1932

Abstract

Chronic inflammation is a common trait in the pathogenesis of several diseases of the gut, including inflammatory bowel disease and celiac disease. Control of the inflammatory response is crucial in these pathologies to avoid tissue destruction and loss of intestinal function. Over the last 50 years, the identification of the mechanisms and mediators involved in the acute phase of the inflammatory response, which is characterized by massive leukocyte recruitment, has led to a number of therapeutic options. New drugs targeting inflammatory flares are still under development. However, interest on the other end of the spectrum—the resolution and repair phases—has emerged, as promoting tissue functional repair may maintain remission and counteract the chronicity of the disease. This review aims to discuss the current and future pharmacological approaches to the treatment of chronic intestinal inflammation and the restoration of functional tissues.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-051921-084536
2025-01-23
2025-02-07
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/65/1/annurev-pharmtox-051921-084536.html?itemId=/content/journals/10.1146/annurev-pharmtox-051921-084536&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Imbrizi M, Magro F, Coy CSR. 2023.. Pharmacological therapy in inflammatory bowel diseases: a narrative review of the past 90 years. . Pharmaceuticals 16::1272
    [Crossref] [Google Scholar]
  2. 2.
    Nathan C, Ding A. 2010.. Nonresolving inflammation. . Cell 140::87182
    [Crossref] [Google Scholar]
  3. 3.
    Cavaillon JM. 2021.. Once upon a time, inflammation. . J. Venom. Anim. Toxins Incl. Trop. Dis. 27::e20200147
    [Google Scholar]
  4. 4.
    Barone MV, Auricchio R, Nanayakkara M, Greco L, Troncone R, Auricchio S. 2022.. Pivotal role of inflammation in celiac disease. . Int. J. Mol. Sci. 23::7177
    [Crossref] [Google Scholar]
  5. 5.
    Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP. 2013.. The resolution of inflammation. . Nat. Rev. Immunol. 13::5966
    [Crossref] [Google Scholar]
  6. 6.
    Michielan A, D'Inca R. 2015.. Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. . Mediat. Inflamm. 2015::628157
    [Crossref] [Google Scholar]
  7. 7.
    Levartovsky A, Ovdat T, Barash Y, Ben-Shatach Z, Skinezes Y, et al. 2022.. Signs and symptoms of acute bowel inflammation and the risk of progression to inflammatory bowel disease: a retrospective analysis. . J. Clin. Med. 11::4595
    [Crossref] [Google Scholar]
  8. 8.
    Collins SM, Piche T, Rampal P. 2001.. The putative role of inflammation in the irritable bowel syndrome. . Gut 49::74345
    [Crossref] [Google Scholar]
  9. 9.
    Barbara G, Cremon C, Annese V, Basilisco G, Bazzoli F, et al. 2016.. Randomised controlled trial of mesalazine in IBS. . Gut 65::8290
    [Crossref] [Google Scholar]
  10. 10.
    Lam C, Tan W, Leighton M, Hastings M, Lingaya M, et al. 2016.. A mechanistic multicentre, parallel group, randomised placebo-controlled trial of mesalazine for the treatment of IBS with diarrhoea (IBS-D). . Gut 65::9199
    [Crossref] [Google Scholar]
  11. 11.
    Andrews CN, Griffiths TA, Kaufman J, Vergnolle N, Surette MG, Rioux KP. 2011.. Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome. . Aliment. Pharmacol. Ther. 34::37483
    [Crossref] [Google Scholar]
  12. 12.
    Barbara G, Cremon C, Carini G, Bellacosa L, Zecchi L, et al. 2011.. The immune system in irritable bowel syndrome. . J. Neurogastroenterol. Motil. 17::34959
    [Crossref] [Google Scholar]
  13. 13.
    Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, et al. 2004.. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. . Gastroenterology 126::693702
    [Crossref] [Google Scholar]
  14. 14.
    Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, et al. 2007.. Role for protease activity in visceral pain in irritable bowel syndrome. . J. Clin. Investig. 117::63647
    [Crossref] [Google Scholar]
  15. 15.
    Rolland-Fourcade C, Denadai-Souza A, Cirillo C, Lopez C, Jaramillo JO, et al. 2017.. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. . Gut 66::176778
    [Crossref] [Google Scholar]
  16. 16.
    Cenac N, Bautzova T, Le Faouder P, Veldhuis NA, Poole DP, et al. 2015.. Quantification and potential functions of endogenous agonists of transient receptor potential channels in patients with irritable bowel syndrome. . Gastroenterology 149::43344.e7
    [Crossref] [Google Scholar]
  17. 17.
