Chen Z, Maqbool J, Sajid F, Hussain G, Sun T. Human gut microbiota and its association with pathogenesis and treatments of neurodegenerative diseases. Microb Pathog 2021; 150:104675 [View Article] [PubMed]
    [Google Scholar]
  5. Sudo N. Role of gut microbiota in brain function and stress-related pathology. Biosci Microbiota Food Health 2019; 38:75–80 [View Article] [PubMed]
    [Google Scholar]
  6. Gracie DJ, Hamlin PJ, Ford AC. The influence of the brain-gut axis in inflammatory bowel disease and possible implications for treatment. Lancet Gastroenterol Hepatol 2019; 4:632–642 [View Article] [PubMed]
    [Google Scholar]
  7. Santoni M, Miccini F, Battelli N. Gut microbiota, immunity and pain. Immunol Lett 2021; 229:44–47 [View Article] [PubMed]
    [Google Scholar]
  8. Breit S, Kupferberg A, Rogler G, Hasler G. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry 2018; 9:44 [View Article] [PubMed]
    [Google Scholar]
  9. Treede R-D, Rief W, Barke A, Aziz Q, Bennett MI et al. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International Classification of Diseases (ICD-11). Pain 2019; 160:19–27 [View Article]
    [Google Scholar]
  10. Lin L, Lin J, Qiu J, Liufu N, Lin S et al. Genetic liability to multi-site chronic pain increases the risk of cardiovascular disease. Br J Anaesth 2023; 131:373–384 [View Article]
    [Google Scholar]
  11. Guedes KMM, Borges RS, Fontes-Júnior EA, Silva ASB, Fernandes LMP et al. Salicytamide: a new anti-inflammatory designed drug candidate. Inflammation 2018; 41:1349–1360 [View Article] [PubMed]
    [Google Scholar]
  12. Paul AK, Smith CM, Rahmatullah M, Nissapatorn V, Wilairatana P et al. Opioid analgesia and opioid-induced adverse effects: a review. Pharmaceuticals 2021; 14:1091 [View Article] [PubMed]
    [Google Scholar]
  13. Martinez L, Ekman E, Nakhla N. Perioperative opioid-sparing strategies: utility of conventional NSAIDs in adults. Clin Ther 2019; 41:2612–2628 [View Article] [PubMed]
    [Google Scholar]
  14. Tai FWD, McAlindon ME. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clin Med (Lond) 2021; 21:131–134 [View Article] [PubMed]
    [Google Scholar]
  15. Zhang P, Yang M, Chen C, Liu L, Wei X et al. Toll-like receptor 4 (TLR4)/opioid receptor pathway crosstalk and impact on opioid analgesia, immune function, and gastrointestinal motility. Front Immunol 2020; 11:1455 [View Article] [PubMed]
    [Google Scholar]
  16. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol 2020; 180:114147 [View Article] [PubMed]
    [Google Scholar]
  17. Domper Arnal M-J, Hijos-Mallada G, Lanas A. Gastrointestinal and cardiovascular adverse events associated with NSAIDs. Expert Opin Drug Saf 2022; 21:373–384 [View Article]
    [Google Scholar]
  18. Handa O, Takayama S, Mukai R, Suyama Y, Majima A et al. A review of the mechanism and prophylaxis of acetyl salicylic acid-induced injury of the small intestine. Free Radic Res 2018; 52:1266–1270 [View Article] [PubMed]
    [Google Scholar]
  19. Shim YK, Kim N. Nonsteroidal anti-inflammatory drug and aspirin-induced peptic ulcer disease. Korean J Gastroenterol 2016; 67:300–312 [View Article] [PubMed]
    [Google Scholar]
  20. Rueda-Ruzafa L, Cruz F, Cardona D, Hone AJ, Molina-Torres G et al. Opioid system influences gut-brain axis: Dysbiosis and related alterations. Pharmacol Res 2020; 159:104928 [View Article] [PubMed]
    [Google Scholar]
  21. Severino A, Chen W, Hakimian JK, Kieffer BL, Gaveriaux-Ruff C et al. Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain. Pain 2018; 159:1607–1620 [View Article] [PubMed]
    [Google Scholar]
  22. Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol 2020; 11:1153 [View Article] [PubMed]
    [Google Scholar]
  23. Lin L, Lin J, Qiu J, Wei F, Bai X et al. Gut microbiota alterations may increase the risk of prescription opioid use, but not vice versa: a two-sample bi-directional Mendelian randomization study. Front Microbiol 2022; 13: [View Article]
    [Google Scholar]
  24. Richmond RC, Davey Smith G. Mendelian randomization: concepts and scope. Cold Spring Harb Perspect Med 2022; 12:a040501 [View Article] [PubMed]
    [Google Scholar]
  25. Ference BA, Holmes MV, Smith GD. Using mendelian randomization to improve the design of randomized trials. Cold Spring Harb Perspect Med 2021; 11:a040980 [View Article] [PubMed]
    [Google Scholar]
  26. Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res 2019; 4:186 [View Article] [PubMed]
