Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review
Abstract
1. Introduction
2. Pathophysiology
3. Current Treatment Landscape
3.1. Conventional Therapies
3.2. Biologic Therapies
3.3. Small-Molecule Therapies
3.4. Precision Medicine and Treatment Selection
4. Emerging Therapies in IBD
4.1. Next-Generation Biologics
4.2. Fecal Microbiota Transplantation (FMT)
4.3. Gene Therapy and CRISPR-Cas9
4.4. Stem Cell Therapies
5. Limitations and Future Directions
5.1. Current Limitations
5.2. The Ceiling of Advanced Therapy: Understanding Therapeutic Plateaus
5.3. Future Research Directions
6. Conclusions
6.1. Precision Medicine and Biomarker-Guided Therapy
6.2. Mechanistic Diversification Beyond TNF α
6.3. Microbiome as a Therapeutic Target
6.4. Regenerative Medicine and Tissue Repair
6.5. Dual and Multi-Target Approaches
6.6. Regulatory and Implementation Advances
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Ungaro, R.; Mehandru, S.; Allen, P.B.; Peyrin-Biroulet, L.; Colombel, J.F. Ulcerative colitis. Lancet 2017, 389, 1756–1770. [Google Scholar] [CrossRef]
- GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 2020, 5, 17–30. [Google Scholar] [CrossRef]
- Park, K.T.; Ehrlich, O.G.; Allen, J.I.; Meadows, P.; Szigethy, E.M.; Henrichsen, K.; Kim, S.C.; Lawton, R.C.; Murphy, S.M.; Regueiro, M.; et al. The Cost of Inflammatory Bowel Disease: An Initiative from the Crohn’s & Colitis Foundation. Inflamm. Bowel Dis. 2020, 26, 1118. [Google Scholar] [CrossRef] [PubMed]
- Benchimol, E.I.; Bernstein, C.N.; Bitton, A.; Carroll, M.W.; Singh, H.; Otley, A.R.; Vutcovici, M.; El-Matary, W.; Nguyen, G.C.; Griffiths, A.M.; et al. Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases. Am. J. Gastroenterol. 2017, 112, 1120–1134. [Google Scholar] [CrossRef] [PubMed]
- Ye, Y.; Pang, Z.; Chen, W.; Ju, S.; Zhou, C. The epidemiology and risk factors of inflammatory bowel disease. Int. J. Clin. Exp. Med. 2015, 8, 22529–22542. [Google Scholar] [PubMed]
- Khor, B.; Gardet, A.; Xavier, R.J. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011, 474, 307–317. [Google Scholar] [CrossRef]
- Smillie, C.S.; Biton, M.; Ordovas-Montanes, J.; Sullivan, K.M.; Burgin, G.; Graham, D.B.; Herbst, R.H.; Rogel, N.; Slyper, M.; Waldman, J.; et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 2019, 178, 714–730.e22. [Google Scholar] [CrossRef]
- Martin, J.C.; Chang, C.; Boschetti, G.; Ungaro, R.; Giri, M.; Grout, J.A.; Gettler, K.; Chuang, L.-S.; Nayar, S.; Greenstein, A.J.; et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 2019, 178, 1493–1508.e20. [Google Scholar] [CrossRef]
- Livanos, A.E.; Jha, D.; Cossarini, F.; Gonzalez-Reiche, A.S.; Tokuyama, M.; Aydillo, T.; Parigi, T.L.; Ladinsky, M.S.; Ramos, I.; Dunleavy, K.; et al. Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients with Gastrointestinal Symptoms. Gastroenterology 2021, 160, 2435–2450.e34. [Google Scholar] [CrossRef]
- Brennan, G.T.; Melton, S.D.; Spechler, S.J.; Souza, R.F.; Kovbasnjuk, O. The role of post-infectious functional gastrointestinal disorders and inflammatory bowel disease in the COVID-19 pandemic. Gastroenterology 2020, 159, 1538–1540. [Google Scholar] [CrossRef]
- Baumgart, D.C.; Sandborn, W.J. Inflammatory bowel disease: Clinical aspects and established and evolving therapies. Lancet 2007, 369, 1641–1657. [Google Scholar] [CrossRef]
- Ben-Horin, S.; Chowers, Y. Review article: Loss of response to anti-TNF treatments in Crohn’s disease. Aliment. Pharmacol. Ther. 2011, 33, 987–995. [Google Scholar] [CrossRef]