    Marasco G, Cremon C, Barbaro MR, Stanghellini V, Barbara G. 2022.. Gut microbiota signatures and modulation in irritable bowel syndrome. . Microbiome Res. Rep. 1::11
    [Google Scholar]
  18. 18.
    Oka A, Sartor RB. 2020.. Microbial-based and microbial-targeted therapies for inflammatory bowel diseases. . Dig. Dis. Sci. 65::75788
    [Crossref] [Google Scholar]
  19. 19.
    Galipeau HJ, Verdu EF. 2022.. The double-edged sword of gut bacteria in celiac disease and implications for therapeutic potential. . Mucosal Immunol. 15::23543
    [Crossref] [Google Scholar]
  20. 20.
    Barbara G, Barbaro MR, Fuschi D, Palombo M, Falangone F, et al. 2021.. Inflammatory and microbiota-related regulation of the intestinal epithelial barrier. . Front. Nutr. 8::718356
    [Crossref] [Google Scholar]
  21. 21.
    Okumura R, Takeda K. 2018.. Maintenance of intestinal homeostasis by mucosal barriers. . Inflamm. Regen. 38::5
    [Crossref] [Google Scholar]
  22. 22.
    Ra YE, Bang YJ. 2024.. Balancing act of the intestinal antimicrobial proteins on gut microbiota and health. . J. Microbiol. 62::16779
    [Crossref] [Google Scholar]
  23. 23.
    Filipp D, Brabec T, Voboril M, Dobes J. 2019.. Enteric α-defensins on the verge of intestinal immune tolerance and inflammation. . Semin. Cell Dev. Biol. 88::13846
    [Crossref] [Google Scholar]
  24. 24.
    Motta JP, Bermudez-Humaran LG, Deraison C, Martin L, Rolland C, et al. 2012.. Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. . Sci. Transl. Med. 4::158ra44
    [Crossref] [Google Scholar]
  25. 25.
    Deraison C, Bonnart C, Langella P, Roget K, Vergnolle N. 2023.. Elafin and its precursor trappin-2: What is their therapeutic potential for intestinal diseases?. Br. J. Pharmacol. 180::14460
    [Crossref] [Google Scholar]
  26. 26.
    Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. 2023.. Pathophysiology of inflammatory bowel disease: innate immune system. . Int. J. Mol. Sci. 24::1526
    [Crossref] [Google Scholar]
  27. 27.
    Chang JT. 2020.. Pathophysiology of inflammatory bowel diseases. . N. Engl. J. Med. 383::265264
    [Crossref] [Google Scholar]
  28. 28.
    Punchard NA, Greenfield SM, Thompson RP. 1992.. Mechanism of action of 5-arninosalicylic acid. . Mediat. Inflamm. 1::15165
    [Crossref] [Google Scholar]
  29. 29.
    Oh-Oka K, Kojima Y, Uchida K, Yoda K, Ishimaru K, et al. 2017.. Induction of colonic regulatory T cells by mesalamine by activating the aryl hydrocarbon receptor. . Cell Mol. Gastroenterol. Hepatol. 4::13551
    [Crossref] [Google Scholar]
  30. 30.
    Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, et al. 2005.. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor γ. . J. Exp. Med. 201::120515
    [Crossref] [Google Scholar]
  31. 31.
    Benedetti E, Viscido A, Castelli V, Maggiani C, d'Angelo M, et al. 2018.. Mesalazine treatment in organotypic culture of celiac patients: comparative study with gluten free diet. . J. Cell. Physiol. 233::438390
    [Crossref] [Google Scholar]
  32. 32.
    Ben-Horin S, Kopylov U, Chowers Y. 2014.. Optimizing anti-TNF treatments in inflammatory bowel disease. . Autoimmun. Rev. 13::2430
    [Crossref] [Google Scholar]
  33. 33.
    Wong U, Cross RK. 2019.. Expert opinion on interleukin-12/23 and interleukin-23 antagonists as potential therapeutic options for the treatment of inflammatory bowel disease. . Expert Opin. Investig. Drugs 28::47379
    [Crossref] [Google Scholar]
  34. 34.
    Bethlehem L, Estevinho MM, Grinspan A, Magro F, Faith JJ, Colombel JF. 2024.. Microbiota therapeutics for inflammatory bowel disease: the way forward. . Lancet Gastroenterol. Hepatol. 9::47686
    [Crossref] [Google Scholar]
  35. 35.
