Digestive Diseases and Sciences

, Volume 64, Issue 7, pp 1740–1747 | Cite as

Going Against the Grains: Gluten-Free Diets in Patients Without Celiac Disease—Worthwhile or Not?

  • Benjamin A. Lerner
  • Peter H. R. Green
  • Benjamin LebwohlEmail author
Invited Review


While the gluten-free diet (GFD) is the only known effective therapy for celiac disease, in recent years it has become increasingly popular in the USA and worldwide, with many believing it to be more “healthful” and others claiming that it has beneficial effects for health conditions, many extraintestinal, other than celiac disease. This review examines the evidence for use of the GFD in patients without celiac disease who self-report intestinal and/or extraintestinal symptoms (non-celiac gluten sensitivity), as well as for enhancement of athletic performance and treatment of autism, rheumatoid arthritis, and psychiatric disorders. Overall, the evidence for use of GFDs in conditions other than celiac disease is poor. Though non-celiac gluten sensitivity may ultimately emerge as a biomarker-defined condition, a large proportion of patients with apparent non-celiac gluten sensitivity have, after careful investigation, an alternative diagnosis. In light of this, and coupled with the potential physical and psychological harms associated with the avoidance of gluten, initiating a GFD should not be encouraged for people who have these other conditions or are seeking physical/athletic enhancement.


Gluten-free diet Gluten Non-celiac gluten sensitivity Rheumatoid arthritis Autism Schizophrenia 


Compliance with ethical standards

Conflict of interest

Benjamin Lebwohl serves as a consultant for Takeda and serves on the Advisory Board of Innovate Biopharmaceuticals. Peter HR Green serves on the advisory board of ImmusanT, ImmunogenX, and Innovate Biopharmaceuticals. Benjamin Lerner has no disclosures.


