Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy

  • Zunirah Ahmed
  • Aamer Imdad
  • James A. Connelly
  • Sari AcraEmail author


Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.


Intractable diarrhea Autoimmune enteropathy IPEX APECED Immunosuppressives Stem cell transplant 



Autoimmune enteropathy


Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy






Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome


Major histocompatibility complex


Mesenchymal stem cell


Tumor necrosis factor


Total parenteral nutrition


Author’s contribution

Dr Zunirah Ahmed and Aamer Imdad did the literature search and wrote the first draft. Dr. James A. Connelly and Dr. Sari Acra supervised and gave feedback at each stage of manuscript writing.

Compliance with ethical standards

Conflict of interest

All authors declare that they do not have any conflict of interest.

Supplementary material

10620_2018_5364_MOESM1_ESM.docx (45 kb)
Supplementary material 1 (DOCX 44 kb)
10620_2018_5364_MOESM2_ESM.docx (44 kb)
Supplementary material 2 (DOCX 43 kb)


  1. 1.
    Avery GB, Villavicencio O, Lilly JR, Randolph JG. Intractable diarrhea in early infancy. Pediatrics. 1968;41:712–722.PubMedGoogle Scholar
  2. 2.
    Lo CW, Walker WA. Chronic protracted diarrhea of infancy: a nutritional disease. Pediatrics. 1983;72:786–800.PubMedGoogle Scholar
  3. 3.
    Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of infancy. J Pediatr Gastroenterol Nutr. 2004;38:16–26.CrossRefGoogle Scholar
  4. 4.
    Unsworth DJ, Walker-Smith JA. Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr. 1985;4:375–380.CrossRefGoogle Scholar
  5. 5.
    Gentile NM, Murray JA, Pardi DS. Autoimmune enteropathy: a review and update of clinical management. Curr Gastroenterol Rep. 2012;14:380–385.CrossRefGoogle Scholar
  6. 6.
    Akram S, Murray JA, Pardi DS, et al. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol. 2007;5:1282–1290. (quiz 1245).CrossRefGoogle Scholar
  7. 7.
    Marthinsen LM, Scott H, Ejderhamn J. Autoimmune enteropathy in Swedish children, 1985–2002: a call for strict diagnostic criteria. Scand J Gastroenterol. 2008;43:1102–1107.CrossRefGoogle Scholar
  8. 8.
    Catassi C, Fabiani E, Spagnuolo MI, Barera G, Guarino A. Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. J Pediatr Gastroenterol Nutr. 1999;29:63–68.CrossRefGoogle Scholar
  9. 9.
    Bousvaros A, Leichtner AM, Book L, et al. Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). Gastroenterology. 1996;111:237–243.CrossRefGoogle Scholar
  10. 10.
    Mirakian R, Hill S, Richardson A, Milla PJ, Walker-Smith JA, Bottazzo GF. HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun. 1988;1:263–277.CrossRefGoogle Scholar
  11. 11.
    Mirakian R, Richardson A, Milla PJ, et al. Protracted diarrhoea of infancy: evidence in support of an autoimmune variant. BMJ. 1986;293:1132–1136.CrossRefGoogle Scholar
  12. 12.
    Quirós-Tejeira RE, Ament ME, Vargas JH. Induction of remission in a child with autoimmune enteropathy using mycophenolate mofetil. J Pediatr Gastroenterol Nutr. 2003;36:482–485.CrossRefGoogle Scholar
  13. 13.
    Guarino A, De Marco G. Failure INNfPI. Natural history of intestinal failure, investigated through a national network-based approach. J Pediatr Gastroenterol Nutr. 2003;37:136–141.CrossRefGoogle Scholar
  14. 14.
    Ruemmele FM, Brousse N, Goulet O. Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol. 2004;20:587–591.CrossRefGoogle Scholar
  15. 15.
    Montalto M, D’Onofrio F, Santoro L, Gallo A, Gasbarrini A, Gasbarrini G. Autoimmune enteropathy in children and adults. Scand J Gastroenterol. 2009;44:1029–1036.CrossRefGoogle Scholar
  16. 16.
    Catassi C, Mirakian R, Natalini G, et al. Unresponsive enteropathy associated with circulating enterocyte autoantibodies in a boy with common variable hypogammaglobulinemia and type I diabetes. J Pediatr Gastroenterol Nutr. 1988;7:608–673.CrossRefGoogle Scholar
