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The microbiota and the gut–liver axis in primary sclerosing cholangitis

Nature Reviews Gastroenterology & Hepatology volume 20, pages 135–154 (2023)Cite this article

Subjects

Abstract

Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut–liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut–liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut–liver axis.

Key points

  • The close association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) makes PSC a prototype model disease for exploring the gut–liver axis.

  • Clinical data suggest that intestinal inflammation, an intact colon and antibiotics might influence the disease course of sclerosing cholangitis both before and after liver transplantation.

  • The gut microbiota composition in PSC differs from that of healthy individuals as controls and from those with IBD without PSC, but confounding factors and the potential influence of disease stage and IBD activity are so far understudied.

  • Experimental models suggest that the gut microbiota influences sclerosing cholangitis, with both harmful and beneficial effects having been identified.

  • The relative importance of individual microorganisms (‘pathobionts’) versus specific by-products of microbial activity (microbial metabolites) in PSC development is currently unknown.

  • The current sum of evidence provides a strong rationale for clinical trials of therapies that target the gut in PSC.

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Fig. 1: The gut–liver axis concept in primary sclerosing cholangitis.
Fig. 2: Confounders in the study of the gut microbiota in PSC.
Fig. 3: The enterohepatic circulation of bile acids and other compounds.
Fig. 4: Gut barrier function and possible disturbances in PSC–IBD.
Fig. 5: Composition of lymphocyte populations in liver and gut in humans and mice.

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References

  1. Karlsen, T. H., Folseraas, T., Thorburn, D. & Vesterhus, M. Primary sclerosing cholangitis–a comprehensive review. J. Hepatol. 67, 1298–1323 (2017).

    Article  PubMed  Google Scholar 

  2. Weismuller, T. J. et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 152, 1975–1984 (2017).

    Article  PubMed  Google Scholar 

  3. Boonstra, K. et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 58, 2045–2055 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Karlsen, T. H., Schrumpf, E. & Boberg, K. M. Update on primary sclerosing cholangitis. Dig. Liver Dis. 42, 390–400 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Jiang, X. & Karlsen, T. H. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat. Rev. Gastroenterol. Hepatol. 14, 279–295 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Ji, S. G. et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat. Genet. 49, 269–273 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Liu, J. Z. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 45, 670–675 (2013). Key study delineating the autoimmune genetic architecture of PSC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Peng, X. et al. Immunosuppressive agents for the treatment of primary sclerosing cholangitis: a systematic review and meta-analysis. Dig. Dis. 35, 478–485 (2017).

    Article  PubMed  Google Scholar 

  9. Albillos, A., de Gottardi, A. & Rescigno, M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J. Hepatol. 72, 558–577 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Iliev, I. D. & Cadwell, K. Effects of intestinal fungi and viruses on immune responses and inflammatory bowel diseases. Gastroenterology 160, 1050–1066 (2021).

    Article  CAS  PubMed  Google Scholar 

  11. Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. de Vries, E. et al. Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma. Liver Int. 40, 3042–3050 (2020).

    Article  PubMed  Google Scholar 

  13. Mouchli, M. A. et al. Natural history of established and de novo inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Inflamm. Bowel Dis. 24, 1074–1081 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lunder, A. K. et al. Prevalence of sclerosing cholangitis, detected by magnetic resonance cholangiography, in patients with long-term inflammatory bowel disease. Gastroenterology 151, 660–669 (2016). First study to show that the prevalence of sclerosing cholangitis-like changes on MRC are more common than clinically overt PSC.

    Article  PubMed  Google Scholar 

  15. Broome, U. & Bergquist, A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin. Liver Dis. 26, 31–41 (2006).

    Article  PubMed  Google Scholar 

  16. Marelli, L. et al. Does the severity of primary sclerosing cholangitis influence the clinical course of associated ulcerative colitis? Gut 60, 1224–1228 (2011).

    Article  PubMed  Google Scholar 

  17. Navaneethan, U. et al. Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis. Clin. Gastroenterol. Hepatol. 10, 540–546 (2012).

    Article  PubMed  Google Scholar 

  18. Boden, R. W., Rankin, J. G., Goulston, S. J. & Morrow, W. The liver in ulcerative colitis: the significance of raised serum-alkaline-phosphatase levels. Lancet 2, 245–248 (1959).

    Article  CAS  PubMed  Google Scholar 

  19. Rankin, J. G., Boden, R. W., Goulston, S. J. & Morrow, W. The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. Lancet 2, 1110–1112 (1959).

    Article  CAS  PubMed  Google Scholar 

  20. Farkkila, M. et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 40, 1379–1386 (2004). First randomized clinical trial of antibiotics in PSC.

    Article  PubMed  Google Scholar 

  21. Tabibian, J. H. et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis–a pilot study. Aliment. Pharmacol. Ther. 37, 604–612 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Cangemi, J. R. et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 96, 790–794 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Martin, F. M. et al. Surgical aspects of sclerosing cholangitis. Results in 178 patients. Ann. Surg. 212, 551–556 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nordenvall, C. et al. Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients. Aliment. Pharmacol. Ther. 47, 238–245 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Vera, A. et al. Risk factors for recurrence of primary sclerosing cholangitis of liver allograft. Lancet 360, 1943–1944 (2002).

    Article  PubMed  Google Scholar 

  26. Graziadei, I. W. et al. Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology 29, 1050–1056 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Steenstraten, I. C. et al. Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation. Aliment. Pharmacol. Ther. 49, 636–643 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Peverelle, M., Paleri, S., Hughes, J., De Cruz, P. & Gow, P. J. Activity of inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis predicts poorer clinical outcomes. Inflamm. Bowel Dis. 26, 1901–1908 (2020).

    Article  PubMed  Google Scholar 

  29. Trivedi, P. J. et al. The impact of ileal pouch–anal anastomosis on graft survival following liver transplantation for primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 48, 322–332 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Davies, Y. K. et al. Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case Rep. Transpl. 2013, 314292 (2013).

    Google Scholar 

  31. Hey, P., Lokan, J., Johnson, P. & Gow, P. Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation. BMJ Case Rep. 2017, bcr2017221165 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in IL10−/− mice. Nature 487, 104–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schwartz, D. J., Langdon, A. E. & Dantas, G. Understanding the impact of antibiotic perturbation on the human microbiome. Genome Med. 12, 82 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Acharya, C. & Bajaj, J. S. Chronic liver diseases and the microbiome — translating our knowledge of gut microbiota to management of chronic liver disease. Gastroenterology 160, 556–572 (2021).

