Gastrointestinal microbiome and gluten in celiac disease

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Gastrointestinal microbiome and gluten in celiac

disease

Xingxing Wu, Lin Qian, Kexin Liu, Jing Wu & Zhaowei Shan

To cite this article: Xingxing Wu, Lin Qian, Kexin Liu, Jing Wu & Zhaowei Shan (2021)

Gastrointestinal microbiome and gluten in celiac disease, Annals of Medicine, 53:1, 1797-1805,

DOI: 10.1080/07853890.2021.1990392

To link to this article: https://doi.org/10.1080/07853890.2021.1990392

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REVIEW ARTICLE

Gastrointestinal microbiome and gluten in celiac disease

Xingxing Wu

, Lin Qian

, Kexin Liu

, Jing Wu

and Zhaowei Shan

Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China;

Institute of Chinese Medicine, Nanjing Drum Tower

Hospital, Nanjing University, Drum Tower Clinical Medicine College of Nanjing University of Chinese Medicine, Nanjing, China

ABSTRACT

Coeliac disease (CD), also known as gluten sensitive enteropathy, is an autoimmune intestinal

disease induced by gluten in genetically susceptible individuals. Gluten is a common ingredient

in daily diet and is one of the main environmental factors to induce coeliac disease. Adhering

to gluten free diet (GFD) is an effective method for treating CD. Microbiota plays an extremely

important role in maintaining human health, and diet is the main factor to regulate the com-

position and function of gut microbiota. Recent studies have shown that gluten metabolism is

closely related to gastrointestinal tract (GIT) microbiota. With the increasing prevalence of coel-

iac disease, there is a need for alternative treatments to GFD. In this review, biological medica-

tion of gluten, relationship between gluten and gut microflora, effect of GFD on GIT microflora,

and effect of probiotics on CD were reviewed. By analysing the research progress on relation-

ship between gluten and gastrointestinal microbiome in coeliac disease, this review tried to

explore the prospective and potential mechanism of microecological agents in treating coel-

iac disease.

ARTICLE HISTORY

Received 19 May 2021

Revised 28 June 2021

Accepted 30 September 2021

KEYWORDS

Gluten; gastrointestinal

microbiome; coeliac disease;

gluten free diet; probiotics

1. Introduction

Coeliac disease is an autoimmune disorder that occurs

in genetically predisposed individuals, including adults

and children, who develop an immune reaction to glu-

ten. Even though this disease primarily affects the

small intestine, its clinical manifestations are broad,

with both intestinal and extra-intestinal symptoms.

There are multi-factors might affect this disease, such

as environmental, genetic factors and immune imbal-

ance [1]. The main clinical presentations include intes-

tinal symptoms, such as diarrhoea, abdominal

distension, abdominal pain; and extra-intestinal symp-

toms, such as anaemia, dermatitis herpetiformis, osteo-

penia and peripheral neuropathy. CD patients carry

specific susceptibility genes (HLA-DQ2, HLA-DQ8), but

their existence is not enough to cause the occurrence

of CD, which requires the participation of environmen-

tal factors-gluten [2]. As the consumption of gluten-

containing food increases, the incidence of related

autoimmune diseases has gradually increased (such as

CD, wheat allergic diseases) [3]. In genetically suscep-

tible individuals, gluten is one of the necessary condi-

tions for inducing CD. Gluten is a kind of protein

mainly existing in wheat, barley and rye, accounting

for 80%–85% of the total protein in wheat [4]. It is a

protein mixture composed of hundreds of monomers,

oligomers and polymers, mainly including gliadin and

glutenin. Among them, the main antigen protein caus-

ing CD is gliadin which is rich in glutamine and pro-

line, and cannot be digested by human digestive

enzymes and brush border peptidase [5–6]. Proline-

rich peptides are protected from proteolysis by gastric,

pancreatic and intestinal brush border membrane

enzymes, so they have an opportunity to build up to

high concentrations in the small intestine. However,

oral bacteria that secrete gliadin (gluten) degrading

enzymes had been identified. Their most active glia-

din-cleaving enzymes had also been identified and

purified [7–8]. Apart from interesting biological find-

ings, these bacteria and enzymes may lead to novel

and effective strategies to detoxify immunogenic glu-

ten peptides prior to their reaching the proximal small

intestine. Part of the gluten is hydrolysed by oral

microbial proteases in the oral cavity, thereby reduc-

ing its immunotoxicity. However, most gluten is hydro-

lysed by pepsin into high molecular weight peptides

CONTACT Jing Wu [email protected] Institute of Chinese Medicine, Nanjing Drum Tower Hospital, Nanjing University, Drum Tower Clinical

