Fecal microbiota in celiac disease.
Abstract
Celiac disease (CD) is an autoimmune enteropathy induced by gluten ingestion in genetically susceptible individuals. Genetic predisposition plays an important role in the development of CD, but it is not sufficient by itself for the disease development. Although gluten proteins are the main environmental factor involved in CD pathogenesis and ingestion of gluten is necessary to manifest the disease, recent studies have suggested that alteration of the microbiota could be involved and, in particular, the interplay between gut microbiota and the mucosal immune system. Dysbiosis, the alteration of the microbiota, has been associated with a variety of intestinal pathologies including Crohn disease and CD. Most observational studies in children and adults with CD have shown alterations in the intestinal microbiota composition compared to control subjects, which is only partially recovered after treatment with a gluten‐free diet (GFD). At this time, the only treatment for CD is lifelong adherence to a GFD, which involves the elimination of grains containing gluten, wheat, rye, and barley. However, it is difficult for many patients to follow a GFD. Abnormalities in the gut microbiome in CD patients have led to the use of probiotics as a promising alternative as a therapeutic or preventative approach.
Keywords
- celiac disease
- gluten free diet
- intestinal microbiota
- dysbiosis
- probiotics
1. Introduction
Celiac disease (CD) is an autoimmune enteropathy induced by gluten ingestion in genetically susceptible individuals [1]. The major genetic risk factor for CD is represented by HLA‐DQ genes. Ninety percent of affected individuals carry the HLA‐DQ2 haplotype, 5% the DQ8 haplotype, and the remaining 5% carry at least one of the two DQ2 alleles [1, 2]. Genetic predisposition plays an important role in the development of CD but it is not sufficient by itself for the disease development [3]. Approximately, 30% of the general population carry the HLA‐DQ2/8 CD susceptibility genes, however, only 2–5% of these individuals will develop CD, suggesting that additional environmental factors contribute to disease development [4]. Although gluten proteins are the main environmental factor involved in CD pathogenesis and ingestion of gluten is necessary to manifest the disease, recent studies have suggested that potential factors such as birth delivery, breast‐feeding, infectious agents, and antibiotic intake could contribute to the development of CD [5–7]. The alteration of the microbiota could also be involved and, in particular, the interplay between gut microbiota and the mucosal immune system [8].
The microbiota, the set of microorganisms that colonize the human body, has a fundamental role for the host. It is important for both physiological and metabolic factors, ranging from the absorption of nutrients to the regulation and development of the immune system [9]. Dysbiosis, the alteration of the microbiota, has been associated with a variety of pathologies like Crohn disease and obesity [10, 11]. Most observational studies in children and adults with CD have shown alterations in the intestinal microbiota composition compared to control subjects, which is partially recovered after treatment with a gluten‐free diet (GFD) [12–14]. It has been demonstrated that levels of
At this time, the only treatment for CD is lifelong adherence to a GFD, which involves the elimination of grains containing gluten, wheat, rye, and barley. However, it is difficult for many patients to follow a GFD. Some probiotics have been found to digest or alter gluten polypeptides [18]. Abnormalities in the gut microbiome in CD patients have led to the use of probiotics as a promising alternative as a therapeutic or preventative approach.
Here we focus on the role of microbiota in the pathogenesis of CD and on the chances for probiotics to be involved in an alternative treatment strategy.
2. Microbiota composition in celiac children
Several research papers have suggested that an important risk factor involved in the etiology of CD could be the gut microbiota. Multiple studies investigating the role of gut microbiota in CD have been performed on fecal samples and, later, on duodenal biopsies.