    Article  PubMed  Google Scholar 

  36. Wang, J. et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 48, 1396–1406 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ruhlemann, M. C. et al. Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome. Nat. Genet. 53, 147–155 (2021).

    Article  PubMed  Google Scholar 

  38. Lopera-Maya, E. A. et al. Effect of host genetics on the gut microbiome in 7738 participants of the Dutch Microbiome Project. Nat. Genet. 54, 143–151 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Qin, Y. et al. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat. Genet. 54, 134–142 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xu, Z. & Knight, R. Dietary effects on human gut microbiome diversity. Br. J. Nutr. 113 (Suppl.), 1–5 (2015).

    Article  Google Scholar 

  42. Vujkovic-Cvijin, I. et al. Host variables confound gut microbiota studies of human disease. Nature 587, 448–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yap, C. X. et al. Autism-related dietary preferences mediate autism–gut microbiome associations. Cell 184, 5916–5931 (2021). Key study in highlighting the importance of confounding factors in assessing dietary impact on the gut microbiome.

    Article  CAS  PubMed  Google Scholar 

  44. de Vries, E. M. et al. Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: an international cohort study. Hepatology 65, 907–919 (2017).

    Article  PubMed  Google Scholar 

  45. Mazhar, A. & Russo, M. W. Systematic review: non-invasive prognostic tests for primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 53, 774–783 (2021).

    PubMed  Google Scholar 

  46. Fairfield, B. & Schnabl, B. Gut dysbiosis as a driver in alcohol-induced liver injury. JHEP Rep. 3, 100220 (2021).

    Article  PubMed  Google Scholar 

  47. Aron-Wisnewsky, J. et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat. Rev. Gastroenterol. Hepatol. 17, 279–297 (2020).

    Article  PubMed  Google Scholar 

  48. Iwasawa, K. et al. Characterisation of the faecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis. Gut 66, 1344–1346 (2016).

    Article  PubMed  Google Scholar 

  49. Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619 (2017). First DNA-based study of the faecal microbiota in people with PSC.

    Article  PubMed  Google Scholar 

  50. Sabino, J. et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65, 1681–1689 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Bajer, L. et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J. Gastroenterol. 23, 4548–4558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ruhlemann, M. et al. Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis. Aliment. Pharmacol. Ther. 50, 580–589 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lemoinne, S. et al. Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis. Gut 69, 92–102 (2019).

    Article  PubMed  Google Scholar 

  54. Lapidot, Y. et al. Alterations of the salivary and fecal microbiome in patients with primary sclerosing cholangitis. Hepatol. Int. 15, 191–201 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Liu, Q. et al. Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis. Gut 71, 899–909 (2022).

    Article  PubMed  Google Scholar 

  56. Kummen, M. et al. Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis. Gastroenterology 160, 1784–1798 (2021).

    Article  CAS  PubMed  Google Scholar 

  57. Kevans, D. et al. Characterization of intestinal microbiota in ulcerative colitis patients with and without primary sclerosing cholangitis. J. Crohns Colitis 10, 330–337 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Torres, J. et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 43, 790–801 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rossen, N. G. et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J. Crohns Colitis 9, 342–348 (2015). First DNA-based study of the mucosal microbiota in people with PSC.

    Article  PubMed  Google Scholar 

  60. Quraishi, M. N. et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut 66, 386–388 (2017).

    Article  PubMed  Google Scholar 

  61. Iwasawa, K. et al. Dysbiosis of the salivary microbiota in pediatric-onset primary sclerosing cholangitis and its potential as a biomarker. Sci. Rep. 8, 5480 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Liwinski, T. et al. Alterations of the bile microbiome in primary sclerosing cholangitis. Gut 69, 665–672 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Pereira, P. et al. Bile microbiota in primary sclerosing cholangitis: impact on disease progression and development of biliary dysplasia. PLoS ONE 12, e0182924 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kummen, M. et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J. Am. Coll. Cardiol. 71, 1184–1186 (2018).

    Article  PubMed  Google Scholar 

  65. Nowak, P. et al. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS 29, 2409–1418 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Jorgensen, S. F. et al. Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. Mucosal Immunol. 9, 1455–1465 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Kostic, A. D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tang, R. et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67, 534–541 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Wei, Y. et al. Alterations of gut microbiome in autoimmune hepatitis. Gut 69, 569–577 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Blaser, M. J. & Falkow, S. What are the consequences of the disappearing human microbiota? Nat. Rev. Microbiol. 7, 887–894 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liwinski, T. et al. A disease-specific decline of the relative abundance of Bifidobacterium in patients with autoimmune hepatitis. Aliment. Pharmacol. Ther. 51, 1417–1428 (2020).

    Article  CAS  PubMed  Google Scholar 

  72. Abe, K. et al. Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease. PLoS ONE 13, e0198757 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zhang, Y., Xu, J., Wang, X., Ren, X. & Liu, Y. Changes of intestinal bacterial microbiota in coronary heart disease complicated with nonalcoholic fatty liver disease. BMC Genomics 20, 862 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Chen, Z. et al. Featured gut microbiomes associated with the progression of chronic hepatitis B disease. Front. Microbiol. 11, 383 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Wei, X. et al. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol. 13, 175 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Reddel, S. et al. A parallel tracking of salivary and gut microbiota profiles can reveal maturation and interplay of early life microbial communities in healthy infants. Microorganisms 10, 468 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chalmers, N. I., Palmer, R. J. Jr, Cisar, J. O. & Kolenbrander, P. E. Characterization of a Streptococcus sp.–Veillonella sp. community micromanipulated from dental plaque. J. Bacteriol. 190, 8145–8154 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gibbons, R. J., Socransky, S. S. & Kapsimalis, B. Establishment of human indigenous bacteria in germ-free mice. J. Bacteriol. 88, 1316–1323 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vieira-Silva, S. et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat. Microbiol. 4, 1826–1831 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Ruhlemann, M. C. et al. Gut mycobiome of primary sclerosing cholangitis patients is characterised by an increase of Trichocladium griseum and Candida species. Gut 69, 1890–1892 (2019).