- Peyrin-Biroulet, L.; Sandborn, W.; Sands, B.E.; Reinisch, W.; Bemelman, W.; Bryant, R.V.; D’Haens, G.; Dotan, I.; Dubinsky, M.; Feagan, B.; et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am. J. Gastroenterol. 2015, 110, 1324–1338. [Google Scholar] [CrossRef]
- Turner, D.; Ricciuto, A.; Lewis, A.; D’aMico, F.; Dhaliwal, J.; Griffiths, A.M.; Bettenworth, D.; Sandborn, W.J.; Sands, B.E.; Reinisch, W.; et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021, 160, 1570–1583. [Google Scholar] [CrossRef]
- Waljee, A.K.; Liu, B.; Sauder, K.; Zhu, J.; Govani, S.M.; Stidham, R.W.; Higgins, P.D.R. Predicting corticosteroid-free endoscopic remission with vedolizumab in ulcerative colitis. Aliment. Pharmacol. Ther. 2018, 47, 763–772. [Google Scholar] [CrossRef]
- Dulai, P.S.; Boland, B.S.; Singh, S.; Chaudrey, K.; Koliani-Pace, J.L.; Kochhar, G.; Parikh, M.P.; Shmidt, E.; Hartke, J.; Chilukuri, P.; et al. Development and validation of a scoring system to predict outcomes of vedolizumab treatment in patients with Crohn’s disease. Gastroenterology 2018, 155, 687–695. [Google Scholar] [CrossRef] [PubMed]
- Ananthakrishnan, A.N. Environmental risk factors for inflammatory bowel diseases: A review. Dig. Dis. Sci. 2015, 60, 290–298. [Google Scholar] [CrossRef] [PubMed]
- Vebr, M.; Pomahačová, R.; Sýkora, J.; Schwarz, J. A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis. Biomedicines 2023, 11, 3229. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.Z.; Van Sommeren, S.; Huang, H.; Ng, S.C.; Alberts, R.; Takahashi, A.; Ripke, S.; Lee, J.C.; Jostins, L.; Shah, T.; et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 2015, 47, 979–986. [Google Scholar] [CrossRef]
- Neurath, M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat. Immunol. 2019, 20, 970–979. [Google Scholar] [CrossRef]
- Salas, A.; Hernandez-Rocha, C.; Duijvestein, M.; Faubion, W.; McGovern, D.; Vermeire, S.; Vetrano, S.; Casteele, N.V. JAK–STAT pathway targeting for the treatment of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 323–337. [Google Scholar] [CrossRef]
- Molodecky, N.A.; Kaplan, G.G. Environmental risk factors for inflammatory bowel disease. Gastroenterol. Hepatol. 2010, 6, 339–346. [Google Scholar]
- Narula, N.; Wong, E.C.L.; Dehghan, M.; Mente, A.; Rangarajan, S.; Lanas, F.; Lopez-Jaramillo, P.; Rohatgi, P.; Lakshmi, P.V.M.; Varma, R.P.; et al. Association of ultra-processed food intake with risk of inflammatory bowel disease: Prospective cohort study. BMJ 2021, 374, n1554. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez-Palacios, A.; Harding, A.; Menghini, P.; Himmelman, C.; Retuerto, M.; Nickerson, K.P.; Lam, M.; Croniger, C.M.; McLean, M.H.; Durum, S.K.; et al. The Artificial Sweetener Splenda Promotes Gut Proteobacteria, Dysbiosis, and Myeloperoxidase Reactivity in Crohn’s Disease–Like Ileitis. Inflamm. Bowel Dis. 2018, 24, 1005–1020. [Google Scholar] [CrossRef] [PubMed]
- Neurath, M.F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 2014, 14, 329–342. [Google Scholar] [CrossRef]
- Bernink, J.H.; Peters, C.P.; Munneke, M.; te Velde, A.A.; Meijer, S.L.; Weijer, K.; Hreggvidsdottir, H.S.; Heinsbroek, S.E.; Legrand, N.; Buskens, C.J.; et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 2013, 14, 221–229. [Google Scholar] [CrossRef] [PubMed]
- Zundler, S.; Becker, E.; Spocinska, M.; Slawik, M.; Parga-Vidal, L.; Stark, R.; Wiendl, M.; Atreya, R.; Rath, T.; Leppkes, M.; et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat. Immunol. 2019, 20, 288–300. [Google Scholar] [CrossRef]