  17. 17.
    Valitutti F, Barbato M, Aloi M, et al. Autoimmune enteropathy in a 13-year-old celiac girl successfully treated with infliximab. J Clin Gastroenterol. 2014;48:264–266.CrossRefGoogle Scholar
  18. 18.
    Savage M, Mirakian R, Harries J, Bottazzo G. Could protracted diarrhoea of infancy have an autoimmune pathogenesis? Lancet. 1982;319:966–967.CrossRefGoogle Scholar
  19. 19.
    Martini A, Scotta M, Notarangelo L, Maggiore G, Guarnaccia S, Giacomo Cd. Membranous glomerulopathy and chronic small-intestinal enteropathy associated with autoantibodies directed against renal tubular basement membrane and the cytoplasm of intestinal epithelial cells. Acta Paediatr. 1983;72:931–934.CrossRefGoogle Scholar
  20. 20.
    Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G. Autoimmune enteropathy and villous atrophy in adults. Lancet. 1997;350:106–109.CrossRefGoogle Scholar
  21. 21.
    León F, Olivencia P, Rodríguez-Pena R, et al. Clinical and immunological features of adult-onset generalized autoimmune gut disorder. Am J Gastroenterol. 2004;99:1563–1571.CrossRefGoogle Scholar
  22. 22.
    Hasan SS, Siddiqui NS, Arudra SKC, de Las Casas L, Akpunonu B, Nawras A. Diffuse autoimmune enteropathy and colopathy in an adult patient successfully treated with adalimumab and a review of the literature. Am J Ther. 2014;23:e963.CrossRefGoogle Scholar
  23. 23.
    Al Khalidi H, Kandel G, Streutker CJ. Enteropathy with loss of enteroendocrine and paneth cells in a patient with immune dysregulation: a case of adult autoimmune enteropathy. Hum Pathol. 2006;37:373–376.CrossRefGoogle Scholar
  24. 24.
    Volta U, De Angelis G, Granito A, et al. Autoimmune enteropathy and rheumatoid arthritis: a new association in the field of autoimmunity. Dig Liver Dis. 2006;38:926–929.CrossRefGoogle Scholar
  25. 25.
    Elwing JE, Clouse RE. Adult-onset autoimmune enteropathy in the setting of thymoma successfully treated with infliximab. Dig Dis Sci. 2005;50:928–932. CrossRefPubMedGoogle Scholar
  26. 26.
    Bland P. MHC class II expression by the gut epithelium. Immunol Today. 1988;9:174–178.CrossRefGoogle Scholar
  27. 27.
    Hill S, Milla P, Bottazzo G, Mirakian R. Autoimmune enteropathy and colitis: Is there a generalised autoimmune gut disorder? Gut. 1991;32:36–42.CrossRefGoogle Scholar
  28. 28.
    Cuenod B, Brousse N, Goulet O, et al. Classification of intractable diarrhea in infancy using clinical and immunohistological criteria. Gastroenterology. 1990;99:1037–1043.CrossRefGoogle Scholar
  29. 29.
    Ciccocioppo S R, D’alo S, Sabatino A, et al. Mechanisms of villous atrophy in autoimmune enteropathy and coeliac disease. Clin Exper Immunol. 2002;128:88–93.CrossRefGoogle Scholar
  30. 30.
    Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.CrossRefGoogle Scholar
  31. 31.
    McCarthy D, Katz S, Gazze L, Waldmann T, Nelson D, Strober W. Selective IgA deficiency associated with total villous atrophy of the small intestine and an organ-specific anti-epithelial cell antibody. J Immunol. 1978;120:932–938.PubMedGoogle Scholar
  32. 32.
    Bennett CL, Brunkow ME, Ramsdell F, et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA → AAUGAA) leads to the IPEX syndrome. Immunogenetics. 2001;53:435–439.CrossRefGoogle Scholar
  33. 33.
    Khattri R, Cox T, Yasayko S-A, Ramsdell F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nat Immunol. 2003;4:337–342.CrossRefGoogle Scholar
  34. 34.
    Wildin R, Smyk-Pearson S, Filipovich A. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39:537–545.CrossRefGoogle Scholar
  35. 35.
    Owen CJ, Jennings CE, Imrie H, et al. Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab. 2003;88:6034–6039.CrossRefGoogle Scholar
  36. 36.
    Heltzer ML, Choi JK, Ochs HD, Sullivan KE, Torgerson TR, Ernst LM. A potential screening tool for IPEX syndrome. Pediatr Dev Pathol. 2007;10:98–105.CrossRefGoogle Scholar
  37. 37.
