Re: 장누수 치료에 대하여

[문형철]

Leaky Gut and the Ingredients That Help Treat It: A Review

by 

 1,*

1

School of Nutrition and Food Sciences, Louisiana State University Agricultural Center, Baton Rouge, LA 28081, USA

2

Department of Food, Bioprocessing & Nutrition Sciences and the Plants for Human Health Institute, North Carolina State University, North Carolina Research Campus, Kannapolis, NC 27599, USA

*

Author to whom correspondence should be addressed.

Molecules 2023, 28(2), 619; https://doi.org/10.3390/molecules28020619

Received: 23 November 2022 / Revised: 31 December 2022 / Accepted: 1 January 2023 / Published: 7 January 2023

(This article belongs to the Special Issue Physicochemical Study of Foods)

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Abstract

The human body is in daily contact with potentially toxic and infectious substances in the gastrointestinal tract (GIT). The GIT has the most significant load of antigens. The GIT can protect the intestinal integrity by allowing the passage of beneficial agents and blocking the path of harmful substances. Under normal conditions, a healthy intestinal barrier prevents toxic elements from entering the blood stream. However, factors such as stress, an unhealthy diet, excessive alcohol, antibiotics, and drug consumption can compromise the composition of the intestinal microbiota and the homeostasis of the intestinal barrier function of the intestine, leading to increased intestinal permeability. Intestinal hyperpermeability can allow the entry of harmful agents through the junctions of the intestinal epithelium, which pass into the bloodstream and affect various organs and systems.

인체는 위장관에서 잠재적인 독성 및 감염성 물질과 매일 접촉합니다. 위장관에는 가장 많은 항원이 있습니다. 위장관은 유익한 물질의 통과를 허용하고 유해 물질의 경로를 차단하여 장의 완전성을 보호할 수 있습니다. 정상적인 조건에서 건강한 장 장벽은 독성 요소가 혈류로 유입되는 것을 방지합니다. 그러나 스트레스, 건강에 해로운 식단, 과도한 음주, 항생제 및 약물 섭취와 같은 요인은 장내 미생물 총의 구성과 장의 장벽 기능의 항상성을 손상시켜 장 투과성을 증가시킬 수 있습니다. 장의 과투과성은 장 상피의 접합부를 통해 유해 물질이 혈류로 들어가 다양한 장기와 시스템에 영향을 미칠 수 있습니다. 

Thus, leaky gut syndrome and intestinal barrier dysfunction are associated with intestinal diseases, such as inflammatory bowel disease and irritable bowel syndrome, as well as extra-intestinal diseases, including heart diseases, obesity, type 1 diabetes mellitus, and celiac disease. Given the relationship between intestinal permeability and numerous conditions, it is convenient to seek an excellent strategy to avoid or reduce the increase in intestinal permeability. The impact of dietary nutrients on barrier function can be crucial for designing new strategies for patients with the pathogenesis of leaky gut-related diseases associated with epithelial barrier dysfunctions. In this review article, the role of functional ingredients is suggested as mediators of leaky gut-related disorders.

따라서 새는 장 증후군과 장 장벽 기능 장애는 염증성 장 질환 및 과민성 장 증후군과 같은 장 질환뿐만 아니라 심장 질환, 비만, 제 1 형 당뇨병 및 체강 질병을 포함한 장 외 질환과 관련이 있습니다. 장 투과성과 여러 질환 사이의 관계를 고려할 때 장 투과성의 증가를 피하거나 줄이기 위한 훌륭한 전략을 모색하는 것이 편리합니다. 식이 영양소가 장벽 기능에 미치는 영향은 상피 장벽 기능 장애와 관련된 누수성 장 관련 질환의 발병 기전을 가진 환자를 위한 새로운 전략을 설계하는 데 매우 중요할 수 있습니다. 이 리뷰 기사에서는 새는 장 증후군 관련 질환의 매개체로서 기능성 성분의 역할을 제시합니다.