- Frank, D.N.; St Amand, A.L.; Feldman, R.A.; Boedeker, E.C.; Harpaz, N.; Pace, N.R. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA 2007, 104, 13780–13785. [Google Scholar] [CrossRef]
- Pittayanon, R.; Lau, J.T.; Yuan, Y.; Leontiadis, G.I.; Tse, F.; Surette, M.; Moayyedi, P. Gut Microbiota in Patients with Irritable Bowel Syndrome—A Systematic Review. Gastroenterology 2019, 157, 97–108. [Google Scholar] [CrossRef]
- Lloyd-Price, J.; Arze, C.; Ananthakrishnan, A.N.; Schirmer, M.; Avila-Pacheco, J.; Poon, T.W.; Andrews, E.; Ajami, N.J.; Bonham, K.S.; Brislawn, C.J.; et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019, 569, 655–662. [Google Scholar] [CrossRef]
- Lichtenstein, G.R.; Loftus, E.V., Jr.; Isaacs, K.L.; Regueiro, M.D.; Gerson, L.B.; Sands, B.E. ACG clinical guideline: Management of Crohn’s disease in adults. Am. J. Gastroenterol. 2018, 113, 481–517. [Google Scholar] [CrossRef] [PubMed]
- Ford, A.C.; Kane, S.V.; Khan, K.J.; Achkar, J.P.; Talley, N.J.; Marshall, J.K.; Moayyedi, P. Efficacy of 5-aminosalicylates in Crohn’s disease: Systematic review and meta-analysis. Am. J. Gastroenterol. 2011, 106, 617–629. [Google Scholar] [CrossRef] [PubMed]
- Torres, J.; Bonovas, S.; Doherty, G.; Kucharzik, T.; Gisbert, J.P.; Raine, T.; Adamina, M.; Armuzzi, A.; Bachmann, O.; Bager, P.; et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J. Crohn’s Colitis 2019, 14, 4–22. [Google Scholar] [CrossRef] [PubMed]
- Present, D.H.; Meltzer, S.J.; Krumholz, M.P.; Wolke, A.; Korelitz, B.I. 6-Mercaptopurine in the management of inflammatory bowel disease: Short- and long-term toxicity. Ann. Intern. Med. 1989, 111, 641–649. [Google Scholar] [CrossRef]
- Relling, M.V.; Schwab, M.; Whirl-Carrillo, M.; Suarez-Kurtz, G.; Pui, C.-H.; Stein, C.M.; Moyer, A.M.; Evans, W.E.; Klein, T.E.; Antillon-Klussmann, F.G.; et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin. Pharmacol. Ther. 2018, 105, 1095–1105. [Google Scholar] [CrossRef]
- Danese, S.; Vuitton, L.; Peyrin-Biroulet, L. Biologic agents for IBD: Practical insights. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 537–545. [Google Scholar] [CrossRef]
- Hanauer, S.B.; Feagan, B.G.; Lichtenstein, G.R.; Mayer, L.F.; Schreiber, S.; Colombel, J.F.; Rachmilewitz, D.; Wolf, D.C.; Olson, A.; Bao, W.; et al. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002, 359, 1541–1549. [Google Scholar] [CrossRef]
- Mitrev, N.; Casteele, N.V.; Seow, C.H.; Andrews, J.M.; Connor, S.J.; Moore, G.T.; Barclay, M.; Begun, J.; Bryant, R.; Chan, W.; et al. Review article: Consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment. Pharmacol. Ther. 2017, 46, 1037–1053. [Google Scholar] [CrossRef]
- Papamichael, K.; Chachu, K.A.; Vajravelu, R.K.; Vaughn, B.P.; Ni, J.; Osterman, M.T.; Cheifetz, A.S. Improved Long-term Outcomes of Patients with Inflammatory Bowel Disease Receiving Proactive Compared with Reactive Monitoring of Serum Concentrations of Infliximab. Clin. Gastroenterol. Hepatol. 2017, 15, 1580–1588.e3. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Feagan, B.G.; Rutgeerts, P.; Hanauer, S.; Colombel, J.-F.; Sands, B.E.; Lukas, M.; Fedorak, R.N.; Lee, S.; Bressler, B.; et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N. Engl. J. Med. 2013, 369, 711–721. [Google Scholar] [CrossRef]
- Loftus, E.V., Jr.; Colombel, J.-F.; Feagan, B.G.; Vermeire, S.; Sandborn, W.J.; Sands, B.E.; Danese, S.; D’Haens, G.R.; Kaser, A.; Panaccione, R.; et al. Long-term Efficacy of Vedolizumab for Ulcerative Colitis. J. Crohn’s Colitis 2017, 11, 400–411. [Google Scholar] [CrossRef]