The studies that have addressed the relation between fecal microbiota and CD in the pediatric population are summarized in Table 1 [13, 19–24]. In the earliest report involving a total of 49 children, 26 celiac patients aged 12–48 months and 23 age‐matched controls, Collado et al. evaluated the composition of the fecal microbiota by both culture‐dependent and culture‐independent methods using fluorescent in situ hybridization (FISH) [13]. They showed a high level of
Author/ References |
Year | Country | Patients population and sample size |
Methods | Main results |
---|---|---|---|---|---|
Collado et al. [13] | 2007 | Spain | 26 untreated CD (mean age, 26 months) 23 controls (mean age, 23.1 months) |
Culture+ FISH | In untreated CD: ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ |
Sanz et al. [19] | 2007 | Spain | 10 untreated CD (mean age, 28 months) 10 controls (mean age, 24 months) |
Culture+qPCR+DGGE | In untreated CD: High diversity of fecal microbiota ↑ ↑ ↑ ↓ ↓ |
Collado et al. [20] | 2009 | Spain | 30 untreated CD (mean age, 38.5 months) 18 treated CD (mean age, 37.7 months) 30 controls (mean age, 33.5 months) |
qPCR | In untreated and treated CD: ↑ Bacterial count ↑ ↑ B ↑ ↓ In treated CD: ↑ |
Di Cagno et al. [23] | 2009 | Italy | 7 untreated CD (range, 6–12 years) 7 treated CD (range, 6–12 years) 7 (range, 6–12 years) controls |
PCR+DGGE | In treated and untreated CD: ↓ Ratio of cultivable lactic acid bacteria and In treated CD and in controls: Only in controls: |
De Palma et al. [21] | 2010 | Spain | 24 untreated CD (mean age, 5.5 years) 18 treated CD (mean age, 5.5 years) 20 controls (mean age, 5.3 years) |
FISH+ flow cytometry | In untreated CD: ↓ ↓ ↓ ↓ ↑ In untreated CD and in controls: ↓ Levels of IgA coating the |
Sanchez et al. [22] | 2012 | Spain | 20 (mean age, 57.4 months) untreated CD 20 (mean age, 67.3 months) treated CD 20 (mean age, 54.0 months) controls |
PCR+ DNA sequencing | In untreated CD: ↑ ↑ ↓ ↑ |
Lorenzo Pisarello et al. [24] | 2015 | Argentina | 15 treated CD (mean age, 7.5 years) 15 controls (mean age, 6.5 years) |
Culture (autoaggregation assay, hydrophobicity assay) | In treated CD ↓ ↑ symptom in CD |
Duodenal microbial composition of pediatric CD patients was explored more extensively later on, with the main findings summarized in Table 2 [20, 25–33]. Microbiota characterization from duodenal biopsy specimens was initially carried out on CD Spanish children by Nadal et al. [25] in 2007. The authors, in an attempt to identify the specific composition of the duodenal microbiota of celiac patients (with active and non‐active disease), evaluated 20 CD patients on GCD, 10 CD patients on GFD for 1–2 years, and 8 healthy controls. Bacteriological analyses of duodenal biopsy specimens, carried out by fluorescent in situ hybridization coupled with flow cytometry, showed that the proportions of total and Gram‐negative potentially pro‐inflammatory bacteria were significantly higher in CD patients with active disease than in patients on GFD and controls. Although, the ratio of beneficial bacterial groups (
Authors/ references |
Years | Country | Patients population and sample size |
Methods | Main results |
---|---|---|---|---|---|
Nadal et al. [25] | 2007 | Spain | 20 (untreated CD (mean age, 5.1 years) 10 treated CD (mean age, 5.6 years) 8 controls (mean age, 4.1 years) |
FISH+ flow cytometry | In untreated CD: ↑ Total bacteria ↑ Gram‐negative bacteria ↑ In treated and untreated CD: ↓ The ratio of |
Collado et al. [20] | 2009 | Spain | 8 untreated CD (mean age, 56.4 months) 8 treated CD (mean age, 65.2 months) 8 controls (mean age, 45.0 months) |
qPCR | In untreated CD: ↑Bacterial counts ↑ ↓ ↑ ↑ ↓ In treated and untreated CD: ↑ ↑ |
Ou et al.[29] | 2009 | Sweden | 33 untreated CD (median age, 5.9 years) 17 treated CD (median age, 7.5 years) 3 challenged CD (median age, 10.8 years) 18 controls (mean age, 3.2 years) |
Culture +Scanning electron microscopy | In untreated CD ↑ ↑ |