Keywords: 

1. Introduction

The human body is exposed daily to potentially harmful substances and agents. These infectious agents can upset the balance between health and disease. The gastrointestinal tract transports water and electrolytes and secretes water and protein towards the intestinal lumen. This action has a defense function that prevents harmful substances from entering the intestinal barrier [1] The intestinal barrier forms two complex layers, which consist of an apical barrier and basolateral barrier (Figure 1). The small intestine mixes food with digestive juices from the pancreas, liver, and intestine and pushes the mixture forward to continue the digestion process. The cellular walls of the small intestine absorb digested nutrients and drugs through diffusion, ATP-binding cassette (ABC) transporters and paracellular transportation into the bloodstream (Figure 1).

인체는 매일 잠재적으로 유해한 물질과 작용제에 노출됩니다. 이러한 감염원은 건강과 질병 사이의 균형을 깨뜨릴 수 있습니다. 위장관은 물과 전해질을 운반하고 장 내강으로 물과 단백질을 분비합니다. 이러한 작용은 유해 물질이 장 장벽으로 유입되는 것을 방지하는 방어 기능을 합니다. [1] 장 장벽은 정단 장벽과 기저측 장벽으로 구성된 두 개의 복잡한 층을 형성합니다(그림 1). 소장은 췌장, 간, 장에서 나온 소화액과 음식물을 혼합하고 혼합물을 앞으로 밀어내어 소화 과정을 계속 진행합니다. 소장의 세포벽은 확산, ATP 결합 카세트(ABC) 수송체 및 세포외 수송을 통해 소화된 영양소와 약물을 혈류로 흡수합니다(그림 1). 

The interaction of both barriers allows the maintenance and balance of intestinal homeostasis [2], which is capable of discriminating between commensal microorganisms (beneficial for the host), pathogens, nutrients and inflammatory particles [3]. Under normal conditions, an intact intestinal barrier prevents the transmission of pathogens, pro-inflammatory substances and antigens to the internal environment. However, a lack of intestinal integrity favors its entry and could trigger a disease or inflammation [4].

두 장벽의 상호 작용을 통해 장내 항상성을 유지하고 균형을 유지할 수 있으며[2], 이는 공생 미생물(숙주에게 유익한), 병원균, 영양소 및 염증 입자를 구별할 수 있습니다[3]. 정상적인 조건에서 온전한 장 장벽은 병원균, 전 염증성 물질 및 항원이 내부 환경으로 전달되는 것을 방지합니다. 그러나 장의 완전성이 부족하면 병원균이 쉽게 침투하여 질병이나 염증을 유발할 수 있습니다[4].

Dysfunction of the intestinal epithelial barrier and increased permeability results in a “leaky gut” that is associated with intestinal disorders such as inflammatory bowel disease (IBD), bowel syndrome irritable liver disease (ILD), alcoholic liver disease, nonalcoholic fatty liver disease, steatohepatitis, liver cirrhosis, and collagen diseases (Figure 2). Leaky gut is also related to diseases that are not intestinal disorders such as diabetes mellitus, among others, represented in Figure 2.

 장 상피 장벽의 기능 장애와 투과성 증가는 염증성 장 질환(IBD), 장 증후군 과민성 간 질환(ILD), 알코올성 간 질환, 비알코올성 지방간 질환, 지방 간염, 간경변 및 콜라겐 질환과 같은 장 질환과 관련된 '새는 장 증후군'을 초래합니다(그림 2). 새는 장 증후군은 그림 2에 표시된 당뇨병과 같이 장 질환이 아닌 다른 질환과도 관련이 있습니다.

Figure 1. Representation of the structure of the intestinal membrane showing the different routes of drug and nutrient transport.

Figure 2. Relationship between leaky gut syndrome and intestinal dysbiosis with various diseases. NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; PBC: primary biliary cholangitis; SAP: severe acute pancreatitis; DM: diabetes mellitus; SIBO: small intestinal bacterial overgrowth; COPD: chronic obstructive pulmonary disease; CHF: congestive heart failure; CD: Crohn’s disease; UC: ulcerative colitis (ulcerative colitis); IBS: inflammatory bowel diseases.

