DIAGNOSTICS AND ENVIRONMENTAL FACTORS

Importance of intestinal microenvironment indevelopment of arthritis. A systematic review

Anna Bazso • Peter Szodoray • Gabor Sut}o •

Yehuda Shoenfeld • Gyula Poor • Emese Kiss

� Springer Science+Business Media New York 2014

Abstract A strong connection between spondylarthropathies and inflammatory bowel diseases (IBD) is well established.

About 10–15 % of IBD are associated with different forms of spondylarthritis. Arthritis can be manifested as axial,

peripheral form or both. The primary functions of the gastrointestinal tract are digestion and absorption of nutrients,

electrocytes and maintenance of water homoeostasis. The anatomic and functional lesions could lead to the development of

IBD based on molecular mimicry and bystander effects. The mechanism of the macromolecules is uptaken may affect

intestinal and extraintestinal manifestation in genetically susceptible individuals by gut-associated lymphoid tissue, the

interplay between innate and adaptive immunity and the neuroendocrine network.

Keywords Intestinal microenvironment � Spondylarthropathy � Colonisation � Gut

Introduction

The entheropathic arthritis is defined as a heterogeneous

group of gastrointestinal and inflammatory musculoskeletal

system disorders. The gastrointestinal tract absorbs the

essential nutrients, serves as a strong barrier against

pathogens and provides an excretion function. About 10–

15 % of inflammatory bowel diseases (IBD) are associated

with different forms of spondylarthritis (SpA) [1]. SpA is

appeared as axial, peripheral form or both [2]. There is a large

spectrum of the functions of the gastrointestinal tract; how-

ever, the digestion and absorption of nutrients, electrolytes

and regulation of water homoeostasis belong into its priority.

The anatomic and functional alteration could result to the

development of inflammatory bowel disease by the bacterial

colonisation, molecular mimicry and bystander effect [3].

Medical researches illustrate the association of the

bowel diseases and arthritis. Lesions of the anatomic and

functional arrangement of gastrointestinal barrier result in

the passage of macromolecules. By these effects, together

with the gut-associated lymphoid tissue (GALT) and the

neuroendocrine network, the intestinal epithelial barrier,

with its intercellular tight junctions could lost the control

between tolerance and immunity to non-self antigen [3, 4].

Colonisations of microbiomes on the surface of the gut

The intestinal epithelium is the largest mucosal area of the

human body, plays an important role in the metabolic

regulation, distinguishes the own and the foreign antigens

A. Bazso (&) � G. Poor � E. Kiss

National Institute of Rheumatology and Physiotherapy, Frankel

L. u. 38-40., Budapest, Hungary

e-mail: bazsoanna@yahoo.com

P. Szodoray

Immunology Department, Medical School, University of Pecs,

Pecs, Hungary

G. Sut}oInstitute of Immunology, Oslo University Hospital,

Rikshospitalet, Oslo, Norway

Y. Shoenfeld

Zabludowicz Center for Autoimmune Diseases, Sheba Medical

Center, Tel-Aviv University, Tel-Hashomer 52621, Israel

G. Poor � E. Kiss

3rd Department of Medicine, Semmelweis University, Budapest,

Hungary

Anna Bazso

123

Immunol Res

DOI 10.1007/s12026-014-8593-1

and control harmful pathogens. There is a huge spectrum of

microorganisms—bacteria and virus species—living in

symbiosis with the human body. While we are highly

aware of the bacteria species, the virus and other popula-

tions are less known. The commensal and pathogen species

are distinguished by several pathways. The harmless bac-

teria can penetrate the epithelial barrier less effectively,

caused by the low endotoxicity—e.g. the Gram-negative

bacteria have the pentaacylated lipid A molecules [5].

The bacterial colonisations serve as a ‘‘trigger’’ function

in the differentiation of the B1 cells into B2 plasma cells,

which cells secrete IgA antibody in the Peyer-patches and

lymphoid tissues. The mucosal Paneth and epithelial cells

can secrete antimicrobial peptides, as alpha and beta

defensins, which are important against pathogens, also.

Altogether, the defensive system involves the defensins

molecules, mucous, the motility, the epithelial barrier and

the GALT [6].