    Article  PubMed  Google Scholar 

  81. Chu, H. et al. The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease. J. Hepatol. 72, 391–400 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Rudolph, G. et al. Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis. J. Hepatol. 51, 149–155 (2009).

    Article  PubMed  Google Scholar 

  83. Bjornsson, E. S., Kilander, A. F. & Olsson, R. G. Bile duct bacterial isolates in primary sclerosing cholangitis and certain other forms of cholestasis — a study of bile cultures from ERCP. Hepatogastroenterology 47, 1504–1508 (2000).

    CAS  PubMed  Google Scholar 

  84. Folseraas, T. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J. Hepatol. 57, 366–375 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zimmer, C. L. et al. A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells. Sci. Transl Med. 13, eabb3107 (2021).

    Article  CAS  PubMed  Google Scholar 

  86. Valestrand, L. et al. Bile from patients with primary sclerosing cholangitis contains mucosal-associated invariant T-cell antigens. Am. J. Pathol. 192, 629–641 (2022).

    Article  CAS  PubMed  Google Scholar 

  87. Valestrand, L. et al. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells. Clin. Exp. Immunol. 203, 304–314 (2021).

    Article  CAS  PubMed  Google Scholar 

  88. D’Amico, F. et al. Bile microbiota in liver transplantation: proof of concept using gene amplification in a heterogeneous clinical scenario. Front. Surg. 8, 621525 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Molinero, N. et al. The human gallbladder microbiome is related to the physiological state and the biliary metabolic profile. Microbiome 7, 100 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Acharya, C. & Bajaj, J. S. Altered microbiome in patients with cirrhosis and complications. Clin. Gastroenterol. Hepatol. 17, 307–321 (2019).

    Article  PubMed  Google Scholar 

  91. Bushyhead, D. & Quigley, E. M. M. Small intestinal bacterial overgrowth pathophysiology and its implications for definition and management. Gastroenterology 163, 593–607 (2022).

    Article  PubMed  Google Scholar 

  92. Pittayanon, R. et al. Differences in gut microbiota in patients with vs without inflammatory bowel diseases: a systematic review. Gastroenterology 158, 930–946 (2020).

    Article  PubMed  Google Scholar 

  93. Lichtman, S. N., Keku, J., Clark, R. L., Schwab, J. H. & Sartor, R. B. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology 13, 766–772 (1991). First experimental evidence of an impact of the gut microbiota on development of sclerosing cholangitis.

    Article  CAS  PubMed  Google Scholar 

  94. Lichtman, S. N., Keku, J., Schwab, J. H. & Sartor, R. B. Evidence for peptidoglycan absorption in rats with experimental small bowel bacterial overgrowth. Infect. Immun. 59, 555–562 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sakiani, S., Kleiner, D. E., Heller, T. & Koh, C. Hepatic manifestations of cystic fibrosis. Clin. Liver Dis. 23, 263–277 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Fiorotto, R. et al. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology 141, 1498–1508 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Debray, D. et al. Diet-induced dysbiosis and genetic background synergize with cystic fibrosis transmembrane conductance regulator deficiency to promote cholangiopathy in mice. Hepatol. Commun. 2, 1533–1549 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Henckaerts, L. et al. Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis. J. Hepatol. 50, 150–157 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Schrumpf, E. et al. The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation. J. Hepatol. 66, 382–389 (2017).

    Article  PubMed  Google Scholar 

  100. Tabibian, J. H. et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis in mice. Hepatology 63, 185–196 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Schneider, K. M. et al. Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nat. Metab. 3, 1228–1241 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Tedesco, D. et al. Alterations in intestinal microbiota lead to production of interleukin 17 by intrahepatic gammadelta T-cell receptor-positive cells and pathogenesis of cholestatic liver disease. Gastroenterology 154, 2178–2193 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Liao, L. et al. Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis. Gut 68, 1477–1492 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17, 588–606 (2018).

    Article  CAS  PubMed  Google Scholar 

  106. Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

    Article  PubMed  Google Scholar 

  107. Nakamoto, N. et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat. Microbiol. 4, 492–503 (2019). First study to highlight a potential role for specific pathobionts in pathogenesis of PSC.

    Article  CAS  PubMed  Google Scholar 

  108. Katt, J. et al. Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology 58, 1084–1093 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Kunzmann, L. K. et al. Monocytes as potential mediators of pathogen-induced T-helper 17 differentiation in patients with primary sclerosing cholangitis (PSC). Hepatology 72, 1310–1326 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Poch, T. et al. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis. J. Hepatol. 75, 414–423 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Johansson, M. E. & Hansson, G. C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 16, 639–649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Spadoni, I. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 350, 830–834 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Wang, L. et al. Methods to determine intestinal permeability and bacterial translocation during liver disease. J. Immunol. Methods 421, 44–53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Camilleri, M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 68, 1516–1526 (2019).

    Article  CAS  PubMed  Google Scholar 

  115. Bjornsson, E. et al. Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis. Scand. J. Gastroenterol. 40, 1090–1094 (2005).

    Article  PubMed  Google Scholar 

  116. Dhillon, A. K. et al. Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis. Liver Int. 39, 371–381 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. Bellot, P., Frances, R. & Such, J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int. 33, 31–39 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Bossen, L. et al. Circulating macrophage activation markers predict transplant-free survival in patients with primary sclerosing cholangitis. Clin. Transl Gastroenterol. 12, e00315 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Krautkramer, K. A., Fan, J. & Backhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat. Rev. Microbiol. 19, 77–94 (2021).

    Article  CAS  PubMed  Google Scholar 

  120. Schirmer, M., Garner, A., Vlamakis, H. & Xavier, R. J. Microbial genes and pathways in inflammatory bowel disease. Nat. Rev. Microbiol. 17, 497–511 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bell, L. N., Wulff, J., Comerford, M., Vuppalanchi, R. & Chalasani, N. Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis. Liver Int. 35, 263–274 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Tietz-Bogert, P. S. et al. Metabolomic profiling of portal blood and bile reveals metabolic signatures of primary sclerosing cholangitis. Int. J. Mol. Sci. 19, 3188 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Hassan, M. et al. Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals. J. Hepatol. 73, 628–639 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Reich, M. et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 65, 487–501 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Reich, M. et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J. Hepatol. 75, 634–646 (2021).