Intestinal permeability is defined as the unmediated passage through the intestinal epithelium of medium-sized hydrophilic molecules that occurs down a gradient of concentration [5,6]. An increase in intestinal permeability is a sign of a disturbed intestinal barrier [7]. According to the leaky gut syndrome (LGS) hypothesis, intestinal hyperpermeability may allow the entry of harmful microorganisms, toxins, or undigested food particles through the junctions of the intestinal epithelium, reaching the bloodstream and being able to affect the hormonal, immune, nervous, respiratory or reproductive systems [8]. In fact, an increase in the permeability of the intestine due to changes in the functioning and/or in the expression‎ levels of the TJ proteins cause leaky gut syndrome or LGS.

장 투과성은 농도 구배에 따라 발생하는 중간 크기의 친수성 분자가 장 상피를 통해 매개되지 않은 상태로 통과하는 것으로 정의됩니다[5,6]. 장 투과성의 증가는 장 장벽 장애의 징후입니다 [7]. 새는 장 증후군(LGS) 가설에 따르면 장 투과성이 증가하면 장 상피의 접합부를 통해 유해한 미생물, 독소 또는 소화되지 않은 음식 입자가 유입되어 혈류에 도달하여 호르몬, 면역, 신경, 호흡기 또는 생식계에 영향을 미칠 수 있습니다[8]. 실제로 TJ 단백질의 기능 및/또는 발현 수준의 변화로 인해 장의 투과성이 증가하면 새는 장 증후군 또는 LGS를 유발합니다.

The incidence of inflammatory bowel and leaky gut diseases is on the rise in countries that adopt a Western lifestyle. Its pathogenesis is not well defined, but it is associated with multifactorial causes. However, in genetically predisposed individuals, different environmental factors trigger alterations in the immune response; as a result, tolerance towards the commensal intestinal microbiota is lost, causing tissue damage and chronic inflammation. Among the environmental risk factors is diet. Diets high in sucrose, refined carbohydrates, polyunsaturated fatty acids, and omega-6 and low in fiber are associated with an increased risk of presenting these intestinal disorders [9].

염증성 장 질환 및 새는 장 증후군 발병률은 서구식 생활 방식을 채택하는 국가에서 증가하고 있습니다. 발병 기전은 잘 정의되어 있지 않지만 다인성 원인과 관련이 있습니다. 그러나 유전적 소인이 있는 사람의 경우 다양한 환경 요인이 면역 반응의 변화를 유발하여 공생 장내 미생물에 대한 내성이 상실되어 조직 손상과 만성 염증을 유발합니다. 환경적 위험 요인 중에는 식단이 있습니다. 자당, 정제 탄수화물, 고도 불포화 지방산, 오메가-6가 많고 섬유질이 적은 식단은 이러한 장 질환의 발생 위험을 증가시키는 것과 관련이 있습니다[9].

Nutritional recommendations for its control cannot be generalized since all patients do not respond in the same way. The emergence of disciplines such as nutrigenetics, nutrigenomics and epigenetics allows a greater understanding of the pathogenesis of this disease and, in turn, opens the possibility of an individualized approach from a nutritional point of view. The research on treating the intestinal permeability is mostly based on avoidance of high amounts of sugar and fat and implementation of FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), prebiotics, probiotics, fibers, glutamine, short-chain fatty acids, quercetin, and metformin [2]. There are some functional foods and ingredients that have shown great potential in treating leaky gut. Some herbs, polyphenols, amino acids, minerals, antioxidants, and food products could increase functionality against intestinal permeability. Therefore, this review article aims to explore foods and ingredients that can help prevent or treat leaky gut syndrome.

