Colitis ulcerosa: Kann eine Modulation der intestinalen Mikrobiota eine langfristige Remission bedingen?

Zusammenfassung

Das Verständnis der Colitis ulcerosa (CU) ist in den letzten Dekaden stetig gewachsen; unterschiedliche Therapiekonzepte sind für verschiedene Krankheitssituationen standardisiert. In der Pathogenese wird der gastrointestinalen Mikrobiota, Umweltfaktoren, überschießenden immunologischen Reaktionen und genetischen Faktoren eine immer größere Bedeutung zugeordnet. So zeigen zahlreiche klinische Beobachtungen eine enge Verbindung zwischen einer dysbiotischen Mikrobiota und der Erstmanifestation und dem Verlauf der CU an. Vor dem Hintergrund, dass genetische Faktoren und inflammatorische Reaktionen die Mikrobiota selber verändern können ist aber nicht klar, was Ursache und Folge ist. Der Fäkale Mikrobiom Transfer (FMT) ist der drastischste Eingriff um eine dysbiotische Mikrobiota zu normalisieren. Mittlerweile ist ein FMT eine akzeptierte Behandlung der rezidivierenden Clostridioides difficile-Infektion; zahlreiche Fallserien und kontrollierte Studien untersuchen dieses Konzept auch bei Patienten mit CU. Vor diesem Hintergrund erfolgt eine Zusammenfassung der aktuellen Literatur bezüglich Effektivität und Sicherheit. Mögliche Limitationen und offene Fragen werden diskutiert, um das Konzept des FMT zur Therapie der CU zu verbessern. Ohne Zweifel sind dringend weitere kontrollierte Studien notwendig; ein FMT sollte bei CU nicht außerhalb dieser erfolgen.

Abstract

Although the pathogenesis of ulcerative colitis (UC) remains elusive, substantial progress in understanding its development and progression has been achieved in the past decades, and novel effective treatment strategies have been developed. Changes in gut microbiota, environmental triggers, deregulation of immunological responses, and genetic predisposition have been identified as pathogenic key factors. There are several lines of clinical observations, which support a close connection of altered gut microbiota with the development and course of UC. Despite a plethora of microbiota alterations in UC, it is currently unclear whether the observed changes in inflammation are cause or effect of the altered microbiota state.

Fecal microbiota transplantation (FMT) provides a novel, perhaps complementary, strategy to restore gut microbial diversity, bacterial richness, and microbial homeostasis in UC. FMT is an already established treatment option for recurrent Clostridioides difficile infection, and several case series and randomized controlled trials have described its use in UC. In this review, we evaluate recent efficacy and safety data on FMT for UC, discuss possible pitfalls and show possible areas of future development. Although FMT could become a promising treatment modality for UC, based on currently available data, FMT should be only performed in clinical trials as controlled studies focusing on long-term outcomes and safety are warranted.