    Aaltonen J, Björses P. Cloning of the APECED gene provides new insight into human autoimmunity. Ann Med. 1999;31:111–116.CrossRefGoogle Scholar
  38. 38.
    Lankisch TO, Strassburg CP, Debray D, Manns MP, Jacquemin E. Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases. J Pediatr. 2005;146:839–842.CrossRefGoogle Scholar
  39. 39.
    Savilahti E, Pelkonen P, Holmberg C, Perkkiö M, Unsworth J. Fatal unresponsive villous atrophy of the jejunum, connective tissue disease and diabetes in a girl with intestinal epithelial cell antibody. Acta Paediatr. 1985;74:472–476.CrossRefGoogle Scholar
  40. 40.
    Fiocchi C, Roche JK, Michener WM. High prevalence of antibodies to intestinal epithelial antigens in patients with inflammatory bowel disease and their relatives. Ann Intern Med. 1989;110:786–794.CrossRefGoogle Scholar
  41. 41.
    Walker-Smith J, Unsworth D, Hutchins P, Phillips A, Holborow E. Autoantibodies against gut epithelium in child with small-intestinal enteropathy. Lancet. 1982;319:566–567.CrossRefGoogle Scholar
  42. 42.
    Virological S. Anti-goblet cell antibodies for the diagnosis of autoimmune enteropathy? Lancet. 1997;350:959–960.Google Scholar
  43. 43.
    Martin-Villa J, Camblor S, Costa R, Arnaiz-Villena A. Gut epithelial cell autoantibodies in AIDS pathogenesis. Lancet. 1993;342:380.CrossRefGoogle Scholar
  44. 44.
    Biagi F, Bianchi PI, Trotta L, Corazza GR. Anti-goblet cell antibodies for the diagnosis of autoimmune enteropathy? Am J Gastroenterol. 2009;104:3112.CrossRefGoogle Scholar
  45. 45.
    Kobayashi I, Imamura K, Kubota M, et al. Identification of an autoimmune enteropathy—related 75-kilodalton antigen. Gastroenterology. 1999;117:823–830.CrossRefGoogle Scholar
  46. 46.
    Colletti RB, Guillot AP, Rosen S, et al. Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies. J Pediatr. 1991;118:858–864.CrossRefGoogle Scholar
  47. 47.
    Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, Ranganathan S. Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Mod Pathol. 2014;27:543–553.CrossRefGoogle Scholar
  48. 48.
    de Serre NP-M, Canioni D, Ganousse S, et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol. 2009;22:95–102.CrossRefGoogle Scholar
  49. 49.
    Masia R, Peyton S, Lauwers GY, Brown I. Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol. 2014;38:1319–1329.CrossRefGoogle Scholar
  50. 50.
    Scialom S, Malamut G, Meresse B, et al. Gastrointestinal disorder associated with olmesartan mimics autoimmune enteropathy. PLoS ONE. 2015;10:e0125024.CrossRefGoogle Scholar
  51. 51.
    Assarzadegan N, Montgomery E, Anders RA. Immune checkpoint inhibitor colitis: the flip side of the wonder drugs Virchows. Archiv Int J Pathol. 2018;472:125–133.CrossRefGoogle Scholar
  52. 52.
    Jonas MM, Bell MD, Eidson MS, Koutouby R, Hensley GT. Congenital diabetes mellitus and fatal secretory diarrhea in two infants. J Pediatr Gastroenterol Nutr. 1991;13:415–425.CrossRefGoogle Scholar
  53. 53.
    Barzaghi F, Amaya Hernandez LC, Neven B, et al. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol. 2018;141:e1035.CrossRefGoogle Scholar
  54. 54.
    von Hahn T, Stopik D, Koch M, Wiedenmann B, Dignass A. Management of severe refractory adult autoimmune enteropathy with infliximab and tacrolimus. Digestion. 2004;71:141–144.CrossRefGoogle Scholar
  55. 55.
    Vanderhoof JA, Young RJ. Autoimmune enteropathy in a child: response to infliximab therapy. J Pediatr Gastroenterol Nutr. 2002;34:312–316.CrossRefGoogle Scholar
  56. 56.
    Gupta NK, Yilmaz O, Fisher M, Yajnik V. Abatacept: a new treatment option for refractory adult autoimmune enteropathy. J Clin Gastroenterol. 2014;48:55–58.CrossRefGoogle Scholar
  57. 57.
    Murch SH, Fertleman CR, Rodrigues C, et al. Autoimmune enteropathy with distinct mucosal features in T-cell activation deficiency: the contribution of T cells to the mucosal lesion. J Pediatr Gastroenterol Nutr. 1999;28:393–399.CrossRefGoogle Scholar
  58. 58.
