장누수 증후군(leaky gut syndrome)

[문형철]

beyond reason

오랫동안 자가면역질환의 원인이 도대체 뭘까 생각해왔다.

장누수 증후군이 그 원인!!

원인을 알고 원인을 제거하면 자가면역질환 치료가 가능하다는 의미인데!!

Leaky Gut As a Danger Signal for Autoimmune Diseases

Qinghui Mu,¹ Jay Kirby,¹ Christopher M. Reilly,² and Xin M. Luo^1,*

Qinghui Mu

¹Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA

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Jay Kirby

¹Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA

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Christopher M. Reilly

²Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA

Find articles by Christopher M. Reilly

Xin M. Luo

¹Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA

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Author information Article notes Copyright and License information Disclaimer

¹Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA

²Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA

Edited by: Larry J. Dishaw, University of South Florida St. Petersburg, USA

Reviewed by: Rajendra Karki, St. Jude Children’s Research Hospital, USA; Lisa Rizzetto, Fondazione Edmund Mach, Italy

*Correspondence: Xin M. Luo, ude.tv@oulnix

Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

Received 2017 Mar 27; Accepted 2017 May 5.

Copyright

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Abstract

The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease.

- 장상피세포는 외부환경으로부터 호스트를 분리하는 벽을 만듬

- 병리적 조건에서 장상피세포 lining의 투과성은 독성, 항체, 박테리아가 장벽을 타고 들어와 혈액내로 들어오는 '새는 장'을 만들 수 있음. 

- 새는 장은 외부물질이 몸으로 들어오는 것을 허용하여 자가면역질환의 시작과  진행을 트리거함. 

Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required.

- 정상세균총은 장벽을 지지하여 외부물질이 몸으로 들어오는 것을 조절하는데 중요한 역할을 함. 

- 프로바이오틱스(좋은 소장균, 대장균)은  타이트 정션을 만들어 새는 장을 치료할 수 있음이 밝혀지고 있음. 

Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.

-  새는 장을 만들고 자가면역질환을 유도하는 질병을 일으키는 나쁜 박테리아는 항생제치료로부터 시작될 수 있음. 

- 정상세균총의 조절은 장 투과성을 조절할 수 있고 자가면역질환 환자의 질병과정을 변화시킬 수 있음. 

Keywords: leaky gut, microbial translocation, gut microbiota, probiotics, autoimmunity

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Introduction

For digestion and absorption purposes, mammals have developed a very complicated and highly specialized gastrointestinal system maintained by the mucosal barrier (12–677, 8

The gut microbiota has drawn intense attention in the past decade (9

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The Intestinal Barrier

A large variety of exogenous substances colonize the gut lumen, such as microorganisms, toxins, and antigens. Without an intact and properly functioning intestinal barrier, these substances can penetrate the tissues beneath the intestinal epithelial lining, diffuse into blood and lymphatic circulations, and disrupt tissue homeostasis. However, there is an efficient multifaceted intestinal barrier system with physical, biochemical, and immunological components that prevents the entry of most pathogens (Figure ​(Figure1).1

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Figure 1

Illustration of host intestinal barriers, including physical barrier (epithelium, tight junctions, mucus, commensal bacteria), biomedical barrier [antimicrobial proteins (AMPs)], and immunological barrier (lymphocytes and IgA). Also shown is the microbial translocation to remote tissues (for example, kidney and pancreas) in the presence of a leaky gut.

Physical Barrier

In humans, the intestinal epithelium covers as large as 400 m² of surface area (1​(Figure1).11011–13⁺ intestinal epithelial stem cells, which reside within the crypts (1410, 15

The IEC lining is continuous, and the contact between IECs is sealed by TJs (1617

On top of the gut epithelium, there are two layers of mucus, the inner and outer layers, that cover the whole intestinal epithelial lining and provide physical protection to separate luminal microorganisms from the epithelium. Organized by its major component, a highly glycosylated gel-forming mucin MUC2, the mucus contains diverse molecules including IgA as well as enzymes and proteins, such as lactoferrin (1819, 202120

The gut commensal bacteria have been described as one component of the intestinal physical barrier primarily due to its two major functions (2223, 242526

Biochemical Barrier

Biochemical molecules with antimicrobial properties exist in the mucus as well as far into the lumen and include bile acids and AMPs (27, 28) (Figure ​(Figure1).1