Schlüsselwörter

Colitis ulcerosa - Mikrobiota - fäkaler Mikrobiom Transfer

Key words

ulcerative colitis - intestinal microbiota - fecal microbiota transplantation

• Literatur

• 1 Bewtra M, Kaiser LM, TenHave T. et al. Crohn’s disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis. Inflammatory bowel diseases 2013; 19: 599-613
• 2 Ungaro R, Mehandru S, Allen PB. et al. Ulcerative colitis. Lancet 2016; DOI: 10.1016/S0140-6736(16)32126-2.
• 3 Ott C, Obermeier F, Thieler S. et al. The incidence of inflammatory bowel disease in a rural region of Southern Germany: a prospective population-based study. European journal of gastroenterology & hepatology 2008; 20: 917-923
• 4 Solberg IC, Lygren I, Jahnsen J. et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scandinavian journal of gastroenterology 2009; 44: 431-440
• 5 Mao EJ, Hazlewood GS, Kaplan GG. et al. Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn’s disease and ulcerative colitis. Alimentary pharmacology & therapeutics 2017; 45: 3-13
• 6 Kucharzik T, Dignass A, Atreya R. et al. S3-Leitlinie – Colitis ulcerosa. Zeitschrift fur Gastroenterologie 2018; 56: 1087-1169
• 7 Stallmach A, Hagel S, Bruns T. Adverse effects of biologics used for treating IBD. Best practice & research Clinical gastroenterology 2010; 24: 167-182
• 8 Kirchgesner J, Lemaitre M, Carrat F. et al. Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology 2018; 155: 337-346 . doi:10.1053/j.gastro.2018.04.012
• 9 Stallmach A, Dennler U, Marschall U. et al. Patient-relevant endpoints in inflammatory bowel diseases--have changes occurred in Germany over the past twelve years?. Journal of Crohn’s & colitis 2015; 9: 390-397
• 10 Turpin W, Goethel A, Bedrani L. et al. Determinants of IBD Heritability: Genes, Bugs, and More. Inflammatory bowel diseases 2018; 24: 1133-1148
• 11 Kirsner JB. Historical aspects of inflammatory bowel disease. Journal of clinical gastroenterology 1988; 10: 286-297
• 12 Hug LA, Baker BJ, Anantharaman K. et al. A new view of the tree of life. Nature microbiology 2016; 1: 16048
• 13 Arumugam M, Raes J, Pelletier E. et al. Enterotypes of the human gut microbiome. Nature 2011; 473: 174-180
• 14 Haller D, Hörmannsperger G. Die Interaktion zwischen Darmbakterien und Mensch als zentraler Faktor für die Darmgesundheit: Mikrobiom und chronisch entzündliche Darmerkrankungen. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2015; 58: 159-165
• 15 Purchiaroni F, Tortora A, Gabrielli M. et al. The role of intestinal microbiota and the immune system. European review for medical and pharmacological sciences 2013; 17: 323-333
• 16 Kamada N, Seo SU, Chen GY. et al. Role of the gut microbiota in immunity and inflammatory disease. Nature reviews Immunology 2013; 13: 321-335
• 17 Zhu W, Winter MG, Byndloss MX. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 2018; 553: 208-211
• 18 Nemoto H, Kataoka K, Ishikawa H. et al. Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis. Digestive diseases and sciences 2012; 57: 2955-2964
• 19 Noor SO, Ridgway K, Scovell L. et al. Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota. BMC gastroenterology 2010; 10: 134
• 20 Walujkar SA, Dhotre DP, Marathe NP. et al. Characterization of bacterial community shift in human Ulcerative Colitis patients revealed by Illumina based 16S rRNA gene amplicon sequencing. Gut pathogens 2014; 6: 22
• 21 Nishida A, Inoue R, Inatomi O. et al. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clinical journal of gastroenterology 2018; 11: 1-10
• 22 Kolho KL, Korpela K, Jaakkola T. et al. Fecal Microbiota in Pediatric Inflammatory Bowel Disease and Its Relation to Inflammation. The American journal of gastroenterology 2015; 110: 921-930
• 23 Shaw KA, Bertha M, Hofmekler T. et al. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome medicine 2016; 8: 75
• 24 Chu Y, Jiang M, Xu B. et al. Specific changes of enteric mycobiota and virome in inflammatory bowel disease. J Dig Dis 2018; 19: 2-7 . doi:10.1111/1751-2980.12570
• 25 Aniwan S, Tremaine WJ, Raffals LE. et al. Antibiotic use and new-onset inflammatory bowel disease in Olmsted County, Minnesota: a population-based case-control study. J Crohns Colitis 2018; 12: 137-144 . doi:10.1093/ecco-jcc/jjx135