  1. 1.
    Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ. 2015;351:h4347.CrossRefGoogle Scholar
  2. 2.
    Choung RS, Unalp-Arida A, Ruhl CE, Brantner TL, Everhart JE, Murray JA. Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014. Mayo Clin Proc. 2016.Google Scholar
  3. 3.
    Laszkowska M, Shiwani H, Belluz J, et al. Socioeconomic vs health-related factors associated with google searches for gluten-free diet. Clin Gastroenterol Hepatol. 2018;16:295–297.CrossRefGoogle Scholar
  4. 4.
    Brenan M. Most Americans Try to Eat Locally Grown Foods. Updated August 7, 2018. Accessed March 2, 2019.
  5. 5.
    The Hartman Group. Health + Wellness 2017 Report. Updated September 13, 2018. Accessed March 2, 2019.
  6. 6.
    Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391:70–81.CrossRefGoogle Scholar
  7. 7.
    Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;5:3839–3853.CrossRefGoogle Scholar
  8. 8.
    Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–1937.CrossRefGoogle Scholar
  9. 9.
    Tavakkoli A, Lewis SK, Tennyson CA, Lebwohl B, Green PH. Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease. Dig Dis Sci. 2014;59:1255–1261.CrossRefGoogle Scholar
  10. 10.
    Aziz I, Lewis NR, Hadjivassiliou M, et al. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur J Gastroenterol Hepatol. 2014;26:33–39.CrossRefGoogle Scholar
  11. 11.
    Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106:508–514. quiz 15.CrossRefGoogle Scholar
  12. 12.
    Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145:320–328. e1-3.CrossRefGoogle Scholar
  13. 13.
    Vazquez-Roque MI, Camilleri M, Smyrk T, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013;144:903–911. e3.CrossRefGoogle Scholar
  14. 14.
    Catassi C, Elli L, Bonaz B, et al. Diagnosis of non-celiac gluten sensitivity (NCGS): the Salerno experts’ criteria. Nutrients. 2015;7:4966–4977.CrossRefGoogle Scholar
  15. 15.
    Elli L, Tomba C, Branchi F, et al. Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: results from a multicenter randomized double-blind placebo-controlled gluten challenge. Nutrients. 2016;8:84.CrossRefGoogle Scholar
  16. 16.
    Picarelli A, Borghini R, Di Tola M, et al. Intestinal, systemic, and oral gluten-related alterations in patients with nonceliac gluten sensitivity. J Clin Gastroenterol. 2016;50:849–858.CrossRefGoogle Scholar
  17. 17.
    Shahbazkhani B, Sadeghi A, Malekzadeh R, et al. Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: a double-blind randomized placebo-controlled trial. Nutrients. 2015;7:4542–4554.CrossRefGoogle Scholar
  18. 18.
    Zanini B, Basche R, Ferraresi A, et al. Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity. Aliment Pharmacol Ther. 2015;42:968–976.CrossRefGoogle Scholar
  19. 19.
    Di Sabatino A, Volta U, Salvatore C, et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clin Gastroenterol Hepatol. 2015;13:1604–1612. e3.CrossRefGoogle Scholar
  20. 20.
    Molina-Infante J, Carroccio A. Suspected nonceliac gluten sensitivity confirmed in few patients after gluten challenge in double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol. 2017;15:339–348.CrossRefGoogle Scholar
  21. 21.
    Lis DM, Stellingwerff T, Shing CM, Ahuja KD, Fell JW. Exploring the popularity, experiences, and beliefs surrounding gluten-free diets in nonceliac athletes. Int J Sport Nutr Exerc Metab. 2015;25:37–45.CrossRefGoogle Scholar
  22. 22.
    Djokovic N. Serve to Win: The 14-Day Gluten-Free Plan for Physical and Mental Excellence. New York: Zinc Ink; 2013.Google Scholar
  23. 23.
    Lis D, Stellingwerff T, Kitic CM, Ahuja KD, Fell J. No effects of a short-term gluten-free diet on performance in nonceliac athletes. Med Sci Sports Exerc. 2015;47:2563–2570.CrossRefGoogle Scholar
  24. 24.
    Halson SL, Martin DT. Lying to win-placebos and sport science. Int J Sports Physiol Perform. 2013;8:597–599.CrossRefGoogle Scholar
  25. 25.