Schippa et al. [30] | 2010 | Italy | 20 CD (before and after GFD) (mean age, 8.3 years) 10 controls (mean age, 11.7 years) |
TTGE | Differences in biodiversity between untreated CD and treated CD ↑ |
Sanchez et al. [26] | 2010 | Spain | 20 treated CD (mean age, 51.1 months) 12 untreated CD (mean age, 54.9 months) 8 controls (mean age, 50.1 months) |
PCR‐DDGE | In untreated and treated CD: ↓ In untreated CD: ↓ ↑ ↑ ↑ ↓ ↓ ↓ ↓ |
Di Cagno et al. [31] | 2011 | Italy | 19 treated CD (mean age 9.7 years) 15 controls (mean age, 10.4 years) |
PCR‐DDGE | In treated CD: ↓ ↓ ↓ ↑ ↑ ↑ |
Sanchez et al. [28] | 2013 | Spain | 32 untreated CD ( mean age, 5.1 years) 17 treated CD (mean age, 5.9 years) 8 controls (mean age, 6.9 years) |
Culture +PCR | In untreated CD: ↑ ↓ ↓ ↓ |
Nistal et al. [27] | 2012 | 8 untreated CD (mean age, 3.75 years) 5 controls (mean age, 7.2 years) |
16SrRNA gene sequencing | ↓ |
|
De Meij et al. [32] | 2013 | Netherland | 21 untreated CD (median age, 6.8 years) 21 controls (median age, 8.1 years) |
IS‐pro | In treated and untreated CD: ↑ ↑ ↑ |
Cheng et al. [33] | 2013 | Finland | 10 untreated CD (median age 9.5 years) 9 controls (median age, 8.5 years) |
qRT‐PCR+ HIPchip microarray | No significant differences in the abundance of bacterial phylum‐like groups between CD and controls The bacterial diversity was comparable between CD and controls In treated and untreated CD: ↑TLR2 expression ↑ IL‐10, IFN‐g, C-X-C chemokine receptor type 6 expression |
Giron Fernandez‐Crehuet et al. [34] | 2015 | Spain | 11untreated CD (median age, 5.0 years) 6 controls (median age, 8.8 years) |
DGGE | The intestinal microbiota of children with Marsh 3c lesion showed similarity of 98% and differs from other CD children with lesion as Marsh 3a, 3b and Marsh 2 In CD: ↓ Richness, diversity and abitability of In untreated CD: ↓ ↓ ↑ |
In contrast, two recent studies reached different results. De Meij et al. [33], analyzing the total microbiome profile in small bowel biopsies of 21 untreated CD and 21 age‐matched controls, found that mucosa‐associated duodenal microbiome composition and diversity did not differ between children with untreated CD and controls. The same results were obtained by Cheng et al. using bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of 10 CD and nine healthy children, suggesting that the duodenal mucosa‐associated bacteria do not play an important role in the pathogenesis of CD [34].
In summary, although the majority of the studies available have confirmed the presence of intestinal dysbiosis in CD children characterized by low levels of
3. Pathogenetic role of intestinal dysbiosis in CD
The intestinal microbiota composition and function play a fundamental role in the balance between the host's health and disease by different mechanisms: (1) regulation of epithelial cell proliferation and expression of tight junction proteins which act on intestinal permeability; (2) influence on mucin gene expression by goblet cells and their glycosylation pattern; 3) secretion of antimicrobial peptides (defensins, angiogenins, Reg3γ, etc.) by intestinal cells, which contribute to control gut bacterial adhesion. Certain components of the gut microbiota also affect the expression and activation of pattern recognition receptors (PRR), such as toll‐like receptors (TLRs), which are expressed by epithelial cells and innate immune cells. The mammalian TLR recognizes specific patterns of microbial components, called pathogen‐associated molecular patterns (PAMPs). After the PRR‐PAMP interaction, activated innate immune cells start the adaptive immune response by presenting the antigen and by producing cytokines, which leads to antigen‐specific, protective immune response. In inflammatory and autoimmune diseases this response causes damage to host's tissues [36]. The gut microbiota impacts on adaptive immunity. Recently, specific commensal bacteria have been shown to influence T lymphocyte production (Th1, Th17) or anti‐inflammatory regulatory T cells (Tregs) [36].