모든 환자가 같은 방식으로 반응하지 않기 때문에 이를 조절하기 위한 영양 권장 사항을 일반화할 수는 없습니다. 영양 유전학, 영양 유전체학 및 후성 유전학과 같은 분야의 출현으로이 질병의 발병 기전을 더 잘 이해할 수있게되었으며, 결과적으로 영양 학적 관점에서 개별화 된 접근 방식의 가능성이 열렸습니다. 장 투과성 치료에 대한 연구는 주로 다량의 설탕과 지방을 피하고 FODMAP(발효성 올리고당, 이당류, 단당류 및 폴리올), 프리바이오틱스, 프로바이오틱스, 섬유질, 글루타민, 단쇄 지방산, 케르세틴 및 메트포르민 [2]을 섭취하는 것을 기반으로 합니다. 새는 장 증후군 치료에 큰 잠재력을 보이는 기능성 식품과 성분도 있습니다. 일부 허브, 폴리페놀, 아미노산, 미네랄, 항산화제 및 식품은 장 투과성에 대한 기능을 향상시킬 수 있습니다. 따라서 이 리뷰 기사에서는 새는 장 증후군을 예방하거나 치료하는 데 도움이 될 수 있는 식품과 성분을 살펴보고자 합니다.

2. Components of the Intestinal Barrier

The composition and anatomical structure of the gut barrier is shown in Figure 3. From top to bottom, there is a microbiota barrier, a chemical barrier, a physical barrier, and an immune barrier. The chemical barrier contains microorganisms, immunoglobulin A (Ig A), mucins, AMPs (adenosine monophosphates) and antibacterial peptides. The physical barrier comprises intestinal epithelial cells (IECs), goblet cells (synthesis and release of mucins), Paneth cells (synthetic AMPs), and intestinal stem cells. The immune barrier is mainly consists of T cells, B cells, macrophages, dendritic cells (DC), and mast cells.

장 장벽의 구성과 해부학적 구조는 그림 3에 나와 있습니다. 위에서부터 아래로 미생물 장벽, 화학 장벽, 물리적 장벽, 면역 장벽이 있습니다. 화학적 장벽에는 미생물, 면역글로불린 A(Ig A), 뮤신, AMP(아데노신 모노포스페이트) 및 항균 펩타이드가 포함됩니다. 물리적 장벽은 장 상피 세포(IEC), 고블릿 세포(뮤신 합성 및 방출), 파네스 세포(합성 AMP), 장 줄기 세포로 구성됩니다. 면역 장벽은 주로 T세포, B세포, 대식세포, 수지상세포(DC), 비만세포로 구성됩니다.

Figure 3. Composition and anatomical structure of the gut barrier.

The first line of defense is found in the gastrointestinal tract and the intestinal lumen. The intestinal barrier constitutes the interface between the external and internal environment [10]. It comprises various physical, cellular, and chemical components that contribute to immunological functions (Figure 3) [11]. The inhibition of pathogenic microorganisms and antigens is produced by the action of gastric, pancreatic, and bile secretions. Digestive enzymes, including proteases, lipases, amylases, and nucleases, act as a barrier to those pathogens that could come from the diet [12]. It is desired to have a microflora that competes with pathogens for nutrients, metabolizing proteins and carbohydrates, and synthesizing vitamins [13]. The beneficial microflora can also produce many metabolic products that moderate the interaction between the epithelium and the immune system and generate antimicrobial substances, inhibiting pathogens [14].

첫 번째 방어선은 위장관 및 장 내강에서 발견됩니다. 장 장벽은 외부 환경과 내부 환경 사이의 인터페이스를 구성합니다[10]. 장 장벽은 면역 기능에 기여하는 다양한 물리적, 세포적, 화학적 구성 요소로 이루어져 있습니다(그림 3) [11]. 병원성 미생물과 항원의 억제는 위, 췌장 및 담즙 분비물의 작용에 의해 생성됩니다. 프로테아제, 리파아제, 아밀라아제 및 뉴클레아제를 포함한 소화 효소는 식단에서 나올 수있는 병원균에 대한 장벽 역할을합니다 [12]. 병원균과 영양분을 놓고 경쟁하고 단백질과 탄수화물을 대사하며 비타민을 합성하는 미생물을 보유하는 것이 바람직합니다[13]. 유익한 미생물은 또한 상피와 면역 체계 간의 상호 작용을 조절하고 항균 물질을 생성하여 병원균을 억제하는 많은 대사 산물을 생성 할 수 있습니다 [14].