The proximal small intestine harbors very few microorganisms (29302731

Immunological Barrier

Below the intestinal epithelium, there are organized lymphoid follicles, including the Peyer’s patches and isolated lymphoid follicles. Inside the follicles, a variety of immune cells, including B cells, T cells, dendritic cells (DCs), and neutrophils, orchestrate the immune response by presenting antigens, secreting cytokines, and producing antigen-binding antibodies (Figure ​(Figure1).114⁺ DCs in lamina propria in small intestine by forming goblet cell-associated antigen passages (GAPs) (32, 3334353637, 3839, 40⁺ macrophages and the expression‎ of CX3CL1 by certain IECs (41, 42

Another component of the immunological barrier is secretory IgA (SIgA). As the most abundant immunoglobulin in the body, IgA resides primarily on intestinal mucosal surfaces. While some people with selective IgA deficiency appear to be healthy, SIgA is important as it presumably interacts with commensal bacteria to provide protection against pathogens. A unique feature about SIgA is that is structurally resilient in protease-rich environments allowing it to remain functionally active compared to other antibody isotypes on mucosal surfaces (43

Though not mentioned here, self-modulating factors, such as nerves and diverse cytokines, are also important for maintaining the normal functions of the intestinal barrier.

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Gut Microbiota and the Intestinal Barrier

Microbiota can be sensed by the host through pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). In the gut, the bacteria–host communications are largely dependent on the recognition of microbe-associated molecular patterns by PRRs expressed on immune and non-immune cells. Certain microbiota, bacterial products, and metabolites affect the intestinal barrier function and are responsible for the subsequent breakdown of tissue homeostasis. 

When there is a leaky gut, commensal bacteria in gut lumen, together with their products, are able to escape the lumen of the gut, which may induce inflammation and cause systemic tissue damages if translocated into peripheral circulation (Figure ​(Figure1).144

Evidence from GF animals suggests that the development and function of the intestinal barrier are dependent on microbiota. In GF animals, due to the lack of bacterial stimulations, the thickness of the mucus layers is extremely reduced (45–4849, 5046, 5146, 47481152, 53Lactobacilli and Bifidobacteria, has been shown to restore the properties of RegIIIγ and control bacterial overgrowth (53Bacteroides thetaiotaomicron (54

In addition, an interaction exists between gut microbes and AMPs, such as IAP. Predominately produced by IECs, IAP is active either anchored on the epithelium membrane or secreted into gut lumen (55, 56Lactobacillaceae (57, 58Bifidobacterium), while reducing LPS-producing bacteria (e.g., Escherichia coli) (59in vivo, IAP is vital in preventing the translocation of LPS, the pro-inflammatory stimulus originated from bacteria (60, 61626364, 65

Intestinal epithelial cells compose the single layer of intestinal epithelium, and the generation of new IECs from local intestinal stem cells is vital in maintaining the barrier function due to the high frequency of apoptosis and shedding of IECs (666768, 69E. coli can induce cell shedding in a dose-dependent manner (70, 71Bifidobacterium breve, or more precisely its surface component, exopolysaccharide, can positively modulate LPS-induced epithelium cell shedding through epithelial MyD88 signaling (70⁺ intestinal stem cells. In mice bearing selective TLR4 deletion in intestinal stem cells, LPS is no longer able to inhibit the renewal of IECs (727374Lactobacillus rhamnosus (75–78), Streptococcus thermophilus (79), Lactobacillus reuteri (80), and Bifidobacterium infantis (81

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Mechanisms of Leaky Gut

A large variety of gut barrier disruptors and/or gut microbiota disturbers may potentially result in microbial translocation and subsequent inflammation locally and systemically. These include diet, infections, alcohol consumption, and burn injury.

Diet-Induced Gut Leakiness

Nutrients and food ingredients have been reported to contribute to the maintenance or alterations of gut microbiota and the intestinal barrier function (82838485Akkermansia muciniphila and Bacteroides caccae (45Muc2 gene was surprisingly heightened, possibly as a compensatory response. The thinner mucus and compromised intestinal barrier function lead to a higher susceptibility to certain colitis-causing pathogens (45Lactobacillus and increase Oscillibacter, and these changes were correlated with significantly increased permeability in the proximal colon (86Oscillospira genus was negatively correlated with the mRNA expression‎ of barrier-forming TJ protein ZO-1.