• 26 Imhann F, Vich VilaA, Bonder MJ. et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 2018; 67: 108-119
• 27 Taurog JD, Richardson JA, Croft JT. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. The Journal of experimental medicine 1994; 180: 2359-2364
• 28 Sellon RK, Tonkonogy S, Schultz M. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infection and immunity 1998; 66: 5224-5231
• 29 Hoentjen F, Harmsen HJ, Braat H. et al. Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice. Gut 2003; 52: 1721-1727
• 30 Harper PH, Lee EC, Kettlewell MG. et al. Role of the faecal stream in the maintenance of Crohn’s colitis. Gut 1985; 26: 279-284
• 31 Rutgeerts P, Goboes K, Peeters M. et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991; 338: 771-774
• 32 Prantera C, Lochs H, Grimaldi M. et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology 2012; 142: 473-481 e474
• 33 Lepage P, Hasler R, Spehlmann ME. et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011; 141: 227-236
• 34 Hakansson A, Tormo-Badia N, Baridi A. et al. Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice. Clinical and experimental medicine 2015; 15: 107-120
• 35 Walters WA, Xu Z, Knight R. Meta-analyses of human gut microbes associated with obesity and IBD. FEBS letters 2014; 588: 4223-4233
• 36 Manichanh C, Rigottier-Gois L, Bonnaud E. et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 2006; 55: 205-211
• 37 Frank DN, St Amand AL, Feldman RA. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 13780-13785
• 38 McLaughlin SD, Walker AW, Churcher C. et al. The bacteriology of pouchitis: a molecular phylogenetic analysis using 16S rRNA gene cloning and sequencing. Annals of surgery 2010; 252: 90-98
• 39 Narula N, Kassam Z, Yuan Y. et al. Systematic Review and Meta-analysis: Fecal Microbiota Transplantation for Treatment of Active Ulcerative Colitis. Inflammatory bowel diseases 2017; 23: 1702-1709
• 40 Keshteli AH, Millan B, Madsen KL. Pretreatment with antibiotics may enhance the efficacy of fecal microbiota transplantation in ulcerative colitis: a meta-analysis. Mucosal immunology 2017; 10: 565-566
• 41 Allegretti JR, Kassam Z, Carrellas M. et al. Fecal Microbiota Transplantation in Patients With Primary Sclerosing Cholangitis: A Pilot Clinical Trial. The American journal of gastroenterology 2019; DOI: 10.14309/ajg.0000000000000115.
• 42 Sood A, Mahajan R, Juyal G. et al. Efficacy of fecal microbiota therapy in steroid dependent ulcerative colitis: a real world intention-to-treat analysis. Intestinal research 2019; 17: 78-86
• 43 Rossen NG, Fuentes S, van der Spek MJ. et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology 2015; 149: 110-118 e114
• 44 Moayyedi P, Surette MG, Kim PT. et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015; 149: 102-109 e106
• 45 Paramsothy S, Kamm MA, Kaakoush NO. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017; 389: 1218-1228 . doi:10.1016/S0140-6736(17)30182-4
• 46 Costello SP, Hughes PA, Waters O. et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. Jama 2019; 321: 156-164
• 47 Vermeire S, Joossens M, Verbeke K. et al. Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease. Journal of Crohn’s & colitis 2016; 10: 387-394
• 48 Siegmund B. Is intensity the solution for FMT in ulcerative colitis?. Lancet 2017; DOI: 10.1016/S0140-6736(17)30313-6.
• 49 Nishida A, Imaeda H, Ohno M. et al. Efficacy and safety of single fecal microbiota transplantation for Japanese patients with mild to moderately active ulcerative colitis. Journal of gastroenterology 2017; 52: 476-482
• 50 Cao Y, Zhang B, Wu Y. et al. The Value of Fecal Microbiota Transplantation in the Treatment of Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis. Gastroenterology research and practice 2018; 2018: 5480961
• 51 Fischer M, Kao D, Kelly C. et al. Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease. Inflammatory bowel diseases 2016; 22: 2402-2409
• 52 Allegretti J, Eysenbach LM, El-Nachef N. et al. The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease: Past, Present, and Future. Inflammatory bowel diseases 2017; 23: 1710-1717