Secondly, it is essential to consider the microflora from the mucus. The mucus varies throughout the intestine. In the small intestine, the mucus forms a thin, discontinuous layer, which facilitates the absorption of nutrients, while in the large intestine, it has two layers. The two layers consist of an inner layer, in which there are no bacteria, and a layer of external mucus that physically separates the intestinal lumen from the epithelium. These layers limit the entry of the microbiota to the apical side of the epithelium and provide protection [3]. The mucus components are water (more than 98%), mucins, and glycoproteins. More than 18 mucin-type glycoproteins have been identified [1]. The glycocalyx (carbohydrate-rich layer that covers the mucosal epithelial cells) from the inner layer and MUC2 from the outer layer is essential for disease prevention [11]. In addition, mucus contains secretory immunoglobulin A, antimicrobial products, peptides trefoil (trefoil factor family, TFF), cathelicidins, and ribonucleases, which are responsible for reinforcing the physical separation of the microbiota, forming a gradient from the epithelium to the lumen [11].

둘째, 점액의 미생물을 고려하는 것이 필수적입니다. 점액은 장 전체에 걸쳐 다양합니다. 소장에서는 점액이 얇고 불연속적인 층을 형성하여 영양소 흡수를 촉진하는 반면, 대장에서는 두 개의 층을 가지고 있습니다. 이 두 층은 박테리아가 없는 내층과 장 내강과 상피를 물리적으로 분리하는 외부 점액층으로 구성됩니다. 이 층은 미생물이 상피의 정단면으로 유입되는 것을 제한하고 보호 기능을 제공합니다 [3]. 점액 성분은 물(98% 이상), 뮤신, 당단백질입니다. 18개 이상의 뮤신형 당단백질이 확인되었습니다[1]. 점막 상피 세포를 덮고 있는 탄수화물이 풍부한 층인 내층의 글리코칼릭스와 외층의 MUC2는 질병 예방에 필수적입니다 [11]. 또한 점액에는 분비 면역 글로불린 A, 항균 제품, 펩타이드 트레포일(트레포일 인자군, TFF), 카테리시딘 및 리보뉴클레아제가 포함되어 있어 미생물의 물리적 분리를 강화하여 상피에서 내강까지 구배를 형성합니다[11].

Thirdly, the intestinal epithelium, with its tight junctions, is the essential component of the intestinal barrier and separates the microbiota from underlying immune cells forming an epithelial barrier [15]. The epithelial barrier is composed of a monolayer of specialized and polarized epithelial cells renewed every 3 to 5 days. The crypts contain the pluripotent stem cells that continually divide and differentiate themselves as they emigrate towards the tip of the villus, generating the different cell types of the epithelium (Figure 3)—enterocytes, Goblet cells, enteroendocrine cells, and M cells—or remain in the crypts: Paneth cells [16]. The epithelial cells are capable of phagocytizing bacteria and can neutralize bacterial toxins [17]. The epithelial cells also contain the recognition receptor patterns (RRPs) and pathogen-associated molecular patterns (PAMs) that must be subject to stringent controls to avoid inappropriate immune stimulation and inflammation. RRPs include Toll-like receptors (TLRs) and proteins with nucleotide oligomerization domains (NODs) [18]. These defense mechanisms are stimulated and activated when increasing the secretion of peptides, antimicrobials, cytokines, and chemokines [19].