Stress-Induced Gut Leakiness

Under certain circumstances, stress-induced alterations of gut microbiota and the impaired intestinal barrier would allow the occurrence of microbial translocation. Burn injury and alcohol consumption are examples of such stress. Burn injury results in increased intestinal permeability, which is mediated by increased activity of myosin light-chain (MLC) kinase (87, 8889–9187Enterobacteriaceae family (8892

Chronic alcohol consumption is responsible for intestinal barrier dysfunction, alterations on both the quality and quantity of gut microbiota, LPS translocation, and alcoholic liver disease (ALD). In both human and mouse, it has been well established that alcohol can disrupt intestinal barrier function, which is closely related to increased tumor necrosis factor (TNF) production from intestinal monocytes/macrophages and enterocytes bearing TNF-receptor 1, followed by downstream activation of MLC kinase (93939453, 93, 95–97Lactobacillus is significantly suppressed during alcohol consumption (53, 97Lactobacillus strains or indirect stimulation of Lactobacilli with prebiotics or diets can decrease bacterial overgrowth, restore mucosal integrity of the intestine, and suppress microbial translocation (53, 94, 98, 99100, 101E. coli and Weissella confusa, and this may be the mechanism by which they compromise the intestinal barrier function (102, 103

Infections can play a role in regulating the mucosal barrier. A good example is Helicobacter pylori, a Gram-negative bacterium infecting the human stomach (104H. pylori is known to directly increase epithelial permeability by redistributing TJ protein ZO-1 (105, 106Salmonella enterica, disruption of the intestinal barrier integrity was observed (107

Taken together, perturbation of gut microbiota, which may be the consequence of diverse interventions, can lead to increased intestinal permeability and translocation of bacterial components and products. Such microbial translocation can subsequently trigger an abnormal immune response, causing inflammation and/or tissue damage in extraintestinal organs.

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Leaky Gut and Autoimmune Disorders

Several disease states have been associated with gut microbiota dysbiosis, intestinal barrier dysfunction, and microbial translocation. These include Alzheimer’s disease, ALD, cancer, and multiple autoimmune disorders. Autoimmune disorders are characterized by the generation of autoantibodies against self-antigens that attack the body’s own tissues, resulting in damage. Genetic and environmental triggers have been long known as the major contributors to the development of autoimmunity. Increasing evidence in recent years suggests that microbial translocation and intestinal barrier dysfunction, which may be affected by gut microbiota, are another important causative element for autoimmune disorders (2–6

Type 1 Diabetes

Type 1 diabetes is an organ-specific autoimmune disorder characterized by an autoimmune response against the host’s own pancreatic β cells, leading to insufficient insulin production from the pancreas (108109110–112113114115115

Systemic Lupus Erythematosus

Systemic lupus erythematosus, or lupus, is an autoimmune disorder characterized by severe and persistent inflammation that leads to tissue damage in multiple organs (116117118119–121121122–124125, 126127125, 128–130131

Several downstream proteins in the TLR signaling cascade are highly relevant to the pathogenesis of SLE and are potential therapeutic targets, including MyD88, IRAKs, and IFNα (132133, 134135, 136137Fas^lpr mice led to exacerbation of lupus-like disease (138

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Reversing the Leaky Gut as a Potential Therapy

Considering the contributions of leaky gut and bacterial translocation to inflammation and multiple diseases, reversing gut leakiness appears to be an attractive therapeutic strategy. 

Prebiotics and probiotics, for example, can be used to reduce intestinal permeability (139Bacteroides fragilis may serve as such a probiotic (140B. fragilis reduced the translocation of disease-causative 4EPS, and significantly ameliorated the behavior defects. 

 The therapeutic benefit of B. fragilis is believed to be due to its ability to alter microbial composition and enhance intestinal barrier function (140B. fragilis is also known for its capability to induce the development of Foxp3⁺ regulatory T cells, a process regulated by another product of B. fragilis, polysaccharide A (PSA) (141, 142B. fragilis and PSA are beneficial against inflammatory diseases, such as colitis and experimental autoimmune encephalomyelitis (141, 143B. fragilis to prevent the leaky gut and reverse autoimmunity warrants further investigation. In a practical point of view, probiotic candidates with different targets on reversing the leaky gut may synergistically act to attenuate disease as thus may serve as a probiotic cocktail. As probiotics are generally considered safe, it is anticipated that they will become cost-effective treatment options for people with autoimmune diseases in the foreseeable future. This is a very young but exciting field in which much still remains to be learned.

