TABLE 1.
Summary of studies evaluating the gut microbiota characteristics in patients with celiac disease1
| Study (publication year) (reference) | Patients | Age group | Sampling site/methods | Outcomes | Main findings |
|---|---|---|---|---|---|
| Forsberg et al. (2004) (92) | Patients with untreated celiac disease (n = 55), patients with treated celiac disease (n = 53), patients challenged for celiac disease (n = 42), and control individuals (n = 78) | Children with median (range) age of 5.4 (0.8–15.8), 5.9 (1.8–17.4), 6.8 (3–12.7), and 5.4 (0.8–17.9) y in the untreated, treated, challenged, and control group, respectively | Intestinal biopsies from proximal jejunum/scanning electron microscopy; qRT-PCR, antibody and lectin immunohistochemistry | Bacteria associated with intestinal epithelium, and epithelial innate immune status in jejunal biopsies | Bacteria commonly found in the intestinal mucosa of patients with celiac disease but not in that of control individualsRod-shaped bacteria frequently associated with the mucosa of patients with celiac disease, in both active and inactive diseaseRod-shaped bacteria frequently associated with the mucosa of patients with celiac disease, in both active and inactive diseaseUnique carbohydrate structures of the glycocalyx/mucous layer are features of patients with celiac diseaseIncreased production of mucin-2, α-defensins HD-5/HD-6, and lysozyme in patients with active celiac disease |
| Collado et al. (2007) (15) | Patients with celiac disease (n = 26) and age-matched control individuals (n = 23) | Infants, median (range) age of 26.3 (12–48) and 23.0 (11–45) mo in the celiac disease and control group, respectively | Fecal samples/FISH | Fecal microbiota composition | Higher amounts of Bacteroides, Clostridium, and Staphylococcus in patients with celiac diseaseBifidobacterium tended to be higher in healthy control individualsBifidobacteriumtended to be higher in healthy control individualsLevels of Bacteroides-Prevotella, Clostridium histolyticum, Eubacterium rectale-C. coccoides, Atopobium, and sulfate-reducing bacterial groups were also significantly higher in patients with celiac disease |
| Nadal et al. (2007) (20) | Patients with active celiac disease (n = 20), patients with inactive celiac disease consuming a GFD (n = 10), and control individuals (n = 8) | Children, mean (range) age 5.1 (1.6–12) y, 5.6 (2–7.8) y, 4.1 (1.9–9) y, in active and inactive disease, and control individuals, respectively | Duodenal biopsies/FISH and flow cytometry | Composition and duodenal microbiota | Higher gram-negative bacteria in patients with active celiac diseaseIncreased abundance of Bacteroides and Escherichia coli in patients with active celiac disease compared with control individualsLower Lactobacillus-Bifidobacterium to Bacteroides-Escherichia coli ratio in both groups of patients with celiac disease compared with control individuals |
| Collado et al. (2008) (93) | Patients with active celiac disease (n = 30), nonactive celiac disease (n = 18), and age-matched control individuals (n = 30)For duodenal biopsies: Patients with active celiac disease (n = 25), nonactive celiac disease (n = 8), and age-matched control individuals (n = 8) | Children, mean age 56.4 ± 38.5 mo, 65.2 ± 37.7 mo, and 45.0 ± 33.5 mo in active celiac disease, nonactive celiac disease, and control group, respectively | Fecal and duodenal biopsies/qRT-PCR analysis | Bifidobacterium species composition of duodenal biopsies and fecal samples | Lower numbers of total Bifidobacterium and B. longum species in feces and duodenal biopsies in patients with celiac disease than those of control individualsLower prevalence of B. catenulatumin duodenal biopsies of both patient groups with celiac disease. B. dentium higher in feces of patients with nonactive celiac disease compared with control individuals |
| Ou et al. (2009) (94) | Untreated patients with celiac disease (n = 33), patients with celiac disease consuming a GFD (n = 17) and challenger celiac disease (n = 3), and control individuals (n = 18) | Children, median (range) age 5.9 (1.2–16) y, 7.5 (2.4–17) y, 10.8 (5.2–18) y, 3.2 (1–18.5) y, in untreated, treated, challenged, and control groups, respectively | Intestinal biopsies (distal duodenum proximal jejunum/16S rDNA sequencing, culture-methods, and scanning electron microscopy) | Microbiota composition of the proximal small intestine | Quite similar proximal small intestine microbiota in patients with celiac disease compared with control individualsFrom celiac disease biopsies positive for rod-shaped bacteria at scanning electron microscopy, the microbiota was enriched in Clostridium, Prevotella, and Actinomyces |