셋째, 단단한 접합부를 가진 장 상피는 장 장벽의 필수 구성 요소이며 상피 장벽을 형성하는 기저 면역 세포로부터 미생물을 분리합니다 [15]. 상피 장벽은 3~5일마다 재생되는 특수하고 분극화된 상피 세포의 단층으로 구성됩니다. 융모 끝으로 이동하면서 지속적으로 분열하고 분화하여 상피의 다양한 세포 유형(그림 3)인 장세포, 잔세포, 장내분비세포, M 세포를 생성하거나 융모에 남아있는 만능 줄기세포를 포함합니다: 파네스 세포 [16]. 상피 세포는 박테리아를 포식할 수 있고 박테리아 독소를 중화할 수 있습니다[17]. 상피 세포에는 또한 부적절한 면역 자극과 염증을 피하기 위해 엄격한 통제를 받아야 하는 인식 수용체 패턴(RRP)과 병원체 관련 분자 패턴(PAM)이 포함되어 있습니다. RRP에는 톨 유사 수용체(TLR)와 뉴클레오티드 올리고머화 도메인(NOD)이 있는 단백질이 포함됩니다[18]. 이러한 방어 메커니즘은 펩타이드, 항균제, 사이토카인 및 케모카인의 분비를 증가시킬 때 자극되고 활성화됩니다 [19].

Beneath the intestinal epithelium resides the lamina propria that contains innate and adaptive immune cells, including macrophages, regulatory T cells, B cells, neutrophils, dendritic cells, plasma cells, and mast cells, protecting against microorganisms that penetrate the epithelium. Intraepithelial T lymphocytes and dendritic cells form a network under the epithelium and emit processes between epithelial cells, to which they bind via tight junctions to maintain the epithelial seal (Figure 3) [10].

장 상피 아래에는 대식세포, 조절 T 세포, B 세포, 호중구, 수지상 세포, 형질 세포 및 비만 세포를 포함한 선천성 및 적응성 면역 세포를 포함하는 층상피가 존재하여 상피에 침투하는 미생물로부터 보호합니다. 상피 내 T 림프구와 수지상 세포는 상피 아래에 네트워크를 형성하고 상피 세포 사이로 방출되며, 이 세포들은 단단한 접합부를 통해 결합하여 상피 봉인을 유지합니다(그림 3) [10].

3. Intercellular Junctions of the Intestinal Epithelium

For cells to form an epithelium, they need to be attached to the membrane by intercellular junctions. These junctions are classified into three groups (Figure 4): intercellular junctions, anchor junctions, and communicating junctions [20,21]. Tight junction proteins (TJs) are generated by assembling multiple proteins located in the apical part of the epithelium between neighboring cells and control the permeability of the transport pathway paracellular, restricting the passage of ions and solutes. In addition, they maintain the polarity of the epithelial cells by preventing the passage of molecules (lipids and proteins) from the apical membrane to the basolateral and vice versa, so the TJs have a very important function in the establishment of the intestinal barrier. They consist of integral transmembrane proteins that include occludin, tricellulin, claudins, and junctional adhesion molecules (JAMs) and peripheral proteins known as zonula occludens (ZO-1, ZO-2, ZO-3), which bind to actin filaments (Figure 4) [22,23].

세포가 상피를 형성하려면 세포 간 접합을 통해 세포가 막에 부착되어야 합니다. 이러한 접합부는 세포 간 접합부, 앵커 접합부, 통신 접합부의 세 가지 그룹으로 분류됩니다(그림 4) [20,21]. 타이트 접합 단백질(TJ)은 상피의 정단부에 위치한 여러 단백질이 인접한 세포 사이에서 조립되어 생성되며, 세포 간 수송 경로의 투과성을 조절하여 이온과 용질의 통과를 제한합니다. 또한 분자 (지질 및 단백질)가 정단막에서 기저측으로 또는 그 반대로 통과하는 것을 방지하여 상피 세포의 극성을 유지하므로 TJ는 장 장벽을 형성하는 데 매우 중요한 기능을합니다. 이들은 오클루딘, 트리셀룰린, 클라우딘, 접합부 접착 분자(JAM)를 포함하는 필수적인 막 통과 단백질과 액틴 필라멘트에 결합하는 조눌라 오클루덴(ZO-1, ZO-2, ZO-3)으로 알려진 주변 단백질로 구성됩니다(그림 4) [22,23]. 