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Author Contributions

All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.

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Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Footnotes

Funding. Preparation of this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R03AI117597. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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장건강 및 면역질환의 보완통합의학적 접근
Complement and Integrative Approach in Gut Health and Immunologic Disease

서 론
장관은 음식물의 소화, 흡수, 배설이라는 기본적인 기능이외에 장관 점막이 관내 미생물이나 이들의 부산물, 항원,독소 등의 혈류로의 유입을 차단하는 방어벽으로서의 면역학적 기능을 수행한다.1 즉, 우리 몸의 면역체계 중 최전선에서 1차 방어벽의 역할을 하는 장관점막 세포는 단일 세포층으로 일정한 세포 사이의 간극을 유지하다가 어떠한 자극이나 손상이 가해지면 이 세포 사이의 치밀 결합(tightjunction)이 약해지면서 세포 사이의 틈으로 여러 고분자물질들이 왕복할 수 있는 소위 투과성이 증가된 상황이 초래하게 되며 이때 나타나는 여러 가지 증상을 총괄하여 새는장증후군(장누수증후군; leaky gut syndrome)이라고 말하는데, 이는 일련의 임상적 현상을 이야기하는 일종의 별칭이며, 정확한 학문적 의미로는 장관 투과성 증가상태(the state of increased intestinal permeability)라고 할수 있겠다.2, 3 (Fig. 1)

이러한 개념은 과거부터 있었으나 정식으로 실험적으로 연구된 것은 약 50년 전 Jacob Fine이며, 그 후 수많은 동물 실험과 임상 실험의 결과가 축적되고 있다.4 분자생물학적인 실험 기법이 발달하기 전에는 정확한 병리기전을 알 수 없었으며 그러한 이유로 보완대책의학 분야에서 간간히 설명되어 오다가 분자생물학의 발달과 특히 , 면역학의 발달에 힘입어 여러 학자들이 연구 결과를 발표하고 있으며, 최근에는 내재면역(innate immunity)분야의 급격한 성장발달에 힘입어 증가된 장관 투과성과여러 질병과의 관계된 의문이 밝혀지고 있다.5

장관 중에서도 소장의 점막세포는 그 표면적이 피부면적의 약 200배에 달하는 약 400 m2 정도로 추산하고 있으며이 넓은 면적에서 매일 섭취하는 음식물을 비롯한 각종 물질의 소화와 흡수가 일어나는데, 이 과정에서 점막세포의 간격이 느슨해지거나 약간의 손상을 입거나 탈락되어 여과나 장벽의 기능을 제대로 못하여 혈액내의 고분자 물질이 장관내의 관강으로 누수 되거나 관강 내의 고분자물질이 직접 혈액으로 들어가는 현상이 초래되는 소위 새는 장(leaky gut)이 야기되는 것이다. 이때 세균이나 곰팡이 및 내독소라 부르는 그람 음성 균주의 세포벽 조각인 지질다당체(lipopolysaccharide, LPS) 등이 혈류로 유입되어 소위 장내세균전위(Bacterial translocation), 장관내독소혈증(intestinal endotoxemia) 등을 야기하여 각종 염증반응 및 면역 반응을 초래하여 여러 질환을 야기시키고 기존의 질환을 악화시키는 역할을 한다.6

특히 여러 자가면역질환과 관련이 있으며 국소면역반응에 의한 염증은 전신면역반응에 영향을 주어 전신적인 염증반응을 초래함으로써 각종 만성염증질환의 원인 및 악화에 기여하게 되어 소위 염증(inflammation)으로 설명할수 있는 모든질환의 병태생리를 설명할 때 필수불가결한 조건이 되어 나날이 임상적인 중요성이 커지고 있으며 최근의 면역학 중 내재면역의 눈부신 발달로 많은 연구가 축적되고 있다.