| Sánchez et al. (2010) (81) | Patients with active celiac disease (n = 20), treated celiac disease (n = 12), and control individuals (n = 8) | Preschool children, mean age 51.1 ± 31.8 mo, 54.9 ± 25.6 mo, 50.1 ± 31.2 mo in active celiac disease, treated celiac disease, and control individuals, respectively | Duodenal biopsies/partial 16S rRNA gene sequencing and PCR-denaturing gradient gel electrophoresis | Bacteroides, Bifidobacterium, and lactic acid bacteria composition | Reduced Bacteroides strains in both groups of patients and higher Bifidobacterium diversity in patients with active celiac disease compared with control childrenHigher lactic acid bacteria diversity found in patients with treated celiac disease and control individuals than in patients with active celiac disease |
| De Palma et al. (2010) (17) | Patients with treated celiac disease (n = 18), patients with untreated celiac disease (n = 24), and healthy control individuals (n = 20) | Children, mean (range) age 5.5 (2.1–12) y, 5.5 (1–12.3) y, and 5.3 (1.8–10.8) y in untreated, treated, and healthy children | Fecal samples/FISH and flow cytometry | Fecal microbiota composition and percentage of immunoglobulin-coated bacteria | Reduced gram-positive to gram-negative bacteria ratio in both groups of patients with celiac diseaseLower abundance of Bifidobacterium, C. histolitycum, C. lituseburense, and Faecalibacterium prausnitzii in patients with untreated celiac disease |
| Sanchez et al. (2012) (95) | Patients with active celiac disease (n = 20), and patients with inactive celiac disease (n = 18), healthy control individuals (n = 20) | Children, median (range) age of 3.9 (1.0–8.8) y, 6.2 (3.3–12.2) y, and 5.7 (2.5–10.8) y in patients with active celiac disease, inactive celiac disease, and healthy control individuals, respectively | Fecal samples/partial 16S rRNA gene sequencing | Diversity of Bacteroides spp. and its role in the generation of gliadin peptides with immunotoxic effect | Similar diversity distribution found among the 3 groups. Lower Renyi diversity in patients with active celiac disease compared with control individualsBacteroides fragilis more often found in patients with celiac disease compared with control individualsParabacteroides distasonis more often isolated from patients with active celiac disease. Bacteroides finegoldii more often isolated from control individuals compared with patients with active celiac disease, and Bacteroides ovatus more commonly found in control individuals than in patients |
| Cheng et al. (2013) (96) | Patients with celiac disease (n = 10), healthy control individuals (n = 9), adult patients with celiac disease consuming a GFD (n = 6) | Children, median (range) age 9.5 (3–14) y and 8.5 (4–16) y, in children with celiac disease and healthy control individuals, respectivelyAdult patients with celiac disease, mean age 46 (30–60) y | Duodenal biopsies/16S rRNA gene of intestinal phylotypes | To characterize duodenal microbiota and assess microbiota differences between groups | Similar microbiota composition and diversity, as well as similar microbe-associated molecular pattern of the microbiota, were found in patients and healthy control individuals8 bacterial profile groups differed in patients with celiac disease (Prevotella melaninogenica and Prevotella spp. were higher, while Prevotella oralis, Ruminococcus bromii, Papillibacter cinnamivorans, Proteus, and Clostridium stercorarium were decreased) |
| Wacklin et al. (2013) (97) | Patients with celiac disease with clinical symptoms (n = 33), asymptomatic patients with celiac disease (n = 8), and control subjects (n = 18) | Adults, mean (range) age 39 (18–67) y | Small bowel biopsy/PCR denaturing gradient gel electrophoresis and 16S rRNA gene sequencing | Duodenal microbiota composition and its relation with intestinal and extraintestinal symptoms | Patients with celiac disease with gastrointestinal symptoms or anemia exhibited lower microbial diversity compared with patients with dermatitis herpetiformisA higher abundance of Proteobacteria was found in patients with clinical symptomsSimilar microbiota composition between patients with dermatitis herpetiformis and control subjects (high abundance of Firmicutes) |