Medicine College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, China; Zhaowei Shan

[email protected]

Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Han zhong Road, Nanjing 210029, China

This article has been republished with minor changes. These changes do not impact the academic content of the article.

ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits

unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ANNALS OF MEDICINE

2021, VOL. 53, NO. 1, 1797–1805

https://doi.org/10.1080/07853890.2021.1990392

in the stomach. The peptides that enter the small

intestine from the stomach are not easily degraded

due to their rich proline. They stay in the intestine for

a long time and increase the probability of triggering

immune response. A large number of immunogenic

polymer peptides gathered in the intestinal lumen,

mainly including immunodominant peptides (such as

P57-P89 peptide and 33 peptide in a-gliadin) and

non-immune dominant peptides (such as P31P43),

triggered the adaptive immune response mediated by

CD4 þ Th1 cells and the innate immune response

mediated by intraepithelial lymphocytes respectively,

and leaded to infiltration of intestinal epithelial inflam-

matory cells, villus atrophy and crypt hyperplasia [9].

Thus, it will lead to the destruction of intestinal epi-

thelial cells and the increase of intestinal permeability,

resulting in diarrhoea, abdominal distention, abdom-

inal pain, emaciation, dermatitis herpetiformis and

other clinical symptoms. Although the gluten-free diet

can significantly improve the clinical symptoms of

patients with CD, gluten-free diet is expensive and has

very few products. In order to have a good quality of

life, patients have to adhere to the gluten-free diet. It

not only brings a financial burden to society and

patients themselves, but also brings social and psycho-

logical impact to patients [10]. In addition to gluten,

the microbiota dysbiosis of the digestive tract flora

may be another environmental factor that triggers CD.

Studies have confirmed that patients with CD have

disorders of the digestive tract flora. The abundance

and diversity of beneficial commensals have

decreased, while, pathobionts have increased. Coeliac

disease is associated with intestinal dysbiosis charac-

terized by increases in pathobionts virulence features

[11–12]. Research also shown that, diet has a great

influence on the composition and function of intes-

tinal flora, and gluten can affect the stability of intes-

tinal flora. Therefore, this review will mainly focus on

the relationship between gluten and oral flora, intes-

tinal flora in coeliac disease. It will also pay special

attention to analyse perspectives and trends of probi-

otics in coeliac disease treatment.

2. Gluten and oral flora

2.1. Oral flora

So far, it has been found that there are more than

1,000 kinds of bacteria in the oral cavity inhabiting sal-

iva, teeth, gingiva and other different parts. There are

about 10

bacteria per gram of dental plaque and

bacteria per millilitre of saliva, so the oral cavity

becomes the second place where microorganisms are

densely colonized in digestive tract [13–14]. The latest

research shows that the oral symbiotic flora can

increase the immune function of the oral mucosa to

prevent the invasion of pathogenic microorganisms.

For example, oral microbiota genera Veillonella and

Streptococcus promote the production of anti-micro-

bial peptides and the secretion of inflammatory cyto-

kines, increasing the epithelial barrier function and

thickness characteristic of oral mucosa [15]. However,

other studies have found that some pathogenic bac-

teria in oral microflora are not only related to oral dis-

eases such as dental caries, periodontitis, and oral

ulcers [16], but also related to infective endocarditis

[17] and coronary atherosclerosis [18], pneumonia [19],

obesity [20], intestinal diseases, etc. The flora in the

oral cavity of healthy humans can be transported in

large quantities to the distal end of the digestive tract,

yet the translocation of oral species to the intestine is

considered a rare aberrant event, and a hallmark of

disease [21]. Certain oral microorganisms may induce

intestinal diseases in genetically susceptible individu-

als. For example, Atarashi et al. found that oral

Klebsiella colonises the colon and induces Th1 cell dif-

ferentiation to elicit a severe intestinal mucosal inflam-

mation [22].