    Article  CAS  PubMed  Google Scholar 

  128. Khurana, S., Raufman, J. P. & Pallone, T. L. Bile acids regulate cardiovascular function. Clin. Transl Sci. 4, 210–218 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Fuchs, C. D. & Trauner, M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat. Rev. Gastroenterol. Hepatol. 19, 432–450 (2022).

    Article  CAS  PubMed  Google Scholar 

  130. Schaap, F. G., Trauner, M. & Jansen, P. L. Bile acid receptors as targets for drug development. Nat. Rev. Gastroenterol. Hepatol. 11, 55–67 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Jia, W., Xie, G. & Jia, W. Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 15, 111–128 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Banales, J. M. et al. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16, 269–281 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Fischer, S., Beuers, U., Spengler, U., Zwiebel, F. M. & Koebe, H. G. Hepatic levels of bile acids in end-stage chronic cholestatic liver disease. Clin. Chim. Acta 251, 173–186 (1996).

    Article  CAS  PubMed  Google Scholar 

  134. Trottier, J. et al. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Dig. Liver Dis. 44, 303–310 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Midtvedt, T. Microbial bile acid transformation. Am. J. Clin. Nutr. 27, 1341–1347 (1974).

    Article  CAS  PubMed  Google Scholar 

  136. Heinken, A. et al. Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease. Microbiome 7, 75 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Torres, J. et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol. J. 6, 112–122 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Vaughn, B. P. et al. A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis. Clin. Exp. Gastroenterol. 12, 9–19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Duboc, H. et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62, 531–539 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Quraishi, M. N. et al. A pilot integrative analysis of colonic gene expression, gut microbiota and immune infiltration in primary sclerosing cholangitis-inflammatory bowel disease: association of disease with bile acid pathways. J. Crohns Colitis 30, 935–947 (2020).

    Article  Google Scholar 

  142. Roediger, W. E. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83, 424–429 (1982).

    Article  CAS  PubMed  Google Scholar 

  143. Marino, E. et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 18, 552–562 (2017).

    Article  CAS  PubMed  Google Scholar 

  144. Imhann, F. et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67, 108–119 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Zhuang, X. et al. Systematic review and meta-analysis: short-chain fatty acid characterization in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 25, 1751–1763 (2019).

    Article  PubMed  Google Scholar 

  146. Agus, A., Planchais, J. & Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716–724 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Dhillon, A. K. et al. Associations of neopterin and kynurenine-tryptophan ratio with survival in primary sclerosing cholangitis. Scand. J. Gastroenterol. 56, 443–452 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Nikolaus, S. et al. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology 153, 1504–1516 e1502 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Gallagher, K., Catesson, A., Griffin, J. L., Holmes, E. & Williams, H. R. T. Metabolomic analysis in inflammatory bowel disease: a systematic review. J. Crohns Colitis 15, 813–826 (2020).

    Article  Google Scholar 

  150. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Natividad, J. M. et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 28, 737–749 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. D’Onofrio, F. et al. Indole-3-carboxaldehyde restores gut mucosal integrity and protects from liver fibrosis in murine sclerosing cholangitis. Cells 10, 1622 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. ter Borg, P. C., Fekkes, D., Vrolijk, J. M. & van Buuren, H. R. The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and primary sclerosing cholangitis. BMC Gastroenterol. 5, 11 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Magnusdottir, S., Ravcheev, D., de Crecy-Lagard, V. & Thiele, I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front. Genet. 6, 148 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Henderson, J. M., Codner, M. A., Hollins, B., Kutner, M. H. & Merrill, A. H. The fasting B6 vitamer profile and response to a pyridoxine load in normal and cirrhotic subjects. Hepatology 6, 464–471 (1986).

    Article  CAS  PubMed  Google Scholar 

  157. Selhub, J. et al. Dietary vitamin B6 intake modulates colonic inflammation in the IL10−/− model of inflammatory bowel disease. J. Nutr. Biochem. 24, 2138–2143 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Koeth, R. A. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kummen, M. et al. Elevated trimethylamine-N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function. United European Gastroenterol. J. 5, 532–541 (2017).

    Article  CAS  PubMed  Google Scholar 

  161. Lin, J. K. & Ho, Y. S. Hepatotoxicity and hepatocarcinogenicity in rats fed squid with or without exogenous nitrite. Food Chem. Toxicol. 30, 695–702 (1992).

    Article  CAS  PubMed  Google Scholar 

  162. Sehgal, R. et al. Indole-3-propionic acid, a gut-derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients 13, 3509 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Andrahennadi, S., Sami, A., Manna, M., Pauls, M. & Ahmed, S. Current landscape of targeted therapy in hormone receptor-positive and HER2-negative breast cancer. Curr. Oncol. 28, 1803–1822 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Vesterhus, M. & Karlsen, T. H. Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J. Gastroenterol. 55, 588–614 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Ponsioen, C. Y., Lindor, K. D., Mehta, R. & Dimick-Santos, L. Design and endpoints for clinical trials in primary sclerosing cholangitis. Hepatology 68, 1174–1188 (2018).

    Article  PubMed  Google Scholar 

  167. Vleggaar, F. P., Monkelbaan, J. F. & van Erpecum, K. J. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur. J. Gastroenterol. Hepatol. 20, 688–692 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Rastall, R. A. et al. Structure and function of non-digestible carbohydrates in the gut microbiome. Benef. Microbes 13, 95–168 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. Trakman, G. L. et al. Diet and gut microbiome in gastrointestinal disease. J. Gastroenterol. Hepatol. 37, 237–245 (2021).

    Article  PubMed  Google Scholar 

  171. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Andersen, I. M. et al. Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 12, 1019–1028 (2014).

    Article  PubMed  Google Scholar 

  173. Friedrich, K. et al. Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation. J. Gastroenterol. Hepatol. 31, 1470–1475 (2016).

    Article  PubMed  Google Scholar 

  174. Lammert, C. et al. Reduced coffee consumption among individuals with primary sclerosing cholangitis but not primary biliary cirrhosis. Clin. Gastroenterol. Hepatol. 12, 1562–1568 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Fitzpatrick, J. A., Melton, S. L., Yao, C. K., Gibson, P. R. & Halmos, E. P. Dietary management of adults with IBD — the emerging role of dietary therapy. Nat. Rev. Gastroenterol. Hepatol. 19, 652–669 (2022).