- Feagan, B.G.; Sandborn, W.J.; Gasink, C.; Jacobstein, D.; Lang, Y.; Friedman, J.R.; Blank, M.A.; Johanns, J.; Gao, L.-L.; Miao, Y.; et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N. Engl. J. Med. 2016, 375, 1946–1960. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Rebuck, R.; Wang, Y.; Zou, B.; Adedokun, O.J.; Gasink, C.; Sands, B.E.; Hanauer, S.B.; Targan, S.; Ghosh, S.; et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn’s Disease: The IM-UNITI Trial. Clin. Gastroenterol. Hepatol. 2022, 20, 578–590.e4. [Google Scholar] [CrossRef]
- Yoo, D.H.; Hrycaj, P.; Miranda, P.; Ramiterre, E.; Piotrowski, M.; Shevchuk, S.; Kovalenko, V.; Prodanovic, N.; Abello-Banfi, M.; Gutierrez-Ureña, S.; et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: The PLANETRA study. Ann. Rheum. Dis. 2013, 72, 1613–1620. [Google Scholar] [CrossRef]
- Jørgensen, K.K.; Olsen, I.C.; Goll, G.L.; Lorentzen, M.; Bolstad, N.; Haavardsholm, E.A.; Lundin, K.E.A.; Mørk, C.; Jahnsen, J.; Kvien, T.K.; et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): A 52-week, randomised, double-blind, non-inferiority trial. Lancet 2017, 389, 2304–2316. [Google Scholar] [CrossRef] [PubMed]
- Jefremow, A.; Neurath, M.F. Novel small molecules in IBD: Current state and future perspectives. Cells 2023, 12, 1730. [Google Scholar] [CrossRef] [PubMed]
- Sandborn, W.J.; Su, C.; Sands, B.E.; D’hAens, G.R.; Vermeire, S.; Schreiber, S.; Danese, S.; Feagan, B.G.; Reinisch, W.; Niezychowski, W.; et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 2017, 376, 1723–1736. [Google Scholar] [CrossRef] [PubMed]
- Sandborn, W.J.; Ghosh, S.; Panes, J.; Vranic, I.; Su, C.; Rousell, S.; Niezychowski, W. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 2012, 367, 616–624. [Google Scholar] [CrossRef]
- Singh, S.; Fumery, M.; Sandborn, W.J.; Murad, M.H. Systematic review with network meta-analysis: First- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Aliment. Pharmacol. Ther. 2017, 47, 162–175. [Google Scholar] [CrossRef]
- Olivera, P.; Danese, S.; Jay, N.; Natoli, G.; Peyrin-Biroulet, L. Big data in IBD: A look into the future. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 312–321. [Google Scholar] [CrossRef]
- Feagan, B.G.; Danese, S.; Loftus, E.V.; Vermeire, S.; Schreiber, S.; Ritter, T.; Fogel, R.; Mehta, R.; Nijhawan, S.; Kempiński, R.; et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 2021, 397, 2372–2384. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Feagan, B.G.; Loftus, E.V.; Peyrin-Biroulet, L.; Van Assche, G.; D’hAens, G.; Schreiber, S.; Colombel, J.-F.; Lewis, J.D.; Ghosh, S.; et al. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients with Crohn’s Disease. Gastroenterology 2020, 158, 2123–2138.e8. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Feagan, B.G.; D’hAens, G.; Wolf, D.C.; Jovanovic, I.; Hanauer, S.B.; Ghosh, S.; Petersen, A.; Hua, S.Y.; Lee, J.H.; et al. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 2021, 385, 1280–1291. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Vermeire, S.; Peyrin-Biroulet, L.; Dubinsky, M.C.; Panes, J.; Yarur, A.; Ritter, T.; Baert, F.; Schreiber, S.; Sloan, S.; et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): Two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023, 401, 1159–1171. [Google Scholar] [CrossRef] [PubMed]
- Neurath M., F. Current and emerging therapeutic targets for IBD. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 269–278. [Google Scholar] [CrossRef]