2.2. Oral flora reduces the immunogenicity

of gliadin

At present time, most studies are confined largely to

explore the relationship between microflora and intes-

tinal diseases. However, the oral cavity is the first

digestive organ that comes into contact with food and

is correlated to digestive system diseases directly.

Therefore, on the basis of duodenal flora and colonic

flora studies, the salivary flora should be further ana-

lysed to improve description of the digestive tract

flora characteristics [23]. Patients with CD have oral

flora dysbiosis. There are microbial flora in the oral

cavity, which are related to the metabolism of gluten

in CD (Table 1). Although the food containing gluten

stays in the oral cavity for a short time, the number

and types of flora in the saliva are significantly greater

than those colonized in the stomach and duodenum.

The effect of oral flora on digesting gluten should not

be ignored. Researchers have found that the initial

metabolism of gliadin in the oral cavity may be related

to the genus of Rothia, Actinomyces, Neisseria, and

Streptococcus that colonized the oral cavity [24].

Compared with healthy people, the saliva of patients

with CD is rich in bacteria that could degrade gluten,

and the degradation rate of gluten is higher. The

1798 X. WU ET AL.

significant increase of Lactobacillus species may be

one of the reasons [23]. The protease-resistant highly

immunogenic 33-mer a-gliadin peptide could be com-

pletely degraded by dental plaque bacteria to reduce

immunogenicity [23,25]. However, there were studies

on the contrary standpoint, reported that oral micro-

bial enzymes degrade part of gluten, which in turn

increases immunogenic small molecule peptides epito-

pes and further induces intestinal inflammation [23].

3. Gluten and intestinal flora

3.1. Intestinal flora

As we mentioned before, the oral cavity is the second

place where microorganisms are densely colonized in

digestive tract. However, the gut is the most densely

colonized place of microflora in digestive tract. A

refined estimate showed that microflora in one human

body were in a ratio of 1.3:1 to human cells. It was

estimated that more than 1,000 kinds of microorgan-

isms live in the gut, the gut microbiome of healthy

people mainly includes Firmicutes, Bacteroides,

Proteobacteria, Actinomycetes . And some researchers

estimated that there were thousands of bacterial spe-

cies in the gastrointestinal tract [26–27]. According to

the interaction with the host, the intestinal flora is div-

ided into three categories: probiotics (such as

Lactobacillus, Bifidobacterium, etc.), pathobionts (such

as Clostridium, Enterococcus faecalis , etc.) and oppor-

tunistic pathogens. The intestinal flora of healthy peo-

ple can protect and maintain the intestinal barrier

function, promote the metabolism and absorption of

nutrients, regulate immunity, anti-aging, prevent can-

cer and suppress cancer, etc [28]. There is a mutually

symbiotic relationship between the flora and the host.

The host provides nutrients and the microenvironment

for the flora. The flora helps to maintain human intes-

tinal homeostasis by participating in a series of physio-

logical functions of the host. A large number of

studies have shown that once the balance between

intestinal microflora and the human body is broken, it

will lead to multiple systemic diseases, such as obesity,

diabetes, atherosclerosis, irritable bowel syndrome,

inflammatory bowel disease, and coeliac disease

through bile acid metabolism, brain-gut axis, intestinal

barrier, and immune system and so on [29].