    Article  PubMed  Google Scholar 

  176. Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).

    Article  CAS  PubMed  Google Scholar 

  177. Mendes-Soares, H. et al. Model of personalized postprandial glycemic response to food developed for an Israeli cohort predicts responses in Midwestern American individuals. Am. J. Clin. Nutr. 110, 63–75 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Davies, Y. K. et al. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J. Pediatr. Gastroenterol. Nutr. 47, 61–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Ali, A. H. et al. Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis. Scand. J. Gastroenterol. 55, 941–950 (2020).

    Article  CAS  PubMed  Google Scholar 

  180. Deneau, M. R. et al. Oral vancomycin, ursodeoxycholic acid, or no therapy for pediatric primary sclerosing cholangitis: a matched analysis. Hepatology 73, 1061–1073 (2021).

    Article  CAS  PubMed  Google Scholar 

  181. Rahimpour, S. et al. A triple blinded, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of oral vancomycin in primary sclerosing cholangitis: a pilot study. J. Gastrointestin. Liver Dis. 25, 457–464 (2016).

    Article  PubMed  Google Scholar 

  182. Vrieze, A. et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J. Hepatol. 60, 824–831 (2014).

    Article  CAS  PubMed  Google Scholar 

  183. Isaac, S. et al. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J. Antimicrob. Chemother. 72, 128–136 (2017).

    Article  CAS  PubMed  Google Scholar 

  184. de Chambrun, G. P. et al. Oral vancomycin induces sustained deep remission in adult patients with ulcerative colitis and primary sclerosing cholangitis. Eur. J. Gastroenterol. Hepatol. 30, 1247–1252 (2018).

    Article  PubMed  Google Scholar 

  185. Tan, L. Z. et al. Oral vancomycin induces clinical and mucosal remission of colitis in children with primary sclerosing cholangitis-ulcerative colitis. Gut 68, 1533–1535 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Dao, A. et al. Oral vancomycin induces and maintains remission of ulcerative colitis in the subset of patients with associated primary sclerosing cholangitis. Inflamm. Bowel Dis. 25, e90–e91 (2019).

    Article  PubMed  Google Scholar 

  187. Abarbanel, D. N. et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J. Clin. Immunol. 33, 397–406 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Silveira, M. G. et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am. J. Gastroenterol. 104, 83–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Tabibian, J. H. et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am. J. Ther. 24, e56–e63 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Hsu, C., Duan, Y., Fouts, D. E. & Schnabl, B. Intestinal virome and therapeutic potential of bacteriophages in liver disease. J. Hepatol. 75, 1465–1475 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Principi, N., Silvestri, E. & Esposito, S. Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front. Pharmacol. 10, 513 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Kredo-Russo, S. et al. Use of a bacteriophage cocktail for eradication of Klebsiella pneumoniae in primary sclerosing cholangitis. Hepatology 70, 18A (2019).

    Google Scholar 

  193. Duan, Y. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 575, 505–511 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Liu, X., Li, Y., Wu, K., Shi, Y. & Chen, M. Fecal microbiota transplantation as therapy for treatment of active ulcerative colitis: a systematic review and meta-analysis. Gastroenterol. Res. Pract. 2021, 6612970 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109 (2015).

    Article  PubMed  Google Scholar 

  196. Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    Article  PubMed  Google Scholar 

  198. Allegretti, J. R. et al. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial. Am. J. Gastroenterol. 114, 1071–1079 (2019). First clinical trial of FMT in PSC.

    Article  PubMed  Google Scholar 

  199. Ponsioen, C. Y. et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process. Hepatology 63, 1357–1367 (2016).

    Article  PubMed  Google Scholar 

  200. Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619 e616 (2017).

    Article  CAS  PubMed  Google Scholar 

  201. Fickert, P. et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J. Hepatol. 67, 549–558 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Konigshofer, P. et al. Nuclear receptors in liver fibrosis. Biochim. Biophys. Acta Mol. Basis Dis. 1867, 166235 (2021).

    Article  PubMed  Google Scholar 

  203. Gadaleta, R. M. & Moschetta, A. Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J. Hepatol. 75, 1440–1451 (2021).

    Article  CAS  PubMed  Google Scholar 

  204. Wahlstrom, A., Kovatcheva-Datchary, P., Stahlman, M., Backhed, F. & Marschall, H. U. Crosstalk between bile acids and gut microbiota and its impact on farnesoid X receptor signalling. Dig. Dis. 35, 246–250 (2017).

    Article  PubMed  Google Scholar 

  205. Kowdley, K. V. et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J. Hepatol. 73, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Friedman, E. S. et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid. Gastroenterology 155, 1741–1752 (2018).

    Article  CAS  PubMed  Google Scholar 

  207. Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68, 1574–1588 (2018).

    Article  CAS  PubMed  Google Scholar 

  208. Hirschfield, G. M. et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J. Hepatol. 70, 483–493 (2019).

    Article  CAS  PubMed  Google Scholar 

  209. Al-Dury, S. et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Sci. Rep. 8, 6658 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Hegade, V. S. et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 389, 1114–1123 (2017).

    Article  CAS  PubMed  Google Scholar 

  211. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02061540 (2022).

  212. Hruz, P. et al. Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis. Gut 55, 395–402 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Craddock, A. L. et al. Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am. J. Physiol. 274, G157–G169 (1998).

    CAS  PubMed  Google Scholar 

  214. Stokkeland, K., Hoijer, J., Bottai, M., Soderberg-Lofdal, K. & Bergquist, A. Statin use is associated with improved outcomes of patients with primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 17, 1860–1866 (2018).

    Article  PubMed  Google Scholar 

  215. Xu, J. et al. 5-Aminosalicylic acid alters the gut bacterial microbiota in patients with ulcerative colitis. Front. Microbiol. 9, 1274 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Tada, S., Ebinuma, H., Saito, H. & Hibi, T. Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. J. Gastroenterol. 41, 388–389 (2006).

    Article  PubMed  Google Scholar 

  217. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03561584 (2022).

  218. Hommes, D. W. et al. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J. Clin. Gastroenterol. 42, 522–526 (2008).

    Article  CAS  PubMed  Google Scholar 

  219. Epstein, M. P. & Kaplan, M. M. A pilot study of etanercept in the treatment of primary sclerosing cholangitis. Dig. Dis. Sci. 49, 1–4 (2004).