장관 기능검사는 위, 소장, 대장 등의 소화, 흡수, 배설과 방어능 등을 측정하는 여러 가지 검사가 있고 운동기능을 측정하는 여러 방법들이 있지만 이미 기존의 정통의학에서 널리 다루고 있으므로 본 강좌에서는 주로 장관 방어능의 면역학적인 기능의 임상적 적응의 개념과 검사 방법 및 이에 따른 처방 등 구체적인 적용방법을 설명하고자 한다.

본 론
장관 투과성이 증가되어 있는 질환이나 임상적 상태는(노화, 천식, 항암 요법 후 점막염, 음식물 알러지, 다발성외상, 류마티스성 관절염, 화상, 크론씨병, 궤양성 대장염 등의 염증성 대장질환, 관절염증, 만성피로 증후군, 과민성대장증후군, 정신성 홍반성 낭창등) 매우 광범위하다.7-9
(Fig. 2)

이러한 “새는장증후군'을 일으키는 흔한 원인

1) 진통제로 쓰이는 비스테로이드성 항염증제재를 오래 쓴 경우

2)항생제와 스테로이드를 쓴 경우

3) 항암요법으로 항암 화학요법이나 방사선 치료를 받은 경우

4) 장관 정상세균총의 조성의 변화가 초래되었을 때

5) 곰팡이의 장관 내 번식

6) 부패한 음식의 섭취나 중금속이나 독성물질을 섭취 했을 때

7) 지나치게 자극적인 음식물의 섭취나 특정음식물에 과민반응이 있는 경우

8) 알코올의 과량복용

9) 다발성 외상

10) 급.만성 정신적 스트레스에 노출 되었을 때나 만성적인 장관의 세균, 기생충, 이스트 등의 감염 등을 들 수 있다.9

새는장증후군과 연관된 증상들은 비특이적이고 다양한 증상을 호소할 수 있으므로 세심한 병력청취와 본 질환에대한 개념 확립이 중요하다고 할 수 있다. 흔하게 호소하는 증상은 모호한 복통과 복부 불쾌감, 소화불량, 가스과다. 배출, 변비, 묽은 변이나 설사 등의 소화기증상을 비롯하여 식은땀, 만성피로감, 무기력, 입맛소실 등의 비특이적 증상을 호소하며 잦은 감기나 방광염, 질염 등의 병력을 관찰할 수 있고 관절동통, 근육동통, 기침, 호흡곤란과 천식증상을 호소하며 정신적으로도 불안, 초조 및 우울증, 기억력 감퇴 등을 호소할 수 있다.

장 투과성의 측정은 비침습적이며 경제적인 가격으로 비교적 쉽게 널리 행하여 질 수 있다. 즉 세포 사이의 치밀 결합(tight junction)을 통과할 수 있는 표식자를 사용하여 투과된 표식자의 소변 내 검출량으로 장 투과성을 측정할 수 있으며, 이때 표식자는 우리 몸에서 사용되거나 대사되지 않는 것으로 하여야 한다.9(Fig. 3)

가장 흔히 쓰이는 표식자는 락툴로스/만니톨(lactulose/mannitol)검사 이다. 락툴로스와 만니톨은 수용성의 당분자로 서로 다른 크기와 무게로 혈액 내에 흡수되어 소변으로 배출되며 이때 배출된 양을 측정하여 장 투과성을 간접적으로 측정할 수 있다. 즉 만니톨은 비교적 적은 분자량으로 장관점막세포를 거치거나 좁은 치밀결합을 통해서도 혈중으로 흡수될 수 있고 락툴로스는 만니톨보다 약 10배 이상 큰 분자량이므로 치밀결합이 느슨해지거나 세포손상을 입거나 탈락된 사이로만 흡수가 되므로 이의 소변측정으로 장관의 투과도를 측정할 수 있다. 만니톨 등의 적은 분자량의 표식자들은 건강한 소장의 기능을 나타낼 수 있으며 락툴로스 등의 거대분자량의 표식자들은 투과성이 증가되어 있는 경우를 나타낼 수 있는데 이들의 비율을 계산하여 장투과성의 정도를 나타내고 있다(Table 1).