Tight junction proteins are highly regulated, which is critical for maintaining the integrity of the normal barrier. The epithelial cells of the intestine proliferate and renew rapidly, and the tight junction proteins must be regulated to avoid any deleterious effect on the integrity of the barrier. The tight junction proteins can adapt to the different demands of the cells, sealing, opening, and maintaining paracellular transport under different physiological and pathological conditions [24]. Regulation is complex and performed by multiple proteins and signaling pathways, such as protein kinases C, A, and G (PKC, PKA, and PKG), phosphatase, myosin light-chain kinase (MLCK), mitogen-activated protein kinases (MAPK), and the phosphatidylinositol-3 kinase pathway (B/Akt, PI3K/Akt). Phosphorylation of occludin is responsible for opening and sealing tight junctions [3].

긴밀한 접합 단백질은 고도로 조절되며, 이는 정상 장벽의 무결성을 유지하는 데 매우 중요합니다. 장의 상피 세포는 빠르게 증식하고 재생되며, 장벽의 완전성에 해로운 영향을 미치지 않도록 긴밀한 접합 단백질이 조절되어야 합니다. 긴밀한 접합 단백질은 세포의 다양한 요구에 적응하여 다양한 생리적 및 병리학 적 조건 하에서 세포 간 수송을 밀봉, 개방 및 유지할 수 있습니다 [24]. 조절은 복잡하며 단백질 키나아제 C, A, G(PKC, PKA, PKG), 포스파타제, 미오신 경쇄 키나아제(MLCK), 미토겐 활성화 단백질 키나아제(MAPK), 포스파티딜이노시톨-3 키나아제 경로(B/Akt, PI3K/Akt) 등 여러 단백질 및 신호 경로에 의해 수행됩니다. 오클루딘의 인산화는 단단한 접합부를 열고 봉인하는 역할을 합니다[3]. 

The plasticity of TJs is essential for gastrointestinal functions, epithelial renewal, and morphogenesis. Under normal physiological conditions, tolerance and homeostasis are maintained with intestinal permeability controlled. However, any defects in the barrier with the TJs open in a deregulated and prolonged way can allow the passage of antigens from the diet or bacteria, a situation known as leaky gut syndrome [25].

TJ의 가소성은 위장 기능, 상피 재생 및 형태 형성에 필수적입니다. 정상적인 생리적 조건에서는 장 투과성이 조절되어 내성과 항상성이 유지됩니다. 그러나 장벽에 결함이 발생하여 TJ가 느슨하게 장기간 개방되면 식이 또는 박테리아의 항원이 통과할 수 있으며, 이를 새는 장 증후군이라고 합니다[25].

Figure 4. Intercellular junctions of the intestinal epithelium.

Adherent junctions regulate adhesion between adjacent cells through transmembrane adhesion molecules of the catenins and protein complexes associated with the actin cytoskeleton. The AJs are located on the lateral membrane below the TJs and are necessary to assemble and maintain tight joints. E-cadherin is among the isoforms of cadherin in epithelial tissues and participates in cellular processes, cell proliferation, the establishment of cell polarity, and remodeling of the actin cytoskeleton [26]. Desmosomes are intercellular junctions composed of desmocolins, desmoglein, and cadherins. These intercellular junctions can also act as intracellular signaling mediums [26]. Gap junctions are made up of six transmembrane proteins called connexins. They allow communication between cells, performing an essential function in the development, growth and differentiation of epithelial cells [12].