    Lis DM, Fell JW, Ahuja KD, Kitic CM, Stellingwerff T. Commercial hype versus reality: our current scientific understanding of gluten and athletic performance. Curr Sports Med Rep. 2016;15:262–268.Google Scholar
  26. 26.
    Beedie C, Foad A, Hurst P. Capitalizing on the placebo component of treatments. Curr Sports Med Rep. 2015;14:284–287.CrossRefGoogle Scholar
  27. 27.
    Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–2038.CrossRefGoogle Scholar
  28. 28.
    Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev. 2009;1:CD006400.Google Scholar
  29. 29.
    Koning F, Thomas R, Rossjohn J, Toes RE. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat Rev Rheumatol. 2015;11:450–461.CrossRefGoogle Scholar
  30. 30.
    Paimela L, Kurki P, Leirisalo-Repo M, Piirainen H. Gliadin immune reactivity in patients with rheumatoid arthritis. Clin Exp Rheumatol. 1995;13:603–607.Google Scholar
  31. 31.
    O’Farrelly C, Marten D, Melcher D, et al. Association between villous atrophy in rheumatoid arthritis and a rheumatoid factor and gliadin-specific IgG. Lancet. 1988;2:819–822.CrossRefGoogle Scholar
  32. 32.
    Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, et al. Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet. 1991;338:899–902.CrossRefGoogle Scholar
  33. 33.
    Hafstrom I, Ringertz B, Spangberg A, et al. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology (Oxford). 2001;40:1175–1179.CrossRefGoogle Scholar
  34. 34.
    Elkan AC, Sjoberg B, Kolsrud B, Ringertz B, Hafstrom I, Frostegard J. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study. Arthritis Res Ther. 2008;10:R34.CrossRefGoogle Scholar
  35. 35.
    Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303–1307.CrossRefGoogle Scholar
  36. 36.
    Wang F, Zheng J, Yang B, Jiang J, Fu Y, Li D. Effects of vegetarian diets on blood lipids: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2015;4:e002408.Google Scholar
  37. 37.
    Brar P, Kwon GY, Holleran S, et al. Change in lipid profile in celiac disease: beneficial effect of gluten-free diet. Am J Med. 2006;119:786–790.CrossRefGoogle Scholar
  38. 38.
    Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol. 2015;12:561–571.CrossRefGoogle Scholar
  39. 39.
    Mearns ES, Taylor A, Thomas Craig KJ, et al. Neurological manifestations of neuropathy and ataxia in celiac disease: a systematic review. Nutrients. 2019;11:380.CrossRefGoogle Scholar
  40. 40.
    Vinagre-Aragon A, Zis P, Grunewald RA, Hadjivassiliou M. Movement disorders related to gluten sensitivity: a systematic review. Nutrients. 2018;10:1034.CrossRefGoogle Scholar
  41. 41.
    Hadjivassiliou M, Rao DG, Grinewald RA, et al. Neurological dysfunction in coeliac disease and non-coeliac gluten sensitivity. Am J Gastroenterol. 2016;111:561–567.CrossRefGoogle Scholar
  42. 42.
    Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996;347:369–371.CrossRefGoogle Scholar
  43. 43.
    Hadjivassiliou M, Davies-Jones GA, Sanders DS, Grunewald RA. Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry. 2003;74:1221–1224.CrossRefGoogle Scholar
  44. 44.
    Zis P, Sarrigiannis PG, Rao DG, Hadjivassiliou M. Gluten neuropathy: prevalence of neuropathic pain and the role of gluten-free diet. J Neurol. 2018;265:2231–2236.CrossRefGoogle Scholar
  45. 45.
    Hadjivassiliou M, Kandler RH, Chattopadhyay AK, et al. Dietary treatment of gluten neuropathy. Muscle Nerve. 2006;34:762–766.CrossRefGoogle Scholar
  46. 46.
    Perlmutter D, Loberg K. Grain Brain: The Surprising Truth About Wheat, Carbs, and Sugar–Your Brain’s Silent Killers. New York: Little, Brown & Company; 2013.Google Scholar
  47. 47.
    Yelland GW. Gluten-induced cognitive impairment (“brain fog”) in coeliac disease. J Gastroenterol Hepatol. 2017;32:90–93.CrossRefGoogle Scholar
  48. 48.
    Lichtwark IT, Newnham ED, Robinson SR, et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014;40:160–170.CrossRefGoogle Scholar