최근에는 만니톨이나 락툴로스가 당뇨병이 있는 환자에서는 혈당에 영향을 미칠 수 있고 이러한 다당체들이 장관세균총에도 영향을 줄 수 있다는 보고가 있어 이러한 단점을 보완한 폴리에틸렌글리콜(polyethyleneglycol, PEG)으로 만니톨과 락툴로스와 분자량이 비슷한 PEG 400과 PEG 3350으로 측정하고 있으며 그 외 대장까지의 정확한 흡수율을 측정하고자 동위원소 51Cr-EDTA로 측정하기도 한다.

또한 미생물이나 음식항원이 혈액 내로 이동하는 것을 예방할 수 있고 바이러스를 중화할 수 있는 장관면역기능에 중요한 secretory IgA (sIgA)를 타액에서 측정하여 장관의 sIgA를 간접적으로 예측할 수 있다. 이때 건강하고 안정된 점막 면역에서는 정상범위이지만 점막면역 결핍이 있거나 음식알레르기나 자가면역 질환 때는 sIg의 측정치가 저하되고 소장의 세균과증식(bacterial overgrowth)이나 장관독소증, 바이러스 감염 등에서는 증가되어 있는 것을 관찰할 수 있다.

사실 장관 방어능에 중요한 영향을 주는 것은 세균총(bacterial flora)과 세균집락(baterial colony)인데 이것은 식습관과 음식물이나 약제의 화학적 오염등에 매우 깊은 영향을 받으며 이것들이 장관세균층의 방어기능에 지대한 영향을 주는 것이다. 즉 이러한 음식물에서 기원한 단백질이나 곰팡이, 호기성 박테리아, 염기성 박테리아에 대한 우리 혈액의 면역 단백질인 IgG, IgM, IgA를 측정하여 이들의 조성을 추측할 때 음식물 알러지, 장관세균 불균형, 캔디디아증 장관방어기능 장애, 세균전이, 자가면역질환, 면역결핍 등의 질환을 간파할 수 있다. 이 또한 아직 국내에서는 널리 이용되지 않는 검사법이고 실험적으로만 실시되고 있으나 외국에 의뢰하면 측정이 가능하며 가까운 시일내에 국내에서도 측정이 가능하리라 생각된다. 

또한 소장세균 과증식을 알기 위하여 수소호기검사를 시행하기도 하는데 15분 내지 30분 간격으로 호기검사를 실시하여야 하므로 번거러운 측면도 있으며 국내에서는 실험실에서 연구용으로만 쓰이고 있는 실정이다.

최근에는 혈액에서 직접 내독소를 측정하는 방법이 개발되어 널리 쓰여질 전망이다. 사실 이 방법은 새로운 방법은 아니며 복잡하고 여러 단계의 실험과정을 단순화 시킨것인데 향후 임상에서 쉽게 이용되리라 생각한다.

그 외의 진단 방법으로는 종합적인 대변 분석(Comprehensive digestive stool analysis)으로 곰팡이 검사, 기생충 검사, 세균의 균형과 종류, 소화기능 분석 등을 할 수 있으나 비용이 많이 들고 검사하기가 번거러운 단점이 있으나 먼저 장관투과성 검사에서 증가된 결과를 보이면 정밀검사로서 추천할만한 검사이다. 

이 검사로는 새는장증후군의 원인적인 결과를 추측할 수 있으며 치료의 방향에도 도움을 줄수 있으나 국내에서는 아직 시행하지 않고 있으며외국에 시료를 의뢰 하여야 하는 불편함이 있다. 

또한 음식물에 대한 과민성 검사로 제거/유발 검사(elimination/provacation testing)가 있으나 대부분은 환자가 스스로 알고 있으며, 그렇지 않을 경우는 정확히 알기 어렵고 시간이 수 주이상 걸리는 단점이 있다. 그 외 간 기능 혈액 검사 등을보조적으로 하여 진단하는데 도움을 줄 수 있다.9

이러한 장관 방어능의 저하를 복구하거나 기존의 건강한 방어능을 보존하는 방법으로는 원인 제거와 장관의 기능회복을 들 수 있다.3 (Table 2) 일반적인 원인을 피하는 방법이나 수술, 항암 요법 등과 같이 피치 못할 경우는 빠른 시간 내에 장관의 기능을 보존, 복구시켜 주어야 한다. 이러한 방법을 필자는 소위 장관 보존 ․ 복구 요법(Gut Integrity Repair Therapy, GIRT)라고 명명하고 그 방법을 찾고자 노력하고 있으며 지금까지 알려진 방법과 필자가 찾고 있는 방법을 설명하기로 하겠다.10