- Hueber, W.; E Sands, B.; Lewitzky, S.; Vandemeulebroecke, M.; Reinisch, W.; Higgins, P.D.R.; Wehkamp, J.; Feagan, B.G.; Yao, M.D.; Karczewski, M.; et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: Unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012, 61, 1693–1700. [Google Scholar] [CrossRef] [PubMed]
- Targan, S.R.; Feagan, B.; Vermeire, S.; Panaccione, R.; Melmed, G.Y.; Landers, C.; Li, D.; Russell, C.; Newmark, R.; Zhang, N.; et al. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients with Moderate-to-Severe Crohn’s Disease. Am. J. Gastroenterol. 2016, 111, 1599–1607. [Google Scholar] [CrossRef] [PubMed]
- Danese, S.; Panaccione, R.; Feagan, B.G.; Afzali, A.; Rubin, D.T.; E Sands, B.; Reinisch, W.; Panés, J.; Sahoo, A.; A Terry, N.; et al. Efficacy and safety of 48 weeks of guselkumab for patients with Crohn’s disease: Maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial. Lancet Gastroenterol. Hepatol. 2023, 9, 133–146. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Ferrante, M.; Bhandari, B.R.; Berliba, E.; Feagan, B.G.; Hibi, T.; Tuttle, J.L.; Klekotka, P.; Friedrich, S.; Durante, M.; et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients with Ulcerative Colitis. Gastroenterology 2020, 158, 537–549.e10. [Google Scholar] [CrossRef]
- D’hAens, G.; Dubinsky, M.; Kobayashi, T.; Irving, P.M.; Howaldt, S.; Pokrotnieks, J.; Krueger, K.; Laskowski, J.; Li, X.; Lissoos, T.; et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 2023, 388, 2444–2455. [Google Scholar] [CrossRef]
- Moschen, A.R.; Tilg, H.; Raine, T. IL-12, IL-23 and IL-17 in IBD: Immunobiology and therapeutic targeting. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 185–196. [Google Scholar] [CrossRef]
- Verstockt, B.; Ferrante, M.; Vermeire, S.; Van Assche, G. New treatment options for inflammatory bowel diseases. J. Gastroenterol. 2018, 53, 585–590. [Google Scholar] [CrossRef] [PubMed]
- Ianiro, G.; Tilg, H.; Gasbarrini, A. Antibiotics as deep modulators of gut microbiota: Between good, bad and ugly. Gut 2016, 65, 1906–1915. [Google Scholar] [CrossRef] [PubMed]
- Costello, S.P.; Hughes, P.A.; Waters, O.; Bryant, R.V.; Vincent, A.D.; Blatchford, P.; Katsikeros, R.; Makanyanga, J.; Campaniello, M.A.; Mavrangelos, C.; et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients with Ulcerative Colitis. JAMA 2019, 321, 156–164. [Google Scholar] [CrossRef] [PubMed]
- Paramsothy, S.; Paramsothy, R.; Rubin, D.T.; Kamm, M.A.; Kaakoush, N.O.; Mitchell, H.M.; Castaño-Rodríguez, N. Faecal microbiota transplantation for inflammatory bowel disease: A systematic review and meta-analysis. J. Crohns Colitis 2017, 11, 1180–1199. [Google Scholar] [CrossRef]
- Chehade, N.E.H.; Ghoneim, S.; Shah, S.; Chahine, A.; Mourad, F.H.; Francis, F.F.; Binion, D.G.; A Farraye, F.; Hashash, J.G. Efficacy of Fecal Microbiota Transplantation in the Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Inflamm. Bowel Dis. 2022, 29, 808–817. [Google Scholar] [CrossRef]
- Allegretti, J.R.; Fischer, M.; Sagi, S.V.; Bohm, M.E.; Fadda, H.M.; Ranmal, S.R.; Budree, S.; Basit, A.W.; Glettig, D.L.; de la Serna, E.L.; et al. Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose. Dig. Dis. Sci. 2019, 64, 1672–1678. [Google Scholar] [CrossRef]
- Sokol, H.; Landman, C.; Seksik, P.; Berard, L.; Montil, M.; Nion-Larmurier, I.; Bourrier, A.; Le Gall, G.; Lalande, V.; De Rougemont, A.; et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: A pilot randomized controlled study. Microbiome 2020, 8, 12. [Google Scholar] [CrossRef]