3.2. Gliadin directly induces intestinal

flora dysbiosis

For the coeliac disease patients, the balance between

intestinal microflora and the human body could be bro-

ken by the gliadin. From the mouth and stomach, large

quantity of undegraded gliadin is being pushed into

the small intestine and large intestine, provides abun-

dant substrates for different bacteria in the intestinal

cavity, thereby promotes the reproduction of gliadin-

degrading bacteria and breaks the steady state of intes-

tinal flora [30–31]. At present time, the composition

and structure of the small intestinal flora are mainly

evaluated by detecting the abundance and diversity of

the duodenal flora. D’Argenio et al. tested the duo-

denal mucosal flora of patients with active CD and

found that the abundance of Proteobacteria increased,

while the abundance of Firmicutes and Actinobacteria

decreased. Compared with GFD patients and healthy

individuals, members of the Neisseria genus

(Betaproteobacteria class) were significantly more abun-

dant in active CD patients. Neisseria flavescens was the

most abundant Neisseria species in active CD duode-

num [32]. Sanchez E et al. found that compared with

children with GFD and healthy children, the duodenal-

mucosal bacteria of children with active CD (normal

gluten-containing food diet) has increased abundance

of Proteobacteria and decreased abundance of

Firmicutes at the phylum level; the abundance of

Enterobacteriaceae and Staphylococcaceae increased,

and Streptococcaceae decreased at family level [33]. In

the CD animal experiment, it was also found that the

intestinal flora was imbalanced. For example, compar-

ing the gluten-sensitive (GS) macaques with healthy

macaques, it was found that the alpha diversity

(Shannon diversity index) and abundance of the faecal

flora of the GS macaques were reduced, and it was

found that, two of the top eight families,

Table 1. The relationship between Oral flora and gluten in CD.

Substrate types Degradability Outcome

Salivary flora [23] Gluten The degradation rate of gluten is

higher than healthy people

unspecified

Rothia, Actinomyces, Neisseria, and

Streptococcus [24]

Gliadin unspecified unspecified

Dental plaque bacteria [23,25] Immunogenic 33-mer

a-gliadin peptide

Complete degradation Reduce immunogenicity

Oral microbial enzymes [23] Gluten Partial degradation Induce immunogenicity

ANNALS OF MEDICINE 1799

Streptococcaceae and Lactobacillaceae, were enriched in

GS macaques [34].

3.3. Intestinal flora promotes the hydrolysis

of gliadin

The human body lacks proteases, which are able to

completely digest gluten. The role of intestinal flora in

the process of such protein metabolism cannot be

ignored. The undegraded gliadin is transported from

the small intestine to the large intestine. Once it

enters the large intestine, it is in close contact with a

large number of microorganisms in the gut. Due to

the diversity of bacterial genes in large intestine and

their different biochemical pathways from the human

body, it makes certain intestinal microorganisms have

the ability to metabolize gliadin [35]. Researchers have

found that there are flora related to the metabolism

of gliadin in the human intestine (such as the genera

Lactobacillus, Streptococcus, Staphylococcus, Clostridium,

Bifidobacterium)[36]. These microorganisms not only

exist in the large intestine, but also in the small intes-

tine to metabolize gluten. Camino et al. showed that,

compared with the healthy group, the duodenal

mucosal flora of CD mice on a gluten-containing diet

had a higher proteolytic activity against gluten

(“glutenasic” activity), and it is related to the abun-

dance of Proteobacteria (including Pseudomonas)[37].

Herr



an et al. studied the small intestinal flora that

decomposes gliadin in healthy people and patients

with CD, and isolated 114 bacterial strains belonging

to 32 different species from the duodenal mucosa, of

which, 85 strains were able to grow in a medium con-

taining gluten as the sole nitrogen source. 31 strains

showed extracellular proteolytic activity against gluten

protein and 27 strains showed peptidolytic activity

towards the 33-mer peptide, an immunogenic peptide

for coeliac disease patients [38].