  49. 49.
    Lebwohl B, Luchsinger JA, Freedberg DE, Green PH, Ludvigsson JF. Risk of dementia in patients with celiac disease: a population-based cohort study. J Alzheimers Dis. 2016;49:179–185.CrossRefGoogle Scholar
  50. 50.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed). Arlington, VA; 2013.Google Scholar
  51. 51.
    Baio J, Wiggins L, Christensen DL, et al. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018;67:1–23.CrossRefGoogle Scholar
  52. 52.
    Perrin JM, Coury DL, Hyman SL, Cole L, Reynolds AM, Clemons T. Complementary and alternative medicine use in a large pediatric autism sample. Pediatrics. 2012;130:S77–S82.CrossRefGoogle Scholar
  53. 53.
    Reichelt KL. Gluten-free diet in infantile autism. Tidsskr Nor Laegeforen. 1991;111:1286–1287.Google Scholar
  54. 54.
    Whiteley P, Shattock P, Knivsberg AM, et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012;6:344.CrossRefGoogle Scholar
  55. 55.
    Ludvigsson JF, Reichenberg A, Hultman CM, Murray JA. A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. JAMA Psychiatry. 2013;70:1224–1230.CrossRefGoogle Scholar
  56. 56.
    Lau NM, Green PH, Taylor AK, et al. Markers of celiac disease and gluten sensitivity in children with autism. PLoS ONE. 2013;8:e66155.CrossRefGoogle Scholar
  57. 57.
    Sponheim E. Gluten-free diet in infantile autism. A therapeutic trial. Tidsskr Nor Laegeforen. 1991;111:704–707.Google Scholar
  58. 58.
    Whiteley P, Rodgers J, Savery D, Shattock P. A gluten-free diet as an intervention for autism and associated spectrum disorders: preliminary findings. Autism. 1999;3:45–65.CrossRefGoogle Scholar
  59. 59.
    Ghalichi F, Ghaemmaghami J, Malek A, Ostadrahimi A. Effect of gluten free diet on gastrointestinal and behavioral indices for children with autism spectrum disorders: a randomized clinical trial. World J Pediatr. 2016;12:436–442.CrossRefGoogle Scholar
  60. 60.
    Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002;5:251–261.CrossRefGoogle Scholar
  61. 61.
    Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006;36:413–420.CrossRefGoogle Scholar
  62. 62.
    Hyman SL, Stewart PA, Foley J, et al. The gluten-free/casein-free diet: a double-blind challenge trial in children with autism. J Autism Dev Disord. 2016;46:205–220.CrossRefGoogle Scholar
  63. 63.
    Navarro F, Pearson DA, Fatheree N, Mansour R, Hashmi SS, Rhoads JM. Are ‘leaky gut’ and behavior associated with gluten and dairy containing diet in children with autism spectrum disorders? Nutr Neurosci. 2015;18:177–185.CrossRefGoogle Scholar
  64. 64.
    Pusponegoro HD, Ismael S, Firmansyah A, Sastroasmoro S, Vandenplas Y. Gluten and casein supplementation does not increase symptoms in children with autism spectrum disorder. Acta Paediatr. 2015;104:e500–e505.CrossRefGoogle Scholar
  65. 65.
    Sathe N, Andrews JC, McPheeters ML, Warren ZE. Nutritional and dietary interventions for autism spectrum disorder: a systematic review. Pediatrics. 2017;139:e20170346.CrossRefGoogle Scholar
  66. 66.
    Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008;2:CD003498.Google Scholar
  67. 67.
    Piwowarczyk A, Horvath A, Lukasik J, Pisula E, Szajewska H. Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. Eur J Nutr. 2018;57:433–440.CrossRefGoogle Scholar
  68. 68.
    Dohan FC. Wheat “consumption” and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr. 1966;18:7–10.CrossRefGoogle Scholar
  69. 69.
    Cascella NG, Kryszak D, Bhatti B, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2011;37:94–100.CrossRefGoogle Scholar
  70. 70.
    Dickerson F, Stallings C, Origoni A, et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010;68:100–104.CrossRefGoogle Scholar
  71. 71.
    Samaroo D, Dickerson F, Kasarda DD, et al. Novel immune response to gluten in individuals with schizophrenia. Schizophr Res. 2010;118:248–255.CrossRefGoogle Scholar
  72. 72.
