Altered Duodenal Microbiota Composition in Celiac Disease Patients Suffering From Persistent Symptoms on a Long-term Gluten-free Diet

Pirjo Wacklin PhD; Pilvi Laurikka; Katri Lindfors PhD; Pekka Collin MD; Teea Salmi MD; Marja-Leena Lähdeaho MD; Päivi Saavalainen PhD; Markku Mäki MD; Jaana Mättö PhD; Kalle Kurppa MD; Katri Kaukinen MD


Am J Gastroenterol. 2014;109(12):1933-1941. 

In This Article

Abstract and Introduction


Objectives A significant fraction of celiac disease patients suffer from persistent symptoms despite a long-term gluten-free diet (GFD) and normalized small bowel mucosa. The commonly suggested reasons, such as inadvertent gluten-intake or presence of other gastrointestinal disease, do not explain the symptoms in all these patients. Recently, alterations in intestinal microbiota have been associated with autoimmune disorders, including celiac disease. This led us to test a hypothesis that abnormal intestinal microbiota may be associated with persisting gastrointestinal symptoms in treated celiac disease patients.

Methods Duodenal microbiota was analyzed in 18 GFD-treated patients suffering from persistent symptoms and 18 treated patients without symptoms by 16S rRNA gene pyrosequencing. The celiac disease patients had been following a strict GFD for several years and had restored small bowel mucosa and negative celiac autoantibodies. Their symptoms on GFD were assessed with Gastrointestinal Symptom Rating Scale.

Results The results of several clustering methods showed that the treated celiac disease patients with persistent symptoms were colonized by different duodenal microbiota in comparison with patients without symptoms. The treated patients with persistent symptoms had a higher relative abundance of Proteobacteria (P=0.04) and a lower abundance of Bacteroidetes (P=0.01) and Firmicutes (P=0.05). Moreover, their microbial richness was reduced. The results indicated intestinal dysbiosis in patients with persistent symptoms even while adhering to a strict GFD.

Conclusions Our findings indicate that dysbiosis of microbiota is associated with persistent gastrointestinal symptoms in treated celiac disease patients and open new possibilities to treat this subgroup of patients.


In celiac disease, the initiation of a gluten-free diet (GFD) usually results in a rapid improvement of the clinical symptoms followed by a slower recovery of the small bowel mucosal damage. Nevertheless, there is evidence that many patients suffer from persistent symptoms despite long-term dietary treatment.[1,2] The most common reason for such ongoing symptoms is continuous intentional or inadvertent gluten intake. Alternative causes are, for example, the presence of another unrecognized gastrointestinal disease, constipation due to low-fiber content in gluten-free products, or refractory celiac disease.[1–3] However, in many cases, the reason for persistent symptoms in otherwise healthy celiac patients with a strict GFD and restored intestinal mucosa cannot be explained.[4] In this respect, the rapidly advancing research focusing on the association of gut microbiota with gastrointestinal disorders is of great interest. There are several studies reporting imbalances in the intestinal microbiota of celiac disease patients.[5–7] For instance, abnormal microbiota composition characterized by decreased numbers of Bifidobacterium spp. and increased numbers of Bacteroides spp. have been found in duodenal biopsies of untreated patients.[5,6] In addition, the composition of duodenal microbiota has been shown to vary depending on the clinical presentation of celiac disease.[8] Interestingly, it appears that dysbiosis of intestinal microbiota does not completely recover even after the commencement of GFD and normalization of the small bowel mucosal morphology.[5,6,9] This led us to hypothesize that sustained intestinal dysbiosis might be associated with inadequate clinical response and persistent gastrointestinal symptoms often seen in treated celiac disease. To address this question, we compared the duodenal microbiota composition between well-defined cohorts of celiac disease patients with and without persistent symptoms while they were on long-term GFD and had normalized intestinal mucosa.