• 53 Fairhurst NG, Travis SPL. Why is it so difficult to evaluate faecal microbiota transplantation as a treatment for ulcerative colitis?. Intestinal research 2018; 16: 209-215
• 54 Kump P, Wurm P, Grochenig HP. et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Alimentary pharmacology & therapeutics 2018; 47: 67-77
• 55 Dicksved J, Halfvarson J, Rosenquist M. et al. Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. The ISME journal 2008; 2: 716-727
• 56 Zhou S, Xu R, He F. et al. Diversity of Gut Microbiota Metabolic Pathways in 10 Pairs of Chinese Infant Twins. PloS one 2016; 11: e0161627
• 57 Mizuno S, Nanki K, Matsuoka K. et al. Single fecal microbiota transplantation failed to change intestinal microbiota and had limited effectiveness against ulcerative colitis in Japanese patients. Intestinal research 2017; 15: 68-74
• 58 Costello S, Waters O, Bryant R. et al. Short duration, low intensity pooled faecal microbiota transplantation induces remission in patients with mild-moderately active ulcerative colitis: a randomised controlled trial. Journal of Crohn’s and Colitis 2017; 11/S1: S23
• 59 Kao D, Roach B, Silva M. et al. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. Jama 2017; 318: 1985-1993
• 60 Ott SJ, Waetzig GH, Rehman A. et al. Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients With Clostridium difficile Infection. Gastroenterology 2017; 152: 799-811 e797
• 61 Vermeire S, Jossens M, Verbeke K. et al. Pilot study on the safety and efficacy of faecal microbiota transplantation in refractory Crohn’s disease. Gastroenterology 2012; 142: S360
• 62 Angelberger S, Reinisch W, Makristathis A. et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. The American journal of gastroenterology 2013; 108: 1620-1630
• 63 Kump PK, Grochenig HP, Lackner S. et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflammatory bowel diseases 2013; 19: 2155-2165
• 64 Kunde S, Pham A, Bonczyk S. et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. Journal of pediatric gastroenterology and nutrition 2013; 56: 597-601
• 65 Suskind D, Wahbeh G, Vendetoulli H. et al. Fecal microbial transplant in pediatric Crohn’s disease. Gastroenterology 2014; 146: S836
• 66 Vaughn BP, Gevers D, Ting A. et al. Fecal microbiota transplantation induces early improvement in symptoms in patients with active Crohn’s disease. Gastroenterology 2014; 2104: S591-S592
• 67 Cui B, Feng Q, Wang H. et al. Fecal microbiota transplantation through mid-gut for refractory Crohn’s disease: safety, feasibility, and efficacy trial results. Journal of gastroenterology and hepatology 2015; 30: 51-58
• 68 Cui B, Li P, Xu L. et al. Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis. Journal of translational medicine 2015; 13: 298
• 69 Suskind DL, Brittnacher MJ, Wahbeh G. et al. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Crohn’s disease. Inflammatory bowel diseases 2015; 21: 556-563
• 70 Ren R, Sun G, Yang Y. et al. A pilot study of treating ulcerative colitis with fecal microbiota transplantation. Zhonghua Nei Ke Za Zhi 2015; 54: 411-415
• 71 Suskind DL, Singh N, Nielson H. et al. Fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. Journal of pediatric gastroenterology and nutrition 2015; 60: 27-29
• 72 Vaughn BP, Vatanen T, Allegretti JR. et al. Increased Intestinal Microbial Diversity Following Fecal Microbiota Transplant for Active Crohn’s Disease. Inflammatory bowel diseases 2016; 22: 2182-2190
• 73 Wei Y, Gong J, Zhu W. et al. Pectin enhances the effect of fecal microbiota transplantation in ulcerative colitis by delaying the loss of diversity of gut flora. BMC microbiology 2016; 16: 255
• 74 Zhang T, Cui B, Li P. et al. Short-Term Surveillance of Cytokines and C-Reactive Protein Cannot Predict Efficacy of Fecal Microbiota Transplantation for Ulcerative Colitis. PloS one 2016; 11: e0158227
• 75 Karolewska-Bochenek K, Grzesiowski P, Banaszkiewicz A. et al. A Two-Week Fecal Microbiota Transplantation Course in Pediatric Patients with Inflammatory Bowel Disease. Advances in experimental medicine and biology 2018; 1047: 81-87