The ability of the mucosal defensive system is regulated

by IL-7 and IL-7 receptor in the embryonic age. Soon, after

the born, on the surface of the gut, harmless bacterial

species are developed and those are remaining during the

whole life period [7, 8]. Otherwise, there are some transient

bacterial population, which contrast to other constant spe-

cies, may have a pathogen role. About 103/ml mucosa-

associated, mostly Gram-negative bacterial species can be

found on the surface of the stomach and duodenum;

however, about 104 and 107/ml species are detected on the

jejunum and ileum. The bacterial species have catalyser

function as they cut the carbohydrates into fat acids, syn-

thesise amino acids, vitamins and have antibacterial roles,

also. The permanent bacterial population synthesise many

immune-modulator saccharides, those are important in the

maintenance of the Th1-Th2 balance [5, 9].

The regulation of the gastrointestinal tract

The defensive role of the intestinal epithelium can be

affected by three important systems as the barrier, the

innate and adaptive immunity. This defensive role cannot

be accepted as a permanent state; however, there is a

consecutive ‘‘communication’’ between the microorgan-

isms and mucosal surface by the epithelial and immune

cells [10].

By the help of this specific, particular structure of the

intestinal tract, it can resist against the penetration of the

microorganisms. The ‘‘physico-chemical barrier’’—that is

capable of rebuilt again easily and shortly—is developed

by mucin layer, several antimicrobial proteins and secre-

tory IgA. The ‘‘interactive’’ relationship between of the

microbiomes and intestinal epithelial cells related to the

secrete function of the humoral and cellular components of

the immune system. The low pH, mucin layer and

peristaltic function also play an essential role in the

defensive function [10, 11]. However, the mucosal epi-

thelium remains an essential part of the intestinal tolerance

in the gut pathophysiology. To distinguish the pathogens

from the harmless species is occurred by the Toll-like-

receptors on the intestinal and immune cells. The mucin

layer has an ‘‘early signal function’’—e.g. through PPAR-csystem and suppresses the NF-jB system, which is a

dominant part of the inflammatory pathway [12].

Less of 5,000 Da molecules can penetrate through the

microvilli of the epithelial membrane of about 300–400 m2

surface intestinal tract; however, the larger molecules can

be entered into Peyer-patches by endocytosis [13]. The

mucin layer is a significant part of the physical barrier,

which is rich of glycolipids and glycoproteins. The gly-

cation is an essential chemical pathway to produce several

enzymes, receptors and transporters. The carbohydrates-

rich mucin layer can provide the microorganisms with

nutrients [14]. It is well established that failure of the

epithelium O-chain glycation may lead to the development

of colitis. The IgA and IgM antibody-rich mucin layer has

a strong filter and absolving function for the antigens

besides its protection function for the gut. Special mucin

granulomas have been appealed by various physical,

chemical and infectious insults, which could initiate the

rapid regeneration of the gut-surface by intestinal trefoil

factor (CD73). Otherwise, some cytokines (e.g. TNF-a or

IFN-c) and nitrogen-monoxide can affect the damage of

the intestinal mucosal barrier [15].

Permeability also is dependent by the microvilli, the gut

brush border and the tight junction which ensure the very

strong intercellular connection between the cells. In this

junction is developed by a member of the claudin as

occludin and a member of the Ig superfamily as junctional

adhesion molecule. The tight junctions are dynamic

structures and the change of its role could lead to auto-

immunity. So, there are many research which have proved

that zonulin is one of the most important fact in the

inflammatory and autoimmune bowel disorders [16, 17].

The innate immunity in the gut physiology

The epithelial cells produce some proteins—as defensins,

cathelicidin and C-type lectins—which can eliminate the

pathogens by osmotic lysis. The Paneth cells—localised in

the bottom of the intestinal crypts—are divided into two

groups as a- and ß-defensins [18]. There are other recep-

tors—as Toll-like receptors (TLR), NOD receptors, RIG

receptors and the C-lectin receptors—which are also

important in the defence regulation/system of the gut [19].