- Paramsothy, S.; Kamm, M.A.; Kaakoush, N.O.; Walsh, A.J.; van den Bogaerde, J.; Samuel, D.; Leong, R.W.L.; Connor, S.; Ng, W.; Paramsothy, R.; et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: A randomised placebo-controlled trial. Lancet 2017, 389, 1218–1228. [Google Scholar] [CrossRef]
- Ianiro, G.; Eusebi, L.H.; Black, C.J.; Gasbarrini, A.; Cammarota, G.; Ford, A.C. Systematic review with meta-analysis: Efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment. Pharmacol. Ther. 2019, 50, 240–248. [Google Scholar] [CrossRef]
- Marcella, C.; Cui, B.; Kelly, C.R.; Ianiro, G.; Cammarota, G.; Zhang, F. Systematic review: The global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment. Pharmacol. Ther. 2020, 53, 33–42. [Google Scholar] [CrossRef]
- Wirtz, S.; Neurath, M.F. Gene transfer approaches for the treatment of inflammatory bowel disease. Gene Ther. 2003, 10, 854–860. [Google Scholar] [CrossRef] [PubMed]
- Cho, J.H.; Brant, S.R. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011, 140, 1704–1712. [Google Scholar] [CrossRef] [PubMed]
- Anzalone, A.V.; Randolph, P.B.; Davis, J.R.; Sousa, A.A.; Koblan, L.W.; Levy, J.M.; Chen, P.J.; Wilson, C.; Newby, G.A.; Raguram, A. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019, 576, 149–157. [Google Scholar] [CrossRef] [PubMed]
- Anzalone, A.V.; Koblan, L.W.; Liu, D.R. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 2020, 38, 824–844. [Google Scholar] [CrossRef]
- van der Marel, S.; Majowicz, A.; van Deventer, S.; Petry, H.; Hommes, D.W.; Ferreira, V. Gene and cell therapy based treatment strategies for inflammatory bowel diseases. World J. Gastrointest. Pathophysiol. 2011, 2, 114–122. [Google Scholar] [CrossRef]
- Isabella, V.M.; Ha, B.N.; Castillo, M.J.; Lubkowicz, D.J.; E Rowe, S.; A Millet, Y.; Anderson, C.L.; Li, N.; Fisher, A.B.; A West, K.; et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat. Biotechnol. 2018, 36, 857–864. [Google Scholar] [CrossRef]
- Kulkarni, J.A.; Cullis, P.R.; van der Meel, R. Lipid nanoparticles enabling gene therapies: From concepts to clinical utility. Nucleic Acid. Ther. 2018, 28, 146–157. [Google Scholar] [CrossRef]
- Wang, D.; Tai, P.W.L.; Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 2019, 18, 358–378. [Google Scholar] [CrossRef]
- Dave, M.; Mehta, K.; Luther, J.; Baruah, A.; Dietz, A.B.; Faubion, W.A. Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2015, 21, 2696–2707. [Google Scholar] [CrossRef]
- Gonzalez-Rey, E.; Anderson, P.; A Gonzalez, M.; Rico, L.; Buscher, D.; Delgado, M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009, 58, 929–939. [Google Scholar] [CrossRef]
- Panés, J.; García-Olmo, D.; Van Assche, G.; Colombel, J.F.; Reinisch, W.; Baumgart, D.C.; Dignass, A.; Nachury, M.; Ferrante, M.; Kazemi-Shirazi, L.; et al. ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology 2018, 154, 1334–1342.e4. [Google Scholar] [CrossRef]
- Forbes, G.M.; Sturm, M.J.; Leong, R.W.; Sparrow, M.P.; Segarajasingam, D.; Cummins, A.G.; Phillips, M.; Herrmann, R.P. A Phase 2 Study of Allogeneic Mesenchymal Stromal Cells for Luminal Crohn’s Disease Refractory to Biologic Therapy. Clin. Gastroenterol. Hepatol. 2014, 12, 64–71. [Google Scholar] [CrossRef] [PubMed]
- Lightner, A.L.; Dozois, E.J.; Dietz, A.B.; Fletcher, J.G.; Friton, J.; Butler, G.; A Faubion, W. Matrix-Delivered Autologous Mesenchymal Stem Cell Therapy for Refractory Rectovaginal Crohn’s Fistulas. Inflamm. Bowel Dis. 2019, 26, 670–677. [Google Scholar] [CrossRef] [PubMed]
