A Prospective Pilot Study of a Gluten-free Diet for Primary Sclerosing Cholangitis and Associated Colitis

Timur Liwinski; Sina Hübener; Lara Henze; Peter Hübener; Melina Heinemann; Marcus Tetzlaff; Marie I. Hiller; Bettina Jagemann; Rambabu Surabattula; Diana Leeming; Morten Karsdal; Erika Monguzzi; Guido Schachschal; Thomas Rösch; Corinna Bang; Andre Franke; Ansgar W. Lohse; Detlef Schuppan; Christoph Schramm


Aliment Pharmacol Ther. 2023;57(2):224-236. 

In This Article

Abstract and Introduction


Background: Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC-IBD).

Aim: To investigate whether patients with PSC-IBD benefit from a gluten-free and amylase trypsin inhibitor (ATI)-free diet (GFD).

Methods: We performed a prospective clinical pilot study administering an eight-week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis.

Results: Fifteen patients with PSC-IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro-inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down-regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin-2 and -4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well-being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly.

Conclusions: This study did not demonstrate a clinical improvement with short-term GFD in patients with PSC-IBD. However, a gluten/ATI-free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated changes in the enteric microbiota. Further investigation of the therapeutic potential of the GFD in PSC-IBD is warranted.


Primary sclerosing cholangitis (PSC) is a chronic and progressive bile duct disease featuring hepatobiliary inflammation, bile duct fibrosis, and cholestasis, often resulting in end-stage liver disease.[1] PSC is strongly associated with a distinct type of inflammatory bowel disease (PSC-IBD; resembling ulcerative colitis), ranging in co-prevalence from about 20% in Japan to over 70% in Europe.[2] The inflammatory and fibrotic nature of the disease represents a premalignant condition with increased mortality from malignancy, mainly cholangiocarcinoma and colorectal cancer.[3,4]

The strong association of PSC with IBD suggests a pathogenetic link to the gut microenvironment.[5] The human intestine is host to a myriad of microorganisms of predominantly bacterial origin. These microbial commensals play a crucial role in host health and disease due to their interaction with the human immune system.[6] Recently, a series of studies have provided strong evidence for altered gut microbiota in patients with PSC, yielding disease-associated microbes and microbial metabolites that are reproducible across studies.[7] The human diet acts as a substrate for defined microbial species and provides direct signals to the digestive and immune systems, thus profoundly impacting the gut microbial composition and the host's metabolism and immune system.[8] Therefore, a close and causal relationship between a dysregulated mucosal immune response against luminal nutrients and the intestinal microbiome on the one hand and intestinal and bile duct inflammation, on the other hand, appears conceivable in patients with PSC-IBD.[9,10] In acute and chronic inflammatory intestinal diseases, dietary interventions represent an increasingly studied therapeutic modality.[11,12]

Wheat has become a major staple food in most parts of the world. Modern hexaploid wheat harbours more than 100,000 coding genes, including gluten and a large spectrum of non-gluten proteins, some with the potential to cause adverse reactions, such as allergies. Three types of inflammatory wheat sensitivities can be distinguished: first, celiac disease, a T helper 1 mediated immune response to specific gluten epitopes in genetically predisposed subjects;[13,14] second, an innate immune response mainly to non-gluten proteins, prominently amylase trypsin inhibitors (ATI)[15–17] and third, immediate and delayed-type 2 immune responses to a variety of wheat allergens.[18–20] ATI-sensitivity and wheat allergies can explain the spectrum of non-celiac wheat sensitivity (NCWS; often incorrectly termed non-celiac gluten sensitivity).[21–23]

Notably, the ATI proteins of wheat that activate intestinal myeloid cells via toll-like receptor 4 (TLR4)[15,24] have been shown to promote not only intestinal but also extra-intestinal inflammation in experimental mouse models of colitis, nonalcoholic steatohepatitis, allergy and Alzheimer's disease,[16] but also in first human pilot studies.[25] Nutritional ATI can also directly compromise the intestinal barrier and alter the intestinal microbiome towards dysbiosis.[17,26]

An association between PSC-IBD and celiac disease was first described by Hay presenting three patients with typical biliary lesions on endoscopic retrograde cholangiography, colitis, severe steatorrhea and total villous atrophy.[27] An increased risk for PSC in celiac disease patients has since been confirmed by population studies[28,29] and large-scale genetic studies have found a striking overlap in genetic risk loci within the human leukocyte antigen (HLA) complex.[30] However, the effects of a wheat (gluten)-free diet (GFD) on outcomes of PSC-IBD are unknown. We hypothesised that dietary exclusion of pro-inflammatory wheat proteins, especially ATI, could directly alter the dysbiotic gut microbiota and alleviate intestinal inflammation in PSC-IBD patients. Because of the close link between intestinal and liver pathology in PSC,[31] we further assumed that restoration of enteric homeostasis might improve hepatic inflammation and biliary fibrosis markers. We, therefore, conducted a prospective clinical pilot trial assessing the effect of a largely gluten-free and thus ATI-free diet on patient well-being, multiple markers of disease activity, gut barrier function, and the gut microbiota in patients with PSC-IBD with low clinical activity and without celiac disease.