    Article  CAS  PubMed  Google Scholar 

  220. Tse, C. S., Loftus, E. V. Jr, Raffals, L. E., Gossard, A. A. & Lightner, A. L. Effects of vedolizumab, adalimumab and infliximab on biliary inflammation in individuals with primary sclerosing cholangitis and inflammatory bowel disease. Aliment. Pharmacol. Ther. 48, 190–195 (2018).

    Article  CAS  PubMed  Google Scholar 

  221. Caron, B. et al. Vedolizumab therapy is ineffective for primary sclerosing cholangitis in patients with inflammatory bowel disease: a GETAID multicentre cohort study. J. Crohns Colitis 13, 1239–1247 (2019).

    Article  PubMed  Google Scholar 

  222. Christensen, B. et al. Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment. Pharmacol. Ther. 47, 753–762 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Lynch, K. D. et al. Effects of vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases. Clin. Gastroenterol. Hepatol. 18, 179–187 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Laborda, T. J. et al. Vedolizumab therapy in children with primary sclerosing cholangitis: data from the pediatric primary sclerosing cholangitis consortium. J. Pediatr. Gastroenterol. Nutr. 71, 459–464 (2020).

    Article  CAS  PubMed  Google Scholar 

  225. Kolho, K. L. et al. Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation. Am. J. Gastroenterol. 110, 921–930 (2015).

    Article  PubMed  Google Scholar 

  226. Magnusson, M. K. et al. Anti-TNF therapy response in patients with ulcerative colitis is associated with colonic antimicrobial peptide expression and microbiota composition. J. Crohns Colitis 10, 943–952 (2016).

    Article  PubMed  Google Scholar 

  227. Ananthakrishnan, A. N. et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21, 603–610 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Hole, M. J. et al. A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation. Hepatology https://doi.org/10.1002/hep.32773 (2022).

    Article  Google Scholar 

  229. Furukawa, M. et al. Gut dysbiosis associated with clinical prognosis of patients with primary biliary cholangitis. Hepatol. Res. 50, 840–852 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Bajaj, J. S. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 60, 940–947 (2014).

    Article  CAS  PubMed  Google Scholar 

  231. Lou, J. et al. Fecal microbiomes distinguish patients with autoimmune hepatitis from healthy individuals. Front. Cell Infect. Microbiol. 10, 342 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Lv, L. X. et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ. Microbiol. 18, 2272–2286 (2016).

    Article  CAS  PubMed  Google Scholar 

  233. Bajaj, J. S. & Khoruts, A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J. Hepatol. 72, 1003–1027 (2020).

    Article  CAS  PubMed  Google Scholar 

  234. Li, B. et al. Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary Cholangitis. Gut Microbes 13, 1946366 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Zhang, H. et al. Bifidobacterium animalis ssp. Lactis 420 mitigates autoimmune hepatitis through regulating intestinal barrier and liver immune cells. Front. Immunol. 11, 569104 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Chen, W. et al. Comprehensive analysis of serum and fecal bile acid profiles and interaction with gut microbiota in primary biliary cholangitis. Clin. Rev. Allergy Immunol. 58, 25–38 (2020).

    Article  PubMed  Google Scholar 

  237. Kakiyama, G. et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J. Hepatol. 58, 949–955 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Feld, J. J., Meddings, J. & Heathcote, E. J. Abnormal intestinal permeability in primary biliary cirrhosis. Dig. Dis. Sci. 51, 1607–1613 (2006).

    Article  PubMed  Google Scholar 

  239. Pascual, S. et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology 50, 1482–1486 (2003).

    PubMed  Google Scholar 

  240. Cariello, R. et al. Intestinal permeability in patients with chronic liver diseases: its relationship with the aetiology and the entity of liver damage. Dig. Liver Dis. 42, 200–204 (2010).

    Article  PubMed  Google Scholar 

  241. Lin, R., Zhou, L., Zhang, J. & Wang, B. Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. Int. J. Clin. Exp. Pathol. 8, 5153–5160 (2015).

    PubMed  PubMed Central  Google Scholar 

  242. Zhang, H. et al. Leaky gut driven by dysbiosis augments activation and accumulation of liver macrophages via RIP3 signaling pathway in autoimmune hepatitis. Front. Immunol. 12, 624360 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Zhao, J. et al. Altered biliary epithelial cell and monocyte responses to lipopolysaccharide as a TLR ligand in patients with primary biliary cirrhosis. Scand. J. Gastroenterol. 46, 485–494 (2011).

    Article  CAS  PubMed  Google Scholar 

  244. Umemura, T. et al. Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis. Liver Int. 37, 897–905 (2017).

    Article  CAS  PubMed  Google Scholar 

  245. Fukui, H. Gut-liver axis in liver cirrhosis: how to manage leaky gut and endotoxemia. World J. Hepatol. 7, 425–442 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Raparelli, V. et al. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology 65, 571–581 (2017).

    Article  CAS  PubMed  Google Scholar 

  247. Jorgensen, K. K. et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm. Bowel Dis. 18, 536–545 (2012).

    Article  PubMed  Google Scholar 

  248. Manzano, M., Abadia-Molina, A. C., Garcia-Olivares, E., Gil, A. & Rueda, R. Absolute counts and distribution of lymphocyte subsets in small intestine of BALB/c mice change during weaning. J. Nutr. 132, 2757–2762 (2002).

    Article  CAS  PubMed  Google Scholar 

  249. Middendorp, S. & Nieuwenhuis, E. E. NKT cells in mucosal immunity. Mucosal Immunol. 2, 393–402 (2009).

    Article  CAS  PubMed  Google Scholar 

  250. Schmitz, F. et al. The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease. Gut 65, 1269–1278 (2016).

    Article  CAS  PubMed  Google Scholar 

  251. Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  252. Freitas-Lopes, M. A., Mafra, K., David, B. A., Carvalho-Gontijo, R. & Menezes, G. B. Differential location and distribution of hepatic immune cells. Cells 6, 48 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Rogler, G. Resolution of inflammation in inflammatory bowel disease. Lancet Gastroenterol. Hepatol. 2, 521–530 (2017).

    Article  PubMed  Google Scholar 

  254. Simoni, Y. & Newell, E. W. Dissecting human ILC heterogeneity: more than just three subsets. Immunology 153, 297–303 (2018).