    Horino S, Sasahara Y, Sato M, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant. 2014;18:E25–E30.CrossRefGoogle Scholar
  59. 59.
    Maccario R, Podestà M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4 + T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica. 2005;90:516–525.PubMedGoogle Scholar
  60. 60.
    Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–372.CrossRefGoogle Scholar
  61. 61.
    Parekkadan B, Tilles AW, Yarmush ML. Bone marrow-derived mesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells. Stem Cells. 2008;26:1913–1919.CrossRefGoogle Scholar
  62. 62.
    Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60:788–798.CrossRefGoogle Scholar
  63. 63.
    Ciccocioppo R, Russo ML, Bernardo ME, et al. Mesenchymal stromal cell infusions as rescue therapy for corticosteroid-refractory adult autoimmune enteropathy. Mayo Clin Proc. 2012;87:909–914.CrossRefGoogle Scholar
  64. 64.
    Gambarara M, Bracci F, Diamanti A, et al. Long-term parenteral nutrition in pediatric autoimmune enteropathies. Transpl Proc. 2005;37:2270–2271.CrossRefGoogle Scholar
  65. 65.
    Rolny P, Sigurjonsdottir H, Remotti H, et al. Role of immunosuppressive therapy in refractory sprue-like disease. Am J Gastroenterol. 1999;94:219–225.CrossRefGoogle Scholar
  66. 66.
    Perheentupa J. APS-I/APECED: the clinical disease and therapy. Endocrinol Metab Clin N Am. 2002;31:295–320.CrossRefGoogle Scholar
  67. 67.
    Rao A, Kamani N, Filipovich A, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007;109:383–385.CrossRefGoogle Scholar
  68. 68.
    Mazzolari E, Forino C, Fontana M, et al. A new case of IPEX receiving bone marrow transplantation. Bone Marrow Transplant. 2005;35:1033–1034.CrossRefGoogle Scholar
  69. 69.
    Baud O, Goulet O, Canioni D, et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N Engl J Med. 2001;344:1758–1762.CrossRefGoogle Scholar
  70. 70.
    Zhan H, Sinclair J, Adams S, et al. Immune reconstitution and recovery of FOXP3 (forkhead box P3)-expressing T cells after transplantation for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Pediatrics. 2008;121:e998–e1002.CrossRefGoogle Scholar
  71. 71.
    Seidel MG, Fritsch G, Lion T, et al. Selective engraftment of donor CD4 + 25 high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113:5689–5691.CrossRefGoogle Scholar
  72. 72.
    Nademi Z, Slatter M, Gambineri E, et al. Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Bone Marrow Transplant. 2014;49:310–312.CrossRefGoogle Scholar
  73. 73.
    Lucas KG, Ungar D, Comito M, Bayerl M, Groh B. Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome. Bone Marrow Transplant. 2007;39:55–56.CrossRefGoogle Scholar
  74. 74.
    Kucuk ZY, Bleesing JJ, Marsh R, Zhang K, Davies S, Filipovich AH. A challenging undertaking: Stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2016;137:953.e954–955.e954.CrossRefGoogle Scholar
  75. 75.
    Burroughs LM, Torgerson TR, Storb R, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. 2010;126:1000–1005.CrossRefGoogle Scholar
  76. 76.
    Dorsey MJ, Petrovic A, Morrow MR, Dishaw LJ, Sleasman JW. FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Immunol Res. 2009;44:179–184.CrossRefGoogle Scholar
  77. 77.
    Kasow KA, Morales-Tirado VM, Wichlan D, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol (Orlando, Fla.). 2011;141:169–176.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Zunirah Ahmed
    • 1
  • Aamer Imdad
    • 2
  • James A. Connelly
    • 3
  • Sari Acra
    • 4
    Email author
  1. 1.School of MedicineUniversity of AlabamaMontgomeryUSA
  2. 2.Division of Pediatric GastroenterologySUNY Upstate Medical UniversitySyracuseUSA
  3. 3.Division of Pediatric Hematology-OncologyVanderbilt University Medical CenterNashvilleUSA
  4. 4.Division of Pediatric Gastroenterology, Hepatology and NutritionVanderbilt University Medical CenterNashvilleUSA

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