- de la Portilla, F.; Alba, F.; García-Olmo, D.; Herrerías, J.M.; González, F.X.; Galindo, A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: Results from a multicenter phase I/IIa clinical trial. Int. J. Color. Dis. 2012, 28, 313–323. [Google Scholar] [CrossRef] [PubMed]
- Ciccocioppo, R.; Bernardo, M.E.; Sgarella, A.; Maccario, R.; Avanzini, M.A.; Ubezio, C.; Minelli, A.; Alvisi, C.; Vanoli, A.; Calliada, F.; et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 2011, 60, 788–798. [Google Scholar] [CrossRef]
- Nakamura, T. Recent progress in organoid culture to model intestinal epithelial barrier functions. Int. Immunol. 2019, 31, 13–21. [Google Scholar] [CrossRef]
- Galipeau, J.; Krampera, M.; Barrett, J.; Dazzi, F.; Deans, R.J.; DeBruijn, J.; Dominici, M.; Fibbe, W.E.; Gee, A.P.; Gimble, J.M.; et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016, 18, 151–159. [Google Scholar] [CrossRef]
- Marks, P.W.; Witten, C.M.; Califf, R.M. Clarifying stem-cell therapy’s benefits and risks. N. Engl. J. Med. 2017, 376, 1007–1009. [Google Scholar] [CrossRef]
- Lewis, J.D.; Lichtenstein, G.R.; Stein, R.B.; Deren, J.J.; Judge, T.A.; Fogt, F.; Furth, E.E.; Demissie, E.J.; Hurd, L.B.; Su, C.G.; et al. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. Am. J. Gastroenterol. 2001, 96, 3323–3328. [Google Scholar] [CrossRef]
- Danese, S.; Sandborn, W.J.; Colombel, J.-F.; Vermeire, S.; Glover, S.C.; Rimola, J.; Siegelman, J.; Jones, S.; Bornstein, J.D.; Feagan, B.G. Endoscopic, Radiologic, and Histologic Healing with Vedolizumab in Patients with Active Crohn’s Disease. Gastroenterology 2019, 157, 1007–1018.e7. [Google Scholar] [CrossRef] [PubMed]
- Pavlidis, P.; Tsakmaki, A.; Pantazi, E.; Li, K.; Cozzetto, D.; Bell, J.D.; Yang, F.; Lo, J.W.; Alberts, E.; Sa, A.C.C.; et al. Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy. Nat. Commun. 2022, 13, 5820. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Andersen, N.N.; Andersson, M.; Loftus, E.V., Jr.; Jess, T. Comparison of infliximab and adalimumab in biologic-naive patients with ulcerative colitis: A nationwide Danish cohort study. Clin. Gastroenterol. Hepatol. 2017, 15, 1218–1225.e7. [Google Scholar] [CrossRef] [PubMed]
- Johnston, M.T.; Alharbi, A.; Alharbi, M.; Alharbi, M. Prevalence and clinical implications of anti-drug antibody formation to infliximab and adalimumab in patients with inflammatory bowel disease. Saudi J. Gastroenterol. 2025, 30, 123–130. [Google Scholar]
- Kim, H.S.; Kim, Y.S. Current and emerging biologics for ulcerative colitis. Gut and Liver 2021, 15, 669–679. [Google Scholar] [CrossRef]
- Kugathasan, S.; A Denson, L.; Walters, T.D.; Kim, M.-O.; Marigorta, U.M.; Schirmer, M.; Mondal, K.; Liu, C.; Griffiths, A.; Noe, J.D.; et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: A multicentre inception cohort study. Lancet 2017, 389, 1710–1718. [Google Scholar] [CrossRef]
- Reinisch, W.; Panés, J.; Khurana, S.; Toth, G.; Hua, F.; Comer, G.M.; Hinz, M.; Page, K.; O’TOole, M.; Moorehead, T.M.; et al. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: Efficacy and safety from a phase IIa randomised multicentre study. Gut 2015, 64, 894–900. [Google Scholar] [CrossRef]
- Gevers, D.; Kugathasan, S.; Denson, L.A.; Vázquez-Baeza, Y.; Van Treuren, W.; Ren, B.; Schwager, E.; Knights, D.; Song, S.J.; Yassour, M.; et al. The Treatment-Naive Microbiome in New-Onset Crohn’s Disease. Cell Host Microbe 2014, 15, 382–392. [Google Scholar] [CrossRef]