These receptors can recognise the harmless/useful and the

harmful/strange microbial structures play a cyto-protective

role. Therefore, the microbial-associated molecular pattern

Diagnostics and Environmental Factors

123

(MAMPS)—as bacterial lipopolysaccharides, lipoproteins,

peptidoglycans, flagellins, and the non-methylated DNA or

the double-strained RNA—are a prominent part of the

microbiomes and could recognise by through the TLR.

However, the MAMPS are also parts of physiological and

harmful pathogens [20]. The TLRs appear on the surface of

the intestinal epithelium, immune cells, endothelial cells,

mostly. The TLR-2 can recognise the bacterial lipoproteins

and zymosan, the TLR-3 can recognise the double-strained

RNA, and the TLR-5 can recognise the bacterial flagellin.

Otherwise, the TLR-4 localised intracellular, in the Golgi-

apparatus, and can absolve some internalised LPS mole-

cules [21]. These LPS molecules can absolve into the cells

by secretory IgA, therefore the inflammatory pathways will

not process. This mechanism can be an appropriate

explanation of the intestinal tolerance. So, to distinguish

the commensal and the pathogen bacteria are depended by

the sensitivity of the TLR for the different elements of the

cells [22].

The NOD receptors localised intracellular only, and

recognise muramyl-peptides, mostly. NOD receptors

especially important in the development of the IBD. The

mutations of the NOD receptors reach the failure of rec-

ognising of PAMP, therefore the apoptosis of the intraep-

ithelial immune cells will not be appropriate. The failure to

distinguish of the commensal and pathogen flora and the

loss of tolerance will lead to the inflammatory disorders

[23, 24]. Both receptors have a common process as the NF-

jB protein phosphorylation in the proinflammatory path-

way. However, there are some other nuclear receptors

which play an important role in the pathomechanism of the

IBD as PPARc, or vitamin D receptor [22–24].

The adaptive immunity

The intestinal epithelial cells, the antigen presenting cells

and the lymphoid cells all have a major role in the filtration

pathogens and in the physiology of the gut. All of these

elements of the immune system ‘‘work’’ in the follicle-

associated epithelium, which contains a special M-cell.

These unique cells can transport the antigens and the

microorganisms from the intestinal lumen to the baso-lat-

eral part of the epithelium and induce immune response

[25]. By this ‘‘procedure’’, it could ensure the communi-

cation among the lymphocytes, antigens and antigen pre-

senting cells. Likewise, the dendritic cells—which can

reach the antigens with their arms through the tight junc-

tions—and can be ‘‘retired’’ rapidly; however, the integrity

of the gut will not disturbed [26].

A prominent unit, called GALT, which is the largest,

third lymphoid tissue system and its components can be

found in the Peyer-patches, in the gut lymphoid follicles

and in the lamina propria. It is well characterised by

excreting IgA and IgM into the gut-lumen that is the first

protection line in the healthy physiology [27].

The other important process, i.e. ‘‘homing’’ also could

be an appropriate mechanism in the IBD. Regards to the

inflammation, the altered mucosal vasculature system,

vasodilation, hyperaemia and increased permeability can

process the B and T cells transport into the circulation from

the Peyer-patches and finally all can overwhelm the lymph

nodes, and some target organs as the salivary glands, lung

and synovium [28]. The vascular adhesion protein-1 (VAP)

on the surface of the synovial epithelial cells regulate the

lymphocyte-homing system, P-selectin can modulate the

macrophages. The VAP-1 as a bifunctional glycoprotein

has oxidative and adhesive functions, and its suppression

could be a predictive target of the entheropathic arthritis in

the future [29].

The association of the inflammatory bowel diseases and

spondylarthropathy

Seronegative spondylarthropathy is a group of joint dis-

eases with common characteristics and genetic background

[2]. Arthritis, as occurs IBD-associated arthritis, reactive

arthritis, psoriatic arthritis, non-differentiated spond-

ylarthropathy and ‘‘classical’’ ankylosing spondylitis (AS)

[2, 30]. Arthropathy in IBDs is a well-recognised extrain-

testinal manifestation. The gut can be a crucial gate of

penetrating of microbiomes and the large amounts of

exogenous and endogenous antigens can be contributed to

the development of enthesopathy, more often oligoarthritis

or axial spondylarthropathy by the pathways detailed

before [31]. Apart from intestinal symptoms, IBD is

associated with variety of extraintestinal manifestations as

ocular, skin, cardiac and urogenital manifestations; more-

over, asthma bronchial and sclerosis multiplex can occur

[32].