    Article  CAS  PubMed  Google Scholar 

  255. Agace, W. W. & McCoy, K. D. Regionalized development and maintenance of the intestinal adaptive immune landscape. Immunity 46, 532–548 (2017).

    Article  CAS  PubMed  Google Scholar 

  256. Geremia, A. & Arancibia-Carcamo, C. V. Innate lymphoid cells in intestinal inflammation. Front. Immunol. 8, 1296 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Faria, A. M. C., Reis, B. S. & Mucida, D. Tissue adaptation: implications for gut immunity and tolerance. J. Exp. Med. 214, 1211–1226 (2017).

    Article  PubMed  Google Scholar 

  258. Van Acker, A. et al. A murine intestinal intraepithelial NKp46-negative innate lymphoid cell population characterized by group 1 properties. Cell Rep. 19, 1431–1443 (2017).

    Article  PubMed  Google Scholar 

  259. Bain, C. C. & Schridde, A. Origin, differentiation, and function of intestinal macrophages. Front. Immunol. 9, 2733 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Mayassi, T. & Jabri, B. Human intraepithelial lymphocytes. Mucosal Immunol. 11, 1281–1289 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Qiu, Z. & Sheridan, B. S. Isolating lymphocytes from the mouse small intestinal immune system. J. Vis. Exp. 132, 57281 (2018).

    Google Scholar 

  262. Sagebiel, A. F. et al. Tissue-resident Eomes+ NK cells are the major innate lymphoid cell population in human infant intestine. Nat. Commun. 10, 975 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  263. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  264. Dillon, S. M., Thompson, T. A., Christians, A. J., McCarter, M. D. & Wilson, C. C. Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults. Immun. Ageing 18, 6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Febbraio, M. A. & Karin, M. “Sweet death”: fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab. 33, 2316–2328 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Xue, R. et al. Bile acid receptors and the gut-liver axis in nonalcoholic fatty liver disease. Cells 10, 2806 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. De Muynck, K., Vanderborght, B., Van Vlierberghe, H. & Devisscher, L. The gut-liver axis in chronic liver disease: a macrophage perspective. Cells 10, 2959 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  268. Chen, Y. & Tian, Z. Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer. Cell Mol. Immunol. 18, 57–72 (2021).

    Article  CAS  PubMed  Google Scholar 

  269. Bozward, A. G., Ronca, V., Osei-Bordom, D. & Oo, Y. H. Gut-liver immune traffic: deciphering immune-pathogenesis to underpin translational therapy. Front. Immunol. 12, 711217 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Kronsten, V. T., Tranah, T. H., Pariante, C. & Shawcross, D. L. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J. Hepatol. 76, 665–680 (2021).

    Article  PubMed  Google Scholar 

  271. Nel, I., Bertrand, L., Toubal, A. & Lehuen, A. MAIT cells, guardians of skin and mucosa? Mucosal Immunol. 14, 803–814 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Schreurs, R. et al. Intestinal CD8+ T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities. Mucosal Immunol. 14, 605–614 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Brescia, P. & Rescigno, M. The gut vascular barrier: a new player in the gut-liver-brain axis. Trends Mol. Med. 27, 844–855 (2021).

    Article  CAS  PubMed  Google Scholar 

  274. Rebelos, E., Iozzo, P., Guzzardi, M. A., Brunetto, M. R. & Bonino, F. Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease. World J. Gastroenterol. 27, 4999–5018 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Stamataki, Z. & Swadling, L. The liver as an immunological barrier redefined by single-cell analysis. Immunology 160, 157–170 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Takikawa, H. & Manabe, T. Primary sclerosing cholangitis in Japan — analysis of 192 cases. J. Gastroenterol. 32, 134–137 (1997).

    Article  CAS  PubMed  Google Scholar 

  277. Tanaka, A. et al. Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan. J. Hepato-Biliary-Pancreat. Sci. 21, 43–50 (2014).

    Article  Google Scholar 

  278. Ang, T. L. et al. Clinical profile of primary sclerosing cholangitis in Singapore. J. Gastroenterol. Hepatol. 17, 908–913 (2002).

    Article  PubMed  Google Scholar 

  279. Escorsell, A. et al. Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J. Hepatol. 21, 787–791 (1994).

    Article  CAS  PubMed  Google Scholar 

  280. Franceschet, I. et al. Primary sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options. Eur. J. Gastroenterol. Hepatol. 28, 508–513 (2016).

    Article  CAS  PubMed  Google Scholar 

  281. Nardelli, M. J. et al. Clinical features and outcomes of primary sclerosing cholangitis in the highly admixed Brazilian population. Can. J. Gastroenterol. Hepatol. 2021, 7746401 (2021).

    PubMed  PubMed Central  Google Scholar 

  282. Wiesner, R. H. et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 10, 430–436 (1989).

    Article  CAS  PubMed  Google Scholar 

  283. Gudnason, H. O. et al. Primary sclerosing cholangitis in Iceland 1992–2012 [Icelandic]. Laeknabladid 105, 371–376 (2019).

    PubMed  Google Scholar 

  284. Bergquist, A. et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J. Hepatol. 36, 321–327 (2002).

    Article  PubMed  Google Scholar 

  285. Lindkvist, B., Benito de Valle, M., Gullberg, B. & Bjornsson, E. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology 52, 571–577 (2010).

    Article  PubMed  Google Scholar 

  286. Culver, E. L. et al. Prevalence and long-term outcome of sub-clinical primary sclerosing cholangitis in patients with ulcerative colitis. Liver Int. 40, 2744–2757 (2020).

    Article  CAS  PubMed  Google Scholar 

  287. Fausa, O., Schrumpf, E. & Elgjo, K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin. Liver Dis. 11, 31–39 (1991).

    Article  CAS  PubMed  Google Scholar 

  288. Loftus, E. V. Jr. et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 54, 91–96 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  289. Krugliak Cleveland, N. et al. Patients with ulcerative colitis and primary sclerosing cholangitis frequently have subclinical inflammation in the proximal colon. Clin. Gastroenterol. Hepatol. 16, 68–74 (2018).

    Article  PubMed  Google Scholar 

  290. Sorensen, J. O. et al. Inflammatory bowel disease with primary sclerosing cholangitis: a Danish population-based cohort study 1977–2011. Liver Int. 38, 532–541 (2018).