- Siegel, C.A.; Horton, H.; Siegel, L.S.; Thompson, K.D.; Mackenzie, T.; Stewart, S.K.; Rice, P.W.; Stempak, J.M.; Dezfoli, S.; Haritunians, T.; et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment. Pharmacol. Ther. 2015, 43, 262–271. [Google Scholar] [CrossRef]
- Kaplan, G.G.; Ng, S.C. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology 2017, 152, 313–321.e2. [Google Scholar] [CrossRef]
Therapy | Mechanism of Action | Indication | Efficacy (Induction) | Efficacy (Maintenance) | Safety Profile |
---|---|---|---|---|---|
Infliximab | Anti-TNFα monoclonal antibody | CD, UC | 60–80% | 40–60% | Infusion reactions, infections, and malignancy |
Adalimumab | Anti-TNFα monoclonal antibody | CD, UC | 60–70% | 50–60% | Injection site reactions, infections, and malignancy |
Vedolizumab | Anti-α4β7 integrin monoclonal antibody | CD, UC | 50–60% | 45–60% | Infusion reactions, infections, and rare PML risk |
Ustekinumab | IL-12/IL-23 inhibitor | CD, UC | 60–70% | 55–70% | Headache, fatigue, upper respiratory infections |
Therapy | Mechanism of Action | Indication | Efficacy | Safety Profile |
---|---|---|---|---|
Tofacitinib | Janus kinase (JAK) inhibitor | UC | Induction: 60–65% Maintenance: 50–55% | Risk of infections, malignancy, and thrombosis |
Ozanimod | S1P receptor modulator | UC | Induction: 60% Maintenance: 45–50% | Increased liver enzymes, infections, and PML |
Filgotinib | Janus kinase (JAK) inhibitor | CD | Induction: 50–60% Maintenance: 45–50% | Infections, liver toxicity |
Etrasimod | S1P receptor modulator | UC | Induction; 55–60% Maintenance; 50–55% | Bradycardia, liver enzyme elevation |
Target/Mechanism | Indication | Clinical Status/Key Findings | |
---|---|---|---|
FMT | Restoring gut microbial balance | UC > CD | Multiple positive RCTs; standardized preparations available |
Gene Therapy and CRISPR Cas9 | Editing immune-related genes (NOD2, IL 10) | Refractory IBD | Preclinical development; improved delivery systems |
Stem Cell Therapies | Immunomodulation tissue repair | Perianal CD, Refractory IBD | ADMIRE CD trial supports efficacy; regulatory approval in Europe |
Anti-IL 17 Biologics | Inhibit IL-17 | CD | Phase II trials; mixed efficacy; safety concerns |
Anti-IL 23 Biologics | Inhibit IL-23 (p19 subunit) | UC & CD | Mirikizumab FDA approved 2023; Phase III trials ongoing |
Dual Targeting Therapies | Anti-TNF + Anti-IL 23 agents | Severe/refractory IBD | Early phase trials; bispecific antibodies in development |
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Appiah, J.K.; Hayat, U.; Garg, N.; Asante, R.; Donneyong, E.; Haider, M.U.; Patel, P.; Khan, Z.; Siddiqui, A.A. Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review. J. Clin. Med. 2025, 14, 6119. https://doi.org/10.3390/jcm14176119
Appiah JK, Hayat U, Garg N, Asante R, Donneyong E, Haider MU, Patel P, Khan Z, Siddiqui AA. Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review. Journal of Clinical Medicine. 2025; 14(17):6119. https://doi.org/10.3390/jcm14176119
Chicago/Turabian StyleAppiah, John K., Umar Hayat, Nikita Garg, Richeal Asante, Evans Donneyong, Muhammad U. Haider, Pranav Patel, Zubair Khan, and Ali A. Siddiqui. 2025. "Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review" Journal of Clinical Medicine 14, no. 17: 6119. https://doi.org/10.3390/jcm14176119
APA StyleAppiah, J. K., Hayat, U., Garg, N., Asante, R., Donneyong, E., Haider, M. U., Patel, P., Khan, Z., & Siddiqui, A. A. (2025). Emerging Therapies in Inflammatory Bowel Disease: A Comprehensive Review. Journal of Clinical Medicine, 14(17), 6119. https://doi.org/10.3390/jcm14176119