3.4. Gliadin combined with intestinal flora induces

intestinal inflammation

Obviously, researchers cannot determine that intestinal

flora dysbiosis is the result of coeliac disease or an

environmental factor for CD, or both. Conventionally,

gliadin was considered to activate innate immunity

and adaptive immunity, and activate intestinal inflam-

mation by inducing the production of cytokines and

chemokines. In particular, the gliadin is deamidated by

tissue transglutaminase in the lamina propria of the

small intestine, and binds to HLA class II DQ2/8 mole-

cules of antigen-presenting cells, activates T cells,

macrophages and dendritic cells, and secretes inflam-

matory cytokines. It follows the activation of the adap-

tive immune response through the production of anti-

endomysium, antigliadin, and anti-transglutaminase

antibodies by B cells that increase intestinal perme-

ability [39]. In addition to gliadin, intestinal microflora

also play an indispensable role in inducing inflamma-

tion in the intestinal mucosa of patients with CD. As

we all know, immune factors are one of the causes for

CD, and adaptive immunity plays an important role in

the pathogenesis of CD. Studies have found that the

intestinal flora is closely related to adaptive immunity,

and intestinal microflora have important regulatory

effects on the two embranchments of host adaptive

immunity, B cells and T cells. The intestinal flora can

promote the production of IgA in the intestine by reg-

ulating the B cells response; it can also maintain the

balance between intestinal inflammation and immune

tolerance by inducing the differentiation of intestinal

Th17 and Treg cells [40].

Gliadin evokes intestinal barrier dysfunction, which

leads to the excessive growth and translocation of intes-

tinal pathogenic bacteria, resulting in intestinal micro-

ecological imbalance; The microecological imbalance

activates the immune inflammatory response by regulat-

ing the B cell and T cell. Inflammatory factors can fur-

ther increase the permeability of the intestinal mucosa

by destroying the intestinal epithel ial cells and aggra-

vate coeliac disease [41]. The CD intestinal mucosal

immune response may directly destroy the biological

barrier, thereby affecting the microbial homeostasis. The

imbalanceoftheflora,ordysbiosisactsasapathogenic

factor to be counteractive at CD, thus forming a vicious

circle and continuing inflammation.

In CD, intestinal flora and gluten have a complex rela-

tionship (Figure 1). There are two essential different sit-

uations, one is the imbalance of intestinal microecology

caused by coeliac disease, the other is abnormal intes-

tinal flora, which is a co-factor of gliadin in inducing

coeliac disease. In CD patients, the abundance of

Firmicute s and Acti nobacte ria decreased , while the abun-

dance of Proteobacteria increased. The intestinal micro-

flora might be sometimes the cause and sometimes the

result, which needs analysis case by case. In the future,

reasonable research methods can be designed to con-

firm it. With the development of research, the role of lac-

tic acid bacteria can be further defined.

4. Gluten-free diet and digestive tract flora

CD patients have disorders of the digestive tract flora.

However, has the digestive tract flora of CD patients

1800 X. WU ET AL.

improved significantly after GFD treatment? Studies

have found that the digestive tract flora of CD

patients who are treated with GFD is still in an imbal-

anced state. A study confirmed that, compared with

the same number of healthy children, Bacteroidetes in

saliva of children with GFD (n ¼ 13) increased,

Actinobacteria and Streptococcus thermophilus

decreased [42]. Di Cagno et al. found that the duo-

denal mucosal flora of CD patients had not fully recov-

ered after two years of GFD treatment. Although the

abundance of the pathogenic bacteria declined, the

abundance of the beneficial bacteria was still low

[39,43]. Research by De Palma et al. showed that after

healthy adults persisted in GFD, Bifidobacterium,

Lactobacillus, and Bifidobacterium longum counts

decreased, while the Enterobacteriaceae and

Escherichia coli increased [44]. A similar study in CD

children outlined differences in the microbiota com-

position before and after GFD treatment; mean Dice

similarity index between coeliac individuals before and

after GFD treatment was 63.9% ± 15.8%. There’s a loss

of 36.1% of inter-individual similarity. This study also

found that, Bacteroides vulgatus and Escherichia coli

were detected more often in CD patients than in con-

trols (Functional Dyspepsia), and a significant higher

biodiversity in CD paediatric patients ’ duodenal

mucosa was shown [45]. GFD is an important factor

affecting the composition of the intestinal flora. GFD

not only fails to fully restore the digestive tract flora

of CD patients, but also affects the homeostasis of the

flora in healthy people (Table 2). A GFD diet clearly

influences the abundance of several species, in par-

ticular those involved specifically in carbohydrate and

starch metabolism such as family Veillonellaceae (class

Clostridia)[46]. Diet is an important factor affecting

the abundance, diversity and function of the flora.

Under physiological conditions, dietary patterns and

nutritional status have certain effects on the intestinal

flora [47–48]. Among different dietary components,

fibre has a positive effect on gut microflora and their

related metabolites. Compared with standard diet,

GFD contains less fibre [49–51]. Therefore, it can be

preliminarily inferred that, GFD, which contains a small

amount of fibre, is a factor leading to the dysbiosis of

intestinal flora.

