Fabian Mermans, Evelien Heiremans, Maud Van Belleghem, Axelle Meersschaut, Emma Hernandez-Sanabria

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Our gut harbours around 1014 bacteria of more than 1000 species, accounting for approximately 2 kg of biomass. The gut microbiome plays several vital functions in processes such as the development of the immune system, food digestion and protection against pathogens. For these functions to be beneficial for both host and microbiome, interactions are tightly regulated. Gut and immune cells continuously interact to distinguish among commensal microbiota, harmless foodstuff, and pathogens. A fine balance between inflammatory and anti-inflammatory state is fundamental to protect intestinal homeostasis. Nonsteroidal anti-inflammatories (NSAIDs) are a class of drugs used for management of pain and inflammation. These compounds have heterologous structures but similar therapeutic activities. The target of all NSAIDs are the isoforms of cyclooxygenase enzymes (COX): the primarily constitutive form COX-1, and the inducible from COX-2. Both isoforms catalyse the conversion of arachidonic acid to PGH2, the immediate substrate for specific prostaglandin and thromboxane synthesis. The gut microbiota plays a role in drug metabolism,  resulting in altered bioavailability of these compounds. Additionally, complex host-microbiome interactions lead to modified xenobiotic metabolism and altered expression of genes involved in drug metabolism. These effects can be at gut tissue-level, or distant, including in the liver. Besides the gut microbiome influencing drug metabolism, drugs also impact the microbial communities in the gut. As different drugs exert selective pressures on the gut microbiome,  understanding this bidirectional relationship is crucial for developing effective therapies for managing chronic inflammation.


gut microbiome, non-steroidal anti-inflammatories, inflammation, dysbiosis

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Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ 2018; 361:k2179.

Zhao L, Zhang X, Zuo T, Yu J. The composition of colonic commensal bacteria according to anatomical localization in colorectal cancer. Engineering 2017; 3:90-97.

Foster KR, Schluter J, Coyte KZ, Rakoff-Nahoum S. The evolution of the host microbiome as an ecosystem on a leash. Nature 2017; 548:43-51.

Zmora N, Zeevi D, Korem T, Segal E, Elinav E. Taking it personally: personalized utilization of the human microbiome in health and disease. Cell Host Microbe 2016; 19:12-20.

De Vuyst L, Leroy F. Cross-feeding during human colon fermentation. In: González-Ortiz G, Bedford MR, Bach Knudsen KE, Courtin CM, Classen HL, editors. The value of fibre: Engaging the second brain for animal nutrition. Wageningen Academic Publishers; 2019. pp 565-569.

Kato LM, Kawamoto S, Maruya M, Fagarasan S. The role of the adaptive immune system in regulation of gut microbiota. Immunol Rev 2014; 260:67-75.

Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh C-S. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011; 478:250.

Shen S, Wong CH. Bugging inflammation: role of the gut microbiota. Clin Transl immunology 2016; 5:e72.

Amidon S, Brown JE, Dave VS. Colon-targeted oral drug delivery systems: design trends and approaches. Aaps PharmSciTech 2015; 16:731-741.

Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol 2016; 14:273-87.

McConnell EL, Fadda HM, Basit AW. Gut instincts: explorations in intestinal physiology and drug delivery. Int J Pharm 2008; 364:213-226.

Hernandez-Sanabria E, Heiremans E, Arroyo MC, Props R, Leclercq L, Snoeys J, et al. Short term supplementation of celecoxib shifted butyrate production on a simulated model of the gut microbial ecosystem and ameliorated in vitro inflammation. bioRxiv 2019; 679050.

Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med 2016; 375:1289-1294.

Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res 2017; 179:204-222.

Arkhipova OV, Akumenko VK. Unsaturated organic acids as terminal electron acceptors for reductase chains of anaerobic bacteria. Microbiology 2005; 74:629-639. [In Russian]

Haiser HJ, Seim KL, Balskus EP, Turnbaugh PJ. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. Gut Microbes 2014; 5:233-238.

Kent DM, Steyerberg E, van Klaveren D. Personalized evidence based medicine: predictive approaches to heterogeneous treatment effects. BMJ 2018; 363:k4245.

Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, et al. Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol 2009; 44:879-888.

Boelsterli UA, Redinbo MR, Saitta KS. Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies. Toxicol Sci 2012; 131:654-667.

Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP. Gut reactions: breaking down xenobiotic–microbiome interactions. Pharmacol Rev 2019; 71:198-224.

Selwyn FP, Cheng SL, Bammler TK, Prasad B, Vrana M, Klaassen C, et al. Developmental regulation of drug-processing genes in livers of germ-free mice. Toxicol Sci 2015; 147:84-103.

Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota–farnesoid X receptor axis modulates metabolic disease. Gastroenterology 2016; 151:845-859.

Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 2016; 352:565-569.

Forbes JD, Van Domselaar G, Bernstein CN. The gut microbiota in immune-mediated inflammatory diseases. Front Microbiol 2016; 7:1081.

Slingerland AE, Schwabkey Z, Wiesnoski DH, Jenq RR. Clinical evidence for the microbiome in inflammatory diseases. Front Immunol 2017; 8:400.