| Sanchez et al. (2013) (98) | Patients with active celiac disease (n = 32), patients with treated celiac disease (n = 17), and control individuals (n = 8) | Children, mean ± SD age 5.1 ± 3.2, 5.9 ± 1.2, and 6.9 ± 4.2 y in patients with active celiac disease, nonactive celiac disease, and control individuals, respectively | Duodenal biopsies/partial 16S rRNA gene sequencing | Composition and diversity of cultivable duodenal mucosa-associated bacteria | Higher amount of Proteobacteria with reduced abundance of Firmicutes in the active celiac disease group compared with nonactive celiac disease and control individualsIncreased abundance of Enterobacteriaceaeand Staphylococcaceae families, but a reduced abundance of members of the Streptococcaceae family in patients with active celiac disease compared with control individuals |
| Wacklin et al. (2014) (99) | Patients with celiac disease treated with a GFD, with (n = 18) and without (n = 18) persisting gastrointestinal symptoms | Middle-age adults with median (range) age of 54 (27–72) and 63 (42–75) y in the group with and without symptoms, respectively | Duodenal biopsies samples/16S rRNA gene pyrosequencing | Microbiota composition comparison between both groups of patients | Reduced microbiota richness with increased abundance of Proteobacteria and lower abundance of Bacteroidetes and Firmicutes in patients with celiac disease with persistent gastrointestinal symptoms |
| Francavilla et al. (2014) (100) | Patients with celiac disease (n = 13) consuming a GFD, and healthy control individuals (n = 13) | Children and early adolescents, mean ± SD age 9.7 ± 1.4 and 10.2 ± 1.4 in patients and control individuals, respectively | Saliva samples/culture-dependent techniques. Microbial diversity by pyrosequencing of the amplified V1-V3 region of 16S rRNA gene | Assessment of salivary microbiota and metabolomes | Reduced total number of anaerobes and lower diversity and substrate richness found in children with celiac diseaseIncreased Lachnospiraceae, Gemellaceae,and Streptococcus sanguinis, but reduced Streptococcus thermophilus in children with celiac diseaseAn increased level of Bacteroidetes with a reduced amount of Actinobacteria(Rothia mucilaginosa was the only Actinobacteria species found to be highest in children with celiac disease) |
| Caminero et al. (2015) (101) | Patients with celiac disease consuming a normal diet (n = 22), patients with celiac disease consuming a GFD (n = 20), healthy volunteers consuming a normal diet (n = 16), healthy volunteers consuming a GFD (n = 11) | Adult patients consuming a regular diet, mean (range) age 39.5 (15–60) y, and 30.6 (22–42) y in patients with celiac disease consuming a GFD; mean (range) age of 30.1 (25–45) y in healthy volunteers consuming a regular diet, and 32.2 (25–45) y in healthy volunteers consuming a GFD | Fecal samples/16S rDNA gene partial sequencing | Proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA, and the amount of gluten in fecal samples | Proteolytic activities and SCFA increased in patients with celiac diseaseAlterations in Clostridium, Lactobacillus, or Bacteroides were reported in patients with celiac diseaseCommensal microbial activity is important in the metabolism of gluten and is altered in patients with celiac disease |
| Lorenzo et al. (2015) (102) | Patients with celiac disease (n = 15) consuming a GFD and healthy control individuals (n = 15) | Children, mean (range) age 7.5 (3–14) y and 6.5 (2–11) y in patients with celiac disease and healthy control group, respectively | Fecal samples/culture-dependent techniques | Change in the composition of common bacteria from the intestinal microbiota | A lower number of Lactobacillus and the tendency to an increased Enterobacteria count in patients with celiac disease |
| Nistal et al. (2016) (19) | Patients with celiac disease (untreated, n = 9) and control individuals without celiac disease (n = 9) | N/A | Duodenal biopsies/pyrosequencing of 16S rRNA | Composition of the duodenal microbiota | A nonsignificant reduction in bacterial richness and diversity in patients with celiac diseaseMain bacterial communities belonged to Firmicutes and Proteobacteria phyla in both patients with celiac disease and control individuals without celiac disease, without differences in the duodenal bacterial composition between groups |