Crohn’ disease (CD) and ulcerative colitis (UC)—

belong into the group of IBD—are associated with arthritis

with a reported prevalence about 25 % [33]. The preva-

lence of polymorphism in the NOD2 gene and CARD15

plays a role in the development of the diseases behind the

strong association between HLA B27 and AS patients. The

CARD 15 is an intracellular protein-receptor which acts as

recognising bacterial peptidoglycan peptide and activating

antibacterial alpha-defensin. There are three independent

single nucleotide polymorphisms have strong association

with CD. Otherwise, there is a connection between

CARD15 and CD and sacroiliitis [34–36]. There are some

critical, proinflammatory cytokines (TNF-alpha, interleu-

kin (IL)-1beta and IL-8) which response for the develop-

ment of CD and UC; however, IL-2, IL-10 and the TGF-

beta have a protective concept. The increased number of

IgG concentration can be resulted in the impaired

Diagnostics and Environmental Factors

123

permeability of the gut [37]. Meanwhile, the strong asso-

ciation of HLA B27 and isolated sacroiliitis in AS does not

present significantly, this genetic connection can be ranged

between 50 and 70 % in IBD-arthropathy. Secondly,

peripheral arthritis may occur about 5–15 % in CD with

less intensively than in UC [38]. Non-destructive, revers-

ible form is characteristic for UC; however, erosive form

also can be presented and the peripheral arthritis can be

activated by the inflammation in the gut [39]. There are

many studies indicating that after total colectomy the

arthritis can be improved in the great majority of the UC

population, otherwise relapses can also appear after sur-

gical intervention [40].

Entheropathy-associated reactive arthritis

The entheropathy-associated arthritis similar to urogenital

arthritis, classified as-post infective arthritis, but the loca-

tion of the penetrating antigen is the gut [30]. The most

common antigens are included as Gram-negative obligate

or facultative intracellular bacteries; however, bacteries

species could not be detected in the quarter part of the

patients [41]. Immune-mediated inflammation is triggered

after penetrating of the gut by pathogens and these antigens

and immune cells, together with their mediators be trans-

formed into the joints, otherwise living antigens could not

be showed, either. The secretory IgA, IgM and IgG imply

the humoral immune-reaction [30]. There are some ex vivo

researches about antigens and lipopolysaccharid and anti-

gen DNA were detected in joints; moreover, after 4 years,

the active inflammation episodes, lipopolysaccharides and

heat-shock-proteins were shown up [42]. The HLA B27

association is also strongly associated with reactive

arthritis [43].

Other diseases

There are many, other intestinal diseases which can be

connected with musculo-skeletal diseases. In coeliakia,

Brucella-arthritis, bypass-arthritis—dermatitis syndrome,

juvenile idopathic arthritis associated megacolon, Whip-

ple’s deasese, Behcet-disease, psudomembranosous colitis

can appear as peripheral or axial arthritis with different

severity and outcome [44–50].

Summary

There are several possible pathways of developing gut

inflammation and arthritis. The association of gut inflam-

mation and arthritis is well established and not a rare

phenomenon. The defensive role of the intestinal epithe-

lium can be affected by the barrier, the innate and adaptive

immunity. This defensive role cannot be accepted as a

permanent state; however, there is a consecutive ‘‘com-

munication’’ between the microbiomes and mucosal sur-

face by the epithelial and immune cells. There are

numerous research works focusing on the coexistence of

the gut and arthritic inflammation, and there are also spe-

cific therapeutic options which target the common path-

ways could result a partial or total remission of both

disorders. However, further, comprehensive researches on

these associations, and moreover, the early recognition and

medication of the gut inflammation and arthritis still take

into consideration for the future.

Acknowledgments The authors declare that they have no conflict of

interest.

Informed consent disclosure For this type of study, formal consent

is not required.

Human and animal rights disclosure This article does not contain

any studies with human participants or animals performed by any of

the authors.

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