5. The effect of probiotics on CD

There were not much studies about probiotics in

affecting CD (Table 3). Olivares et al. found that B. lon-

gum CECT 7347 could help improve the health status

of CD patients who tend to show alterations in gut

microbiota composition and a biased immune

response even on a GFD [52]. A strict diet without

Figure 1. The relationship between Intestinal flora and Gluten in CD.

ANNALS OF MEDICINE 1801

gluten is the only effective way to treat CD for present

time. Although long-term GFD can improve the symp-

toms of CD patients, there are still existing intestinal

flora dysbiosis. At present, there are few studies on

using probiotics as an intervention for CD patients on

the basis of GFD. However, these limited research

results still show that probiotics combined with GFD

can restore the intestinal flora of CD patients. Studies

have confirmed that the ratio of Firmicutes to

Bacteroides and the abundance of Actinobacteria

decrease in children with CD when compared with

healthy controls. In children with GFD, oral probiotics

containing two Bifidobacterium strains (B632 and

BR03) were taken for 3 months. Compared with chil-

dren with GFD who were not supplemented with pro-

biotics, ratio of Firmicutes to Bacteroides and the

abundance of Actinobacteria increased more than

before. And it is basically similar to the faecal flora

composition of healthy children [53]. Probiotic admin-

istration has clearly revealed a negative relationship

between Firmicutes and pro-inflammatory TNF-a.

Moreover, probiotic effect has exposed some new

phyla, particularly Synergistetes, which negatively cor-

related to acetic acid and total SCFAs, suggesting a

potential role in microbiome restoration [54]. A 6-

week probiotic treatment is effective in improving the

severity of IBS-type symptoms in CD patients on strict

GFD, and is associated with a modification of gut

microbiota, characterized by an increase of

Bifidobacteria [55].

There also was study showed that, the probiotic for-

mula when taken orally over the 12-week period did not

significantly alter the microbiota of CD patients who

were strictly adhere to GFD. The probiotic bacteria con-

tained 450 billion viable lyophilized bacteria Streptococcus

thermophilus, Bifidobacterium breve, Bifidoba cter ium lon-

gum, Bifidobacterium infantis, Lactobacillus acidophilus,

Lactobacillus plantarum, Lactobacillus paracasei,and

Lactobacillus delbrueckii subsp. bulgaricus.[56].

6. Summary and outlook

In summary, coeliac disease, gluten, and digestive

tract microflora have complex interactions (Table 4).

CD patients not only have intestinal flora dysbiosis,

but also accompanied by oral microbial dysbiosis. The

current research has not yet determined the exact

microbial model of microflora and CD, and the causal

relationship between the imbalance of the digestive

tract flora and CD is still inconclusive. Gliadin and

digestive tract flora are the environmental factors that

induce CD, and there is a close relationship between

the two factors. In the process of CD intestinal muco-

sal immune response, gliadin and flora play a synergis-

tic effect, so that the intestinal immune response is

continuously activated, causing clinical symptoms of

CD. In addition, gluten-containing food provides abun-

dant material energy for the digestive tract flora,

which further leads to the imbalance of the flora.

Some specific bacteria or some bacterial metabolites

in the digestive tract can degrade gliadin even though

mammals lack proteases to digest gliadin. On one

hand, there is a causal relationship between gliadin

and the imbalance of the flora. On the other hand,

Table 2. The influence of GFD on gastrointestinal flora.

CD with GFD Healthy people with GFD

Francavilla et al. [42] Decreased: Bifidobacterium, Lactobacillus, and

Bifidobacterium longum

Increased: Actinobacteria and Streptococcus

thermophilus

–

Di Cagno et al. [43] Decreased: pathogenic bacteria declined –

De Palma et al. [44] – Decreased: Bifidobacterium, Lactobacillus, and

Bifidobacterium longum

Increased: Enterobacteriaceae and

Escherichia coli

Schippa et al. [45] Increased: Bacteroides vulgatus and Escherichia

coli; biodiversity of flora

–

Bonder et al. [46] – Decreased: Veillonellaceae

Table 3. The effect of probiotics on CD with GFD.