    Article  PubMed  Google Scholar 

  291. Trivedi, P. J. et al. Effects of primary sclerosing cholangitis on risks of cancer and death in people with inflammatory bowel disease, based on sex, race, and age. Gastroenterology 159, 915–928 (2020).

    Article  PubMed  Google Scholar 

  292. Altwegg, R. et al. Effectiveness and safety of anti-TNF therapy for inflammatory bowel disease in liver transplant recipients for primary sclerosing cholangitis: a nationwide case series. Dig. Liver Dis. 50, 668–674 (2018).

    Article  CAS  PubMed  Google Scholar 

  293. Hedin, C. R. H. et al. Effects of tumor necrosis factor antagonists in patients with primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 18, 2295–2304 (2020).

    Article  CAS  PubMed  Google Scholar 

  294. Wang, M. H. et al. Unique phenotypic characteristics and clinical course in patients with ulcerative colitis and primary sclerosing cholangitis: a multicenter US experience. Inflamm. Bowel Dis. 26, 774–779 (2019).

    Article  PubMed Central  Google Scholar 

  295. Soetikno, R. M., Lin, O. S., Heidenreich, P. A., Young, H. S. & Blackstone, M. O. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest. Endosc. 56, 48–54 (2002).

    Article  PubMed  Google Scholar 

  296. Shah, S. C. et al. High risk of advanced colorectal neoplasia in patients with primary sclerosing cholangitis associated with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 16, 1106–1113 (2018).

    Article  PubMed  Google Scholar 

  297. Karlsen, T. H. et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138, 1102–1111 (2010).

    Article  PubMed  Google Scholar 

  298. Hov, J. R., Boberg, K. M. & Karlsen, T. H. Autoantibodies in primary sclerosing cholangitis. World J. Gastroenterol. 14, 3781–3791 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Grant, A. J., Lalor, P. F., Salmi, M., Jalkanen, S. & Adams, D. H. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 359, 150–157 (2002).

    Article  PubMed  Google Scholar 

  300. Graham, J. J. et al. Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis. Hepatology 75, 518–530 (2022).

    Article  CAS  PubMed  Google Scholar 

  301. Trivedi, P. J. et al. Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity. J. Autoimmun. 68, 98–104 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Trivedi, P. J. et al. Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner. Gut 67, 1135–1145 (2017).

    Article  PubMed  Google Scholar 

  303. Henriksen, E. K. et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease. J. Hepatol. 66, 116–122 (2017).

    Article  CAS  PubMed  Google Scholar 

  304. Chung, B. K. et al. Gut and liver B cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease. Hepatol. Commun. 2, 956–967 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Puig, M. et al. Alterations in the HLA-B*57:01 immunopeptidome by flucloxacillin and immunogenicity of drug-haptenated peptides. Front. Immunol. 11, 629399 (2020).

    Article  CAS  PubMed  Google Scholar 

  306. Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713–717 (1998).

    Article  CAS  PubMed  Google Scholar 

  307. Jahnsen, F. L., Baekkevold, E. S., Hov, J. R. & Landsverk, O. J. Do long-lived plasma cells maintain a healthy microbiota in the gut? Trends Immunol. 39, 196–208 (2018).

    Article  CAS  PubMed  Google Scholar 

  308. Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Terjung, B. et al. p-ANCA in autoimmune liver disorders recognize human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 59, 808–816 (2010).

    Article  CAS  PubMed  Google Scholar 

  310. Op De Beeck, K. et al. Immune reactivity to beta-tubulin isotype 5 and vesicular integral-membrane protein 36 in patients with autoimmune gastrointestinal disorders. Gut 60, 1601–1602 (2011).

    Article  PubMed  Google Scholar 

  311. Hov, J. R. et al. Antineutrophil antibodies define clinical and genetic subgroups in primary sclerosing cholangitis. Liver Int. 37, 458–465 (2017).

    Article  CAS  PubMed  Google Scholar 

  312. Sowa, M. et al. Mucosal autoimmunity to cell-bound GP2 isoforms is a sensitive marker in PSC and associated with the clinical phenotype. Front. Immunol. 9, 1959 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  313. Jendrek, S. T. et al. Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 66, 137–144 (2017).

    Article  CAS  PubMed  Google Scholar 

  314. Tornai, T. et al. Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis. Sci. Rep. 8, 399 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  315. Wunsch, E. et al. Anti-glycoprotein 2 (anti-GP2) IgA and anti-neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3-ANCA): antibodies to predict severe disease, poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 53, 302–313 (2021).

    Article  CAS  PubMed  Google Scholar 

  316. Hase, K. et al. Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 462, 226–230 (2009).

    Article  CAS  PubMed  Google Scholar 

  317. von Seth, E. et al. Primary sclerosing cholangitis leads to dysfunction and loss of MAIT cells. Eur. J. Immunol. 48, 1997–2004 (2018).

    Article  Google Scholar 

  318. Olszak, T. et al. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 509, 497–502 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  319. Berntsen, N. L. et al. Natural killer T cells mediate inflammation in the bile ducts. Mucosal Immunol. 11, 1582–1590 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  320. Schrumpf, E. et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 62, 1249–1259 (2015).

    Article  CAS  PubMed  Google Scholar 

  321. Mehta, H., Lett, M. J., Klenerman, P. & Filipowicz Sinnreich, M. MAIT cells in liver inflammation and fibrosis. Semin. Immunopathol. 44, 429–444 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank K. Toverud (http://www.karitoverud.com/), P. Braadland (Institute of Clinical Medicine, University of Oslo) and X. Jiang (Norwegian PSC Research Center, Oslo University Hospital) for help in developing the original drafts of Fig. 1, Fig. 4 and Fig. 5, respectively.

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  1. Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway

    Johannes R. Hov & Tom H. Karlsen

  2. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Johannes R. Hov & Tom H. Karlsen

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J.R.H. reports speaker fees from Roche, Novartis and Amgen, consultancy fees from Novartis and Orkla Health, and research funding from Biogen, all unrelated to the present work. T.H.K. reports speaker fees from AlfaSigma, and consultancy fees from Intercept, Gilead and Albireo, all unrelated to the present work.

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Hov, J.R., Karlsen, T.H. The microbiota and the gut–liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 20, 135–154 (2023). https://doi.org/10.1038/s41575-022-00690-y

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