To date, human microbiota and mucosal barrier function are the key players in etiology of many inflammatory and autoimmune diseases [37]. Changes in mechanisms regulating mucosal immunity and tolerance, can lead to impaired mucosal barrier function, increased penetration of microbial components from lumen into the mucosa and circulation, and consequently lead exaggeration of aberrant immune responses and inflammation.
The exact mechanisms through which the gut microbiota might influence CD onset or progression is unknown, but could include activation of innate immune system, modulation of the epithelial barrier, or exacerbation of the gliadin‐specific immune response [38]. Moreover, the presence of microbiota can significantly influence the inflammatory effect of gluten. The microbiota may facilitate the access of gliadin peptides to the lamina propria and its interaction with infiltrated lymphocytes and antigen presenting cells (APCs) responsible for triggering the immune response via different mechanisms. In genetically predisposed individuals, gluten in association with microbial antigens can stimulate and modulate innate and adaptative immune response, sustaining a chronic mucosal inflammation, underlining this chronic disease [38].
4. Probiotics in the treatment of CD
Probiotics are nonpathogenic live microorganisms, which when orally administered in adequate amounts, alter the microflora of the host and have beneficial health effects. Probiotics have shown to preserve the intestinal barrier promoting its integrity both in vitro and in vivo [39, 40] as well as regulating the response of the innate and adaptative immune system. The association of CD with intestinal dysbiosis and the evidence supporting a role for the microbiota and specific bacteria in maintaining gut barrier function and regulating the response of the innate and adaptive immune system, have supported the potential use of probiotics in CD treatment [41, 42]. Although the data regarding the use of probiotics for CD are encouraging, most of these data come from in vitro experimental models of CD [43, 44]. Studies regarding probiotics and CD in humans are very scarce [45–47]. Smecuol et al. evaluated the effect of the
In children, the clinical trials performed on the effect of probiotics on CD are summarized in Table 3. In the earliest study Olivares et al. [45] evaluated the influence of
At this time, the only treatment for CD is lifelong GFD, which involves the elimination of grains containing gluten, wheat, rye, and barley in addition to food products and additives derived from them [48]. To date, adherence to a diet is difficult for many patients. Studies have shown that dietary transgression in patients with CD is common and can occur anywhere from 32% to 55% [49]. Moreover, a GFD may be rich in high glycemic index foods which can increase insulin resistance and, thus, the risk of obesity and cardiovascular disease. In the last decade, new therapies have been suggested to improve compliance to a GFD or to replace a GFD [50]. The use of probiotics appears to be able to reduce the damage caused by eating gluten‐containing foods and may even accelerate mucosal healing after the initiation of GFD [50, 51]. A specific commercially available probiotic, VSL#3 (containing eight different bacteria), has been shown to reduce the toxicity of gluten when used in a fermentation process [52]. It is thought that the gut microbiota can be modified in its composition and function by probiotic administration. These may counteract or postpone the onset of CD, and it can be useful in patients on GFD, when the normal composition of the intestinal flora has not yet fully recovered.
Authors/ references |
Years | Country | Study design | Patients population and sample size |
Main results | Comments |
---|---|---|---|---|---|---|
Olivares et al. [45] | 2013 | Spain | DB, R, PC | 18 CD (mean age, 6.8 years) received |
↓ |
|
Klemenac et al. [46] | 2015 | Italy Slovenia |
DB, R, PC | 22 CD (age, 10.43) daily received 25 CD (age, 10.81) daily received placebo for 3 months 18 (age, 8.83) controls |
↓TNF‐α levels on CD group | Probiotic intervention with |
5. Conclusions
An alternative treatment that can improve CD patients’ quality of life may lie in probiotics. In particular, probiotics such as
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