Positive result Negative result

GFD combined B. longum CECT 7347 [52] Improve the health status of CD patients –

GFD combined probiotics (containing two

Bifidobacterium strains) [53]

Restore intestinal flora basically –

GFD combined probiotics [55] Increase of Bifidobacteria; improve severity of

IBS–type symptoms of CD patients

–

GFD combined probiotics [56] – No effect on intestinal flora

1802 X. WU ET AL.

there is a synergistic relationship in the process of

inducing CD intestinal immune response. In the future,

we should conduct intensive research to clarify the

common role of intestinal microecology and gluten in

the pathogenesis of CD. Nevertheless, alterations of

microbiota in CD subjects may not be considered

exclusively as a consequence of the disease itself, but

rather as a part of a complex relationship between

many causative factors, including those of diet and

psychological nature.

Persistence of symptoms in patients with CD who

adhere to a GFD is common. Probiotics (especially

Bifidobacterium and Lactobacillus related to gliadin

metabolism) are expected to become an adjuvant

preparation for CD patients and minimize the related

adverse reactions caused by strict GFD. Probiotics may

help to control symptoms in patients with CD adher-

ing to a GFD, however, the data are limited and this

could not be an absolute prediction. After all, previous

research had shown that Lactobacillaceae were

enriched in gluten sensitive animal models, so it can-

not be ruled out the possibility that lactobacilli could

not act as probiotics at some time. Future research

studies involving high-quality clinical trials are needed

to improve the quality of the evidence and to estab-

lish the optimal species, timing, and dosage of probi-

otics that may benefit patients with CD [57].

Author contributions

Conceptualisation, WU Xing xing, QIAN Lin and LIU

Kexin,writing- original draft preparation, WU Jing and

SHAN Zhao wei, editing review. All authors have read

and agreed to the published version of

the manuscript.

Disclosure statement

No potential conflict of interest was reported by

the author(s).

Funding

This review was funded by National Nature Science

Foundation of China. No.81873160.

References

[1] Lebwohl B, Sanders DS, Green PHR. Coeliac disease.

Lancet. 2018;391(10115):70–81.

[2] Bai JC, Ciacci C. World gastroenterology organisation

global guidelines: Celiac Disease February 2017. J Clin

Gastroenterol. 2017;51(9):755–768.

Table 4. Summary of changes in the digestive tract flora of patients with coeliac disease and healthy individuals with GFD.

Increase Decrease

Site A- CD T-CD H-GFD Active CD, T-CD H-GFD

Oral Lactobacillus species [23] (A-CD VS HC)Bacteroidetes

[42] (T-CD

VS HC)

––Actinobacteria,

Streptoco-ccus thermophilus

[42]

(T-CD

VS HC)

–

Small intestine

(Duodenal biopsy)

Proteobacteria [32,33],

Neisseria genus

[32],

Enterobacteriaceae and

Staphylococcus [33]

CD VS T-CD

, HC)

Bacteroides vulgatus and

Escherichia coli [45] (A-CD VS FD)

––Firmicutes [32,33],

Actinomycetes

[32]

Streptococcaccae

[33]

(A-CD VS T-CD

, HC)

––

Large intestine

(faecal)

– the ratio of Firmicutes to Bacteroides,

Actinomycetes [53] (T-CD

VS T-CD

Bifidobactea [55] (T-CD

VS T-CD

)

Enterobacteriaceae

and Escherichia coli [44]

(H-GFD VS HC)

the ratio of Firmicutes

to Bacteroides,

Actinomycetes [53]

(A-CD VS HC)

– Bifidobacterium,

Lactobacillus

and Bifidobacterium longum [44]

(H-GFD VS HC)

A-CD: Active CD; T-CD: Treated Coeliac Disease (1: CD with GFD; 2:CD with GFD combined probiotics; 3: CD with GFD combined placebo); H-GFD: Healthy individuals with GFD; HC: Healthy controls; FD:

Functional Dyspepsia.

ANNALS OF MEDICINE 1803

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