Sobhani I, Tap J, Roudot-Thoraval F, Roperch JP, Letulle S, Langella P, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PloS One 2011; 6:e16393.

Rogers G, Keating D, Young R, Wong M, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 2016; 21:738.

Cani PD, Delzenne NM. Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Curr Opin Pharmacol 2009; 9:737-743.

Li X, Watanabe K, Kimura I. Gut microbiota dysbiosis drives and implies novel therapeutic strategies for diabetes mellitus and related metabolic diseases. Front Immunol 2017; 8:1882.

Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. Gut dysbiosis is linked to hypertension. Hypertension 2015; 65:1331-1340.

Maeda Y, Takeda K. Role of gut microbiota in rheumatoid arthritis. J Clin Med 2017; 6:60.

Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Eng J Med 2016; 375:2369-2379.

Sokol H, Seksik P, Furet J, Firmesse O, Nion‐Larmurier I, Beaugerie L, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 2009; 15:1183-1189.

Qiu X, Zhang M, Yang X, Hong N, Yu C. Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. J Crohns Colitis 2013; 7:e558-e568.

Gkouskou K, Deligianni C, Tsatsanis C, Eliopoulos AG. The gut microbiota in mouse models of inflammatory bowel disease. Front Cell Infect Microbiol 2014; 4:28.

Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. BMJ 2018; 360:j5145.

Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016; 22:1079.

Swanson HI. Drug metabolism by the host and gut microbiota: a partnership or rivalry? Drug Metab Dispos 2015; 43:1499-1504.

Mullard A. Oncologists tap the microbiome in bid to improve immunotherapy outcomes. Nat Rev Drug Discov 2018; 17:153-155.

Viennois E, Gewirtz AT, Chassaing B. Chronic inflammatory diseases: Are we ready for microbiota-based dietary intervention? Cell Mol Gastroenterol Hepatol 2019; 8:61-71.

Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 2017; 14:356-365.

Carbone C, Musumeci T, Pignatello R. Non-steroidal anti-inflammatory drugs. In: Pignatello R, editor. Drug-Biomembrane Interaction Studies.The Application of Colorimetric Techniques. Cambridge: Woodhead Publishing; 2013. p 281-303,

Funk CD, FitzGerald GA. COX-2 inhibitors and cardiovascular risk. J Cardiovasc Pharmacol 2007; 50:470-479.

Wang D, DuBois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 2010l 29:781-788.

Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, A. Van De Putte LB, Lipsky PE. Cyclooxygenase in biology and disease. FASEB J 1998; 12:1063-1073.

Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011; 31:986-1000.

Mullins MN, Lana SE, Dernell WS, Ogilvie GK, Withrow SJ, Ehrhart E. Cyclooxygenase‐2 expression in canine appendicular osteosarcomas. J Vet Intern Med 2004; 18:859-865.

Kang M, Martin A. Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitis-associated colorectal cancer development. Semin Immunol 2017;32:3-13.

Lee HJ, Zhang H, Orlovich DA, Fawcett JP. The influence of probiotic treatment on sulfasalazine metabolism in rat. Xenobiotica 2012; 42:791-797.

Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4554-61.

Mäkivuokko H, Tiihonen K, Tynkkynen S, Paulin L, Rautonen N. The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Brit J Nutr 2010; 103:227-234.

Rogers MA, Aronoff DM. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 2016; 22:178. e1-178. e9.

Bokulich NA, Battaglia T, Aleman JO, Walker J, Blaser MJ, Holt PR. Celecoxib does not alter intestinal microbiome in a longitudinal diet-controlled study. Clin Microbiol Infect 2016; 22:464-465.

Walsh J, Griffin BT, Clarke G, Hyland NP. Drug–gut microbiota interactions: implications for neuropharmacology. Br J Pharmacol 2018; 175:4415-4429.

Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 2009; 106:14728-14733.

Tjalsma H, Boleij A, Marchesi JR, Dutilh BE. A bacterial driver–passenger model for colorectal cancer: beyond the usual suspects. Nat Rev Microbiol 2012; 10:575-582.

Zhu W, Winter MG, Byndloss MX, Spiga L, Duerkop BA, Hughes ER, et al. Precision editing of the gut microbiota ameliorates colitis. Nature 2018; 553:208-211.

Piard JC, Briandet R. Lactic acid bacteria biofilms: from their formation to their health and biotechnological potential. In: Mozzi F, Raya RR, Vignolo GM. Biotechnology of Lactic Acid Bacteria: Novel Applications: 2nd ed. West Sussex, UK: John Wiley & Sons, Ltd; 2015. p. 341-361.

ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS 2014; 18:402-414.

Routy B, Le Chatelier E, Derosa L, Duong CP, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2018; 359:91-97.

Goossens N, Singal AG, King LY, Andersson KL, Fuchs BC, Besa C, et al. Cost-Effectiveness of Risk Score–Stratified Hepatocellular Carcinoma Screening in Patients with Cirrhosis. Clin Transl Gastroenterol 2017; 8:e101.



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