| Tian et al. (2017) (89) | Patients with celiac disease in remission (n = 21), and patients with refractory celiac disease (n = 8), healthy control individuals (n = 20) | Adults, mean ± SD age 36.2 ± 17, 54.1 ± 13.5, and 35.4 ± 15.7 y in patients with celiac disease in remission, refractory celiac disease, and healthy control individuals, respectively | Stimulated whole saliva samples/16S rRNA-based MiSeq analysis | Salivary enzymatic activities and oral microbial profiles | Higher levels of lactobacilli in both groups of patients with celiac diseaseLower microbial diversity in the celiac disease group compared with healthy control individualsHigher Bacteroidetes and Fusobacteria, but lower Actinobacteria in patients with celiac disease under remission compared with the celiac disease refractory groupSeveral species-level differences found when comparing healthy control individuals against both groups with celiac disease |
| Rintala et al. (2018) (103) | Children with high genetic risk of developing celiac disease, who developed (n = 9) or did not develop celiac disease at age 4 yHealthy control individuals (n = 18) | Median age at diagnosis 3.5 (2.6–4.2) y | Fecal samples at age 9 and 12 mo/16S rRNA gene sequencing | Fecal microbiota composition before the onset of the disease | Similar bacterial diversity index between groups at both ages 9 and 12 moNo between-group differences in bacterial composition regarding microbial abundances at phylum and genus levelsSimilar Bacteroides-Prevotella and Bacteroides-Bifidobacterium ratios between groups at both ages (9 and 12 mo) |
| Garcia-Mazcorro et al. (2018) (104) | Patients with celiac disease (n = 6), patients with NCGS (n = 12), and control subjects (n = 12) | Adults with median (range) age of 41.5 (25–73), 24.0 (21–59), and 25.5 (23–64) y in patients with celiac disease, NCGS patients, and control individuals, respectively | Small bowel mucosal biopsies (proximal duodenum) and fecal samples/16S rRNA gene sequencing | Gut microbiota composition | Novispirillum genus increased in duodenal biopsies on patients with celiac disease. Actinobacillus genus and Ruminococcaceae family were higher in duodenal and fecal samples of NCGS patients |
| Caminero et al. (2019) (87) | Patients with celiac disease with clinical symptoms (n = 12), control individuals without celiac disease (n = 8) | Adults with mean (range) age of 42.3 (18–64), and 47 (30–72) y in celiac disease and control groups, respectively | Intestinal duodenal biopsies (second portion)/16S rRNA gene sequencing. Glutenasic activity by bioassay (gluten 1%) | Mucosa-associated microbiota | Proteobacteria and Firmicutes were the most commonly found bacterial types. No major between-group differences found regarding α or β diversityGlutenasic activity showed positive association with Proteobacteria and negative association with Firmicutesand Bacteroidetes relative abundanceIncreased glutenasic activity correlated with increased Pseudomonas and Janthinobacterium, and with reduced Lactobacillus and Clostridium |
| Bodkhe et al. (2019) (105) | Patients with celiac disease in gluten-containing diet (n = 23), healthy first-degree relatives of patients with celiac disease (n = 15), control individuals [patients with hepatitis B carriers or having functional dyspepsia (n = 24)] | Adults with mean ± SD age of 23.4 ± 9.5, 31.6 ± 10.8, 30.6 ± 12.3 y in patients with celiac disease, FDRs of patients, and control individuals, respectively | Duodenal biopsies and fecal samples/16S rRNA gene sequencing | Duodenal and fecal microbiota composition and changes in fecal microbiota between celiac disease, FDRs, and disease-control individuals | No significant differences in abundance of members of duodenal microbiota between celiac disease and FDRs or control. Similar duodenal and fecal α diversity between groupsIncreased duodenal Actinobacteria and Bacteroides phyla in FDRs compared to control individualsGreater abundance of the order Clostridiale in FDRs compared to control individuals, at duodenal and fecal samples. ASVs in duodenal samples was higher for Helicobacter and Megasphaera in patients with celiac diseaseSimilar abundance of phylum of fecal microbiota between groups. Reduced fecal abundance of ASVs classified as Akkermansia and Dorea in patients with celiac disease and FDRs compared to control individuals |
1
ASV, amplicon sequence variant; FDR, first-degree relative; FISH, fluorescence in situ hybridization; GFD, gluten-free diet; N/A, not available; NCGS, nonceliac gluten sensitivity.