    Gulliver EL, Young RB, Chonwerawong M, D'Adamo GL, Thomason T, et al. 2022.. The future of microbiome-based therapeutics. . Aliment. Pharmacol. Ther. 56::192208
    [Crossref] [Google Scholar]
  36. 36.
    Hu KA, Gubatan J. 2023.. Gut microbiome–based therapeutics in inflammatory bowel disease. . Clin. Transl. Discov. 3::e182
    [Crossref] [Google Scholar]
  37. 37.
    Saviano A, Petruzziello C, Brigida M, Morabito Loprete MR, Savioli G, et al. 2023.. Gut microbiota alteration and its modulation with probiotics in celiac disease. . Biomedicines 11::2638
    [Crossref] [Google Scholar]
  38. 38.
    Battat R, Duijvestein M, Guizzetti L, Choudhary D, Boland BS, et al. 2019.. Histologic healing rates of medical therapies for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. . Am. J. Gastroenterol. 114::73345
    [Crossref] [Google Scholar]
  39. 39.
    Pineton de Chambrun G, Peyrin-Biroulet L, Lemann M, Colombel JF. 2010.. Clinical implications of mucosal healing for the management of IBD. . Nat. Rev. Gastroenterol. Hepatol. 7::1529
    [Crossref] [Google Scholar]
  40. 40.
    Onali S, Favale A, Fantini MC. 2019.. The resolution of intestinal inflammation: the peace-keeper's perspective. . Cells 8::344
    [Crossref] [Google Scholar]
  41. 41.
    Gobbetti T, Dalli J, Colas RA, Federici Canova D, Aursnes M, et al. 2017.. Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection. . PNAS 114::396368
    [Crossref] [Google Scholar]
  42. 42.
    Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, et al. 2012.. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. . Gastroenterology 143::120717.e2
    [Crossref] [Google Scholar]
  43. 43.
    Sturm A, Dignass AU. 2008.. Epithelial restitution and wound healing in inflammatory bowel disease. . World J. Gastroenterol. 14::34853
    [Crossref] [Google Scholar]
  44. 44.
    Dignass AU, Podolsky DK. 1993.. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor β. . Gastroenterology 105::132332
    [Crossref] [Google Scholar]
  45. 45.
    Paclik D, Lohse K, Wiedenmann B, Dignass AU, Sturm A. 2008.. Galectin-2 and -4, but not galectin-1, promote intestinal epithelial wound healing in vitro through a TGF-β-independent mechanism. . Inflamm. Bowel Dis. 14::136672
    [Crossref] [Google Scholar]
  46. 46.
    Dignass A, Lynch-Devaney K, Kindon H, Thim L, Podolsky DK. 1994.. Trefoil peptides promote epithelial migration through a transforming growth factor β–independent pathway. . J. Clin. Investig. 94::37683
    [Crossref] [Google Scholar]
  47. 47.
    Motta J-P, Magne L, Descamps D, Rolland C, Squarzoni-Dale C, et al. 2011.. Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis. . Gastroenterology 140::127282
    [Crossref] [Google Scholar]
  48. 48.
    Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, et al. 2004.. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. . Gut 53::68593
    [Crossref] [Google Scholar]
  49. 49.
    Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, et al. 2011.. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. . Am. J. Gastroenterol. 106::66173
    [Crossref] [Google Scholar]
  50. 50.
    Townsend CM, Parker CE, MacDonald JK, Nguyen TM, Jairath V, et al. 2019.. Antibiotics for induction and maintenance of remission in Crohn's disease. . Cochrane Database Syst. Rev. 2::CD012730
    [Google Scholar]
  51. 51.
    Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, et al. 2017.. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: Current management. . J. Crohn's Colitis 11::76984
    [Crossref] [Google Scholar]
  52. 52.
    Shaw SY, Blanchard JF, Bernstein CN. 2010.. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. . Am. J. Gastroenterol. 105::268792
    [Crossref] [Google Scholar]
  53. 53.
    Ganji-Arjenaki M, Rafieian-Kopaei M. 2018.. Probiotics are a good choice in remission of inflammatory bowel diseases: a meta analysis and systematic review. . J. Cell. Physiol. 233::2091103
    [Crossref] [Google Scholar]
  54. 54.
    Kaur L, Gordon M, Baines PA, Iheozor-Ejiofor Z, Sinopoulou V, Akobeng AK. 2020.. Probiotics for induction of remission in ulcerative colitis. . Cochrane Database Syst. Rev. 3::CD005573
    [Google Scholar]
  55. 55.
    Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, et al. 2015.. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. . Gastroenterology 149::1029.e6
    [Crossref] [Google Scholar]
  56. 56.
    Paramsothy S, Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO, et al. 2017.. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. . J. Crohn's Colitis 11::118099
    [Crossref] [Google Scholar]
  57. 57.
    Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, et al. 2010.. Autologous bone marrow–derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. . Gut 59::166269
    [Crossref] [Google Scholar]
  58. 58.
    Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, et al. 2014.. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. . Clin. Gastroenterol. Hepatol. 12::6471
    [Crossref] [Google Scholar]
  59. 59.
    Lopez-Garcia A, Rovira M, Jauregui-Amezaga A, Marin P, Barastegui R, et al. 2017.. Autologous haematopoietic stem cell transplantation for refractory Crohn's disease: efficacy in a single-centre cohort. . J. Crohn's Colitis 11::116168
    [Crossref] [Google Scholar]
  60. 60.
    Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, et al. 2017.. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn's disease. . Gastroenterology 153::5962.e2
    [Crossref] [Google Scholar]
  61. 61.
    Le Cosquer G, Buscail E, Gilletta C, Deraison C, Duffas JP, et al. 2022.. Incidence and risk factors of cancer in the anal transitional zone and ileal pouch following surgery for ulcerative colitis and familial adenomatous polyposis. . Cancers 14::530
    [Crossref] [Google Scholar]
  62. 62.
    Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, et al. 2012.. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. . Nat. Med. 18::61823
    [Crossref] [Google Scholar]
  63. 63.
    Vergnolle N, Cirillo C. 2018.. Neurons and glia in the enteric nervous system and epithelial barrier function. . Physiology 33::26980
    [Crossref] [Google Scholar]
  64. 64.
    Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, et al. 2002.. Anti–tumor necrosis factor treatment restores the gut barrier in Crohn's disease. . Am. J. Gastroenterol. 97::20004
    [Crossref] [Google Scholar]
  65. 65.
    Vernia P, Annese V, Bresci G, d'Albasio G, D'Inca R, et al. 2003.. Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial. . Eur. J. Clin. Investig. 33::24448
    [Crossref] [Google Scholar]
  66. 66.
    Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, et al. 1996.. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. . Scand. J. Gastroenterol. 31::77885
    [Crossref] [Google Scholar]
  67. 67.
    Stremmel W, Ehehalt R, Autschbach F, Karner M. 2007.. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial. . Ann. Intern. Med. 147::60310
    [Crossref] [Google Scholar]
  68. 68.
    El-Tawil AM. 2012.. Zinc supplementation tightens leaky gut in Crohn's disease. . Inflamm. Bowel Dis. 18::e399
    [Crossref] [Google Scholar]
  69. 69.
    Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Inca R. 2001.. Zinc supplementation tightens “leaky gut” in Crohn's disease. . Inflamm. Bowel Dis. 7::9498
    [Crossref] [Google Scholar]
  70. 70.
    Simmons JD, Mullighan C, Welsh KI, Jewell DP. 2000.. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. . Gut 47::21114
    [Crossref] [Google Scholar]
  71. 71.
    Lerner A, Matthias T. 2015.. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. . Autoimmun. Rev. 14::47989
    [Crossref] [Google Scholar]
  72. 72.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, et al. 2012.. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. . Nature 491::11924
    [Crossref] [Google Scholar]
  73. 73.
    de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, et al. 2017.. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. . Nat. Genet. 49::25661
    [Crossref] [Google Scholar]
  74. 74.
    Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, et al. 2022.. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. . Nat. Genet. 54::127583
    [Crossref] [Google Scholar]
  75. 75.
    McGovern DP, Kugathasan S, Cho JH. 2015.. Genetics of inflammatory bowel diseases. . Gastroenterology 149::116376.e2
    [Crossref] [Google Scholar]
  76. 76.
    Wang MH, Friton JJ, Raffals LE, Leighton JA, Pasha SF, et al. 2019.. Novel genetic risk variants can predict anti-TNF agent response in patients with inflammatory bowel disease. . J. Crohn's Colitis 13::103643
    [Crossref] [Google Scholar]
  77. 77.
    Venkataraman GR, Rivas MA. 2019.. Rare and common variant discovery in complex disease: the IBD case study. . Hum. Mol. Genet. 28::R16269
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-051921-084536
Loading
/content/journals/10.1146/annurev-pharmtox-051921-084536
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error