Gut–Liver Axis: An Immune Link Between Celiac Disease and Primary Biliary Cirrhosis

Umberto Volta; Giacomo Caio; Francesco Tovoli; Roberto De Giorgio


Expert Rev Gastroenterol Hepatol. 2013;7(3):253-261. 

In This Article

Abstract and Introduction


The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut–liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients.


Growing evidence demonstrates that the gut–liver axis plays a crucial role in the maintenance of biological homeostasis at the gastrointestinal level.[1] The close anatomical and functional relationship between gut and liver modulates the immune response to bacterial and food antigens in health and disease. The balance of gut microbiome, intestinal permeability, hepatocyte function and Kupffer cell activation is critical for good health, and the breakdown of this equilibrium triggers the development of intestinal and liver disorders.[2] Many microbiome-associated and immunologically active molecules of intestinal origin enter the portal circulation and reach the liver through this 'busy street'. An aberrant intestinal T lymphocyte homing to the liver is thought to be important for the development of T–cell-mediated hepatic disorders associated with gut inflammation.[3] In line with this hypothesis, an increased number of T lymphocytes expressing molecules of intestinal origin, that is, integrin α4b7 and chemokine receptor CCR9, have been detected in liver sinusoidal endothelial cells in patients with hepatic involvement. One of the best examples of gut–liver axis failure is the frequent coexistence of celiac disease (CD) and liver abnormalities.[4]

Liver involvement in CD is well established. In the late 1970s, the first reports demonstrated that transaminases were frequently raised in untreated CD, usually reverting to normal after a few months of a strict gluten-free diet (GFD).[5,6] In the early 1990s, and even more recently, some original studies carried out after the recognition of CD as an autoimmune disease have highlighted the close association between CD and autoimmune liver disorders.[7–10] Two clinical forms of liver damage appear to be strictly related to CD: cryptogenic liver disorders (including mild hypertransaminasemia and severe chronic hepatitis or cirrhosis of unknown etiology) and autoimmune liver diseases. Presently, it is difficult to establish whether these two kinds of presentation of liver injury are discrete entities with a different pathogenesis or whether they are expressions of the same disorder, where genetic factors and duration of gluten exposure may have a different impact on the severity and characteristics of liver damage.[11] The spectrum of autoimmune CD-related liver disorders includes Type 1 and 2 autoimmune hepatitis, overlap syndrome, autoimmune cholangitis, primary sclerosing cholangitis and primary biliary cirrhosis (PBC).[4] PBC is regarded as the most frequent liver CD-related immune disorder, being considered the most frequent expression of autoimmunity detected in CD after Hashimoto thyroiditis, Type 1 diabetes mellitus and Sjogren syndrome.[12]