우선 장관방어능이 저하되었다고 생각되면 원인으로 생각되는 것을 피해야 하는데 대개 세심한 병력청취에서 의심할 수 있다. 즉, 진통제나 항생제의 복용, 과다한 알코올의 섭취, 지나친 편식, 자극적이고 과민한 음식물 섭취, 정신적 신체적 스트레스, 운동부족 등의 원인을 파악하여 제거하여야 하며 이에 따른 스트레스 해소, 적당한 운동, 식습관의 변화, 소화제 복용 및 종합비타민과 항산화제의 복용시 세레늄, 비타민E, 코엔자임 Q-10 등의 복용도 추천할 만하다. 

또한 장관의 기능 중 방어능을 보존하고 손상된 방어능을 복구하자는 것은 증가된 장 투과성을 감소시켜 장관내독소혈증을 억제시켜 각종질환에서 공통적인 기전인 염증반응을 억제 하자는데 그 궁극적인 목적이 있다고 하겠다. 이러한 장관 내독소 억제 방법은 크게 두 가지로 대책을 세울 수 있는데 첫째 장관 점막세포의 투과성을 감소시키기 위하여 세포간의 치밀결합(tight junction)의 능력을 향상시켜 주어야 하며 세포 간의 결합을 유지시키고 세포의 분화와 재생을 촉진하기 위해서는 가장 중요하게 점막세포 성장인자가 필요하다.이의 공급을 위해서는 특별히 약으로 제조된 것은 없으나 영양 치료제로 쓰이는 젖소초유 등에서 구할 수 있다. 즉 젖소초유에는 태어난 송아지의 장관세포의 발달을 돕기 위한 Insulin like Growth Factor (IGF), Transforming Growth Factor (TGF), Epidermal Growth Factor (EGF) 등 여러 점막세포 성장인자가 있는데 이는 종의 특이성이 없으므로 인간이 섭취하면 치밀결합(tight-junction)을 튼튼히 할 수 있고 손상되거나 탈락된 점막세포의 복구에도 도움을 줄 수 있다. 

또한 세포의 영양성분인 글루타민이나 각종 비타민 미네랄 등도 세포대사에 도움을 줄 수 있으며 젖소초유에도 이러한 영양성분이 많이 함유되어 있어 경구섭취로 쉽게 도움을 받을 수 있다.11 장관 점막세포의 방어능 향상에 이어 두 번째로 생각할 수 있는 것은 장관 관내의 환경변화로 내독소혈증을 줄이는 방법을 생각할 수 있다.

즉, 내독소를 주로 생산하는 그람 음성 균주의 성장을 억제함으로써 내독소 혈증을 감소시킬 수 있는데 이를 위해 그람양성균주인 유산균의 공급과 젖소초유에 함유되어있는 면역단백질A(IgA)나 락토페린(lactoferrin) 등은 특이적으로 그람음성 균주 등을 억제하는데 이들의 섭취가 내독소혈증을 억제하는 효과가 있음이 여러 연구에서 보고되고 있어 간접적으로 점막세포의 방어능 향상을 기대할 수 있다고 하겠다. 

본 저자의 교실에서 실시한 동물실험에 의하면 NSAID나 5-FU 등의 항암제로 장관점막의 투과성을 증가시킨 후 초유를 섭취시키면 투과성이 감소하며 이때 혈중알부민이나 내독소혈증의 개선을 관찰할 수 있었다. 12, 13

결 론
장관 점막의 투과성이 증가되면 관내에 있던 병원균과 이들의 부산물, 독소, 항원 등이 혈류로 유입되어 인체의 면역체계를 자극함으로써, 각종 급 ․ 만성 감염성 질환 및 자가면역질환 등의 병태생리에 영향을 주는 질환이 초래되거나 기존의 질환이 악화되므로 잘못된 식이섭취를 바로잡아 원인물질의 섭취를 피하고 장점막에 도움이 되는 물질을 보충함으로써 근본적인 호전을 보일 수 있으며 이러한 개념을 이해함으로써 일반인들뿐만 아니라 의료인들에게도 환자 진료에 많은 도움을 줄 수 있으리라 사료된다.