    [Google Scholar]
  27. Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement. JAMA 2021; 326:1614–1621 [View Article] [PubMed]
    [Google Scholar]
  28. Wu Y, Byrne EM, Zheng Z, Kemper KE, Yengo L et al. Genome-wide association study of medication-use and associated disease in the UK Biobank. Nat Commun 2019; 10: [View Article]
    [Google Scholar]
  29. Cho G, Chang VW. Trends in prescription opioid and nonopioid analgesic use by race, 1996-2017. Am J Prev Med 2022; 62:422–426 [View Article] [PubMed]
    [Google Scholar]
  30. Power I. An update on analgesics. Br J Anaesth 2011; 107:19–24 [View Article] [PubMed]
    [Google Scholar]
  31. Kurilshikov A, Medina-Gomez C, Bacigalupe R, Radjabzadeh D, Wang J et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet 2021; 53:156–165 [View Article]
    [Google Scholar]
  32. Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 2019; 51:600–605 [View Article]
    [Google Scholar]
  33. Auton A, Brooks LD, Durbin RM, Garrison EP et al. A global reference for human genetic variation. Nature 2015; 526:68–74 [View Article] [PubMed]
    [Google Scholar]
  34. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife 2018; 7:e34408 [View Article] [PubMed]
    [Google Scholar]
  35. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 2013; 37:658–665 [View Article] [PubMed]
    [Google Scholar]
  36. Murphy S. Is there an association between periodontitis and breast cancer?. Evid Based Dent 2023; 24:75–76 [View Article]
    [Google Scholar]
  37. Greco M FD, Minelli C, Sheehan NA, Thompson JR. Detecting pleiotropy in mendelian randomisation studies with summary data and a continuous outcome. Stat Med 2015; 34:2926–2940 [View Article] [PubMed]
    [Google Scholar]
  38. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet 2017; 13:e1007081 [View Article]
    [Google Scholar]
  39. Wu X-J, Shu Q-Q, Wang B, Dong L, Hao B. Acetoacetate improves memory in alzheimer’s mice via promoting brain-derived neurotrophic factor and inhibiting inflammation. Am J Alzheimers Dis Other Demen 2022; 37:15333175221124949 [View Article] [PubMed]
    [Google Scholar]
  40. Chatterjee P, Cheong Y-J, Bhatnagar A, Goozee K, Wu Y et al. Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults. J Neurochem 2021; 159:389–402 [View Article] [PubMed]
    [Google Scholar]
  41. Lin P-Y, Cheng C, Satyanarayanan SK, Chiu L-T, Chien Y-C et al. Omega-3 fatty acids and blood-based biomarkers in Alzheimer’s disease and mild cognitive impairment: a randomized placebo-controlled trial. Brain Behav Immun 2022; 99:289–298 [View Article] [PubMed]
    [Google Scholar]
  42. Tynkkynen J, Chouraki V, van der Lee SJ, Hernesniemi J, Yang Q et al. Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer’s disease: a prospective study in eight cohorts. Alzheimers Dement 2018; 14:723–733 [View Article] [PubMed]
    [Google Scholar]
  43. Scholefield M, Church SJ, Xu J, Patassini S, Roncaroli F et al. Severe and regionally widespread increases in tissue urea in the human brain represent a novel finding of pathogenic potential in Parkinson’s disease dementia. Front Mol Neurosci 2021; 14:711396 [View Article] [PubMed]
    [Google Scholar]
  44. Galamba N. Aggregation of a Parkinson’s disease-related peptide: when does urea weaken hydrophobic interactions?. ACS Chem Neurosci 2022; 13:1769–1781 [View Article] [PubMed]
    [Google Scholar]
  45. Liu J, Zong C, Yu X, Ding Y, Chang B et al. Alanyl-glutamine (Ala-Gln) ameliorates dextran sulfate sodium (DSS)-induced acute colitis by regulating the gut microbiota, PI3K-Akt/NF-κB/STAT3 signaling, and associated pulmonary injury. ACS Infect Dis 2023; 9:979–992 [View Article] [PubMed]
    [Google Scholar]
  46. Rao W, Meng X, Li K, Zhang Y, Zhang XY. Association between clinical symptoms and apolipoprotein A1 or apolipoprotein B levels is regulated by apolipoprotein E variant rs429358 in patients with chronic schizophrenia. Ann Gen Psychiatry 2021; 20:56 [View Article] [PubMed]
    [Google Scholar]
  47. Burgess S, Thompson SG. Interpreting findings from mendelian randomization using the MR-Egger method. Eur J Epidemiol 2017; 32:377–389 [View Article] [PubMed]
    [Google Scholar]
  48. Rasooly D, Peloso GM. Two-sample multivariable mendelian randomization analysis using R. Curr Protoc 2021; 1:e335 [View Article] [PubMed]
    [Google Scholar]
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