    Dohan FC, Grasberger JC, Lowell FM, Johnston HT Jr, Arbegast AW. Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Br J Psychiatry. 1969;115:595–596.CrossRefGoogle Scholar
  73. 73.
    Dohan FC, Grasberger JC. Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry. 1973;130:685–688.CrossRefGoogle Scholar
  74. 74.
    Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science. 1976;191:401–402.CrossRefGoogle Scholar
  75. 75.
    Rice JR, Ham CH, Gore WE. Another look at gluten in schizophrenia. Am J Psychiatry. 1978;135:1417–1418.CrossRefGoogle Scholar
  76. 76.
    Vlissides DN, Venulet A, Jenner FA. A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry. 1986;148:447–452.CrossRefGoogle Scholar
  77. 77.
    Potkin SG, Weinberger D, Kleinman J, et al. Wheat gluten challenge in schizophrenic patients. Am J Psychiatry. 1981;138:1208–1211.CrossRefGoogle Scholar
  78. 78.
    Storms LH, Clopton JM, Wright C. Effects of gluten on schizophrenics. Arch Gen Psychiatry. 1982;39:323–327.CrossRefGoogle Scholar
  79. 79.
    Osborne M, Crayton JW, Javaid J, Davis JM. Lack of effect of a gluten-free diet on neuroleptic blood levels in schizophrenic patients. Biol Psychiatry. 1982;17:627–629.Google Scholar
  80. 80.
    Jackson J, Eaton W, Cascella N, et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012;140:262–263.CrossRefGoogle Scholar
  81. 81.
    Kelly DL, Demyanovich HK, Rodriguez KM, et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019;44:1–9.Google Scholar
  82. 82.
    Busby E, Bold J, Fellows L, Rostami K. Mood disorders and gluten: it’s not all in your mind! A systematic review with meta-analysis. Nutrients. 2018;10:1708.CrossRefGoogle Scholar
  83. 83.
    Peters SL, Biesiekierski JR, Yelland GW, Muir JG, Gibson PR. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity—an exploratory clinical study. Aliment Pharmacol Ther. 2014;39:1104–1112.CrossRefGoogle Scholar
  84. 84.
    Martin J, Geisel T, Maresch C, Krieger K, Stein J. Inadequate nutrient intake in patients with celiac disease: results from a German dietary survey. Digestion. 2013;87:240–246.CrossRefGoogle Scholar
  85. 85.
    Vici G, Belli L, Biondi M, Polzonetti V. Gluten free diet and nutrient deficiencies: a review. Clin Nutr. 2016;35:1236–1241.CrossRefGoogle Scholar
  86. 86.
    Wild D, Robins GG, Burley VJ, Howdle PD. Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet. Aliment Pharmacol Ther. 2010;32:573–581.CrossRefGoogle Scholar
  87. 87.
    Ohlund K, Olsson C, Hernell O, Ohlund I. Dietary shortcomings in children on a gluten-free diet. J Hum Nutr Diet. 2010;23:294–300.CrossRefGoogle Scholar
  88. 88.
    Zong G, Lebwohl B, Hu FB, et al. Gluten intake and risk of type 2 diabetes in three large prospective cohort studies of US men and women. Diabetologia. 2018;61:2164–2173.CrossRefGoogle Scholar
  89. 89.
    Lebwohl B, Cao Y, Zong G, et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study. BMJ. 2017;357:j1892.CrossRefGoogle Scholar
  90. 90.
    Raehsler SL, Choung RS, Marietta EV, Murray JA. Accumulation of heavy metals in people on a gluten-free diet. Clin Gastroenterol Hepatol. 2018;16:244–251.CrossRefGoogle Scholar
  91. 91.
    Ludvigsson JF, Lebwohl B, Chen Q, et al. Anxiety after coeliac disease diagnosis predicts mucosal healing: a population-based study. Aliment Pharmacol Ther. 2018;48:1091–1098.CrossRefGoogle Scholar
  92. 92.
    Wolf RL, Lebwohl B, Lee AR, et al. Hypervigilance to a gluten-free diet and decreased quality of life in teenagers and adults with celiac disease. Dig Dis Sci. 2018;63:1438–1448.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Benjamin A. Lerner
    • 1
  • Peter H. R. Green
    • 1
  • Benjamin Lebwohl
    • 1
    • 2
    Email author
  1. 1.Department of Medicine, Celiac Disease CenterColumbia University Medical CenterNew YorkUSA
  2. 2.Department of Epidemiology, Mailman School of Public HealthColumbia University Medical CenterNew YorkUSA

Personalised recommendations