부착 접합부는 액틴 세포 골격과 관련된 카테닌과 단백질 복합체의 막 통과 접착 분자를 통해 인접한 세포 간의 접착을 조절합니다. AJ는 TJ 아래의 측면 막에 위치하며 단단한 접합을 조립하고 유지하는 데 필요합니다. E-카데린은 상피 조직에서 카데린의 동형체 중 하나이며 세포 과정, 세포 증식, 세포 극성 확립 및 액틴 세포 골격의 리모델링에 참여합니다 [26]. 데스모솜은 데스모콜린, 데스모글린, 카데헤린으로 구성된 세포 간 접합체입니다. 이러한 세포 간 접합은 세포 내 신호 전달 매체로도 작용할 수 있습니다 [26]. 갭 접합은 코넥신이라고 하는 6개의 막 통과 단백질로 구성됩니다. 이들은 세포 간의 통신을 허용하여 상피 세포의 발달, 성장 및 분화에 필수적인 기능을 수행합니다 [12].

4. Gut Microbiome and Leaky Gut

The gut has more than 100 trillion bacteria [27], with an aggregate biomass of approximately 1.5 kg [28], composed of more than 200 microbial strains in an individual and more than 90% of the dominant bacterial species belonging to the phylum Firmicutes and Bacteroidetes [29,30]. The genome has between 20,000 and 25,000 protein-coding genes, while the genome of the bacterial community in the human intestine is approximately 9 million genes [31], capable of providing characteristics that the human genome does not possess. Some of the observations made by investigations of the intestinal microbiota in adults are a low amount of Firmicutes and an abundance of Bacteroidetes [32]. Regarding the composition of the intestinal microbiota, it is made up of bacteria, viruses, fungi, and protozoa, although mainly bacteria. The microflora that populates the gut is, for the most part, anaerobes, although we can also find aerobes. The main bacterial species that inhabit the tract are those of the phylum Bacteroidetes (Prevotella, Porphyromonas), Firmicutes (Clostridium, Eubacteria), and Actinobacteria (Bifidobacterium). Other species we can find are those of the Lactobacillus, Streptococcus, and Escherichia coli, although to a lesser extent [32]. The microbial community that harbors the gastrointestinal tract is diverse and host specific.

The implications of the microbiota in the health of individuals are very numerous, from the stimulation of the immune system [10,33,34], the degradation of dietary fibers, the increase in function and motility of the gastrointestinal tract facilitate the absorption of nutrients and the inhibition of pathogens. The gut contributes to the maintenance of the defense and repairs the gastrointestinal mucosa [33]. Through protein degradation and a reduction in sulfur compounds, it generates hydrogen sulfide, which has antihypertensive effects [35] and seems to have overlapping actions with nitric oxide and prostaglandins, exerting many anti-inflammatory and antihypertensive effects [36].

장에는 100조 개 이상의 박테리아가 존재하며[27], 총 바이오매스는 약 1.5kg[28]이며, 한 개체당 200개 이상의 미생물 균주로 구성되어 있고, 90% 이상이 펌미쿠테스 및 박테로이드과에 속하는 지배적인 박테리아 종으로 구성되어 있습니다[29,30]. 인간 게놈은 20,000~25,000개의 단백질 코딩 유전자를 가지고 있는 반면, 장내 박테리아 군집의 게놈은 약 900만 개의 유전자를 가지고 있어[31] 인간 게놈이 가지고 있지 않은 특성을 제공할 수 있습니다. 성인의 장내 미생물을 조사하여 관찰한 결과 중 일부는 적은 양의 펌미쿠테스균과 풍부한 박테로이데테스균입니다[32]. 장내 미생물의 구성과 관련하여 장내 미생물은 박테리아, 바이러스, 곰팡이 및 원생 동물로 구성되어 있지만 주로 박테리아로 구성되어 있습니다. 장에 서식하는 미생물은 대부분 혐기성 세균이지만 호기성 세균도 있습니다. 장에 서식하는 주요 박테리아 종은 박테로이데테스 문(박테로이데테스, 포르피로모나스), 펌미쿠테스 문(클로스트리디움, 유박테리아), 액티노박테리아 문(비피도박테리움)에 속하는 박테리아입니다. 그 외 락토바실러스, 스트렙토코커스, 대장균도 발견할 수 있지만 그 수는 적습니다[32]. 위장관에 서식하는 미생물 군집은 다양하고 숙주에 따라 다릅니다.

면역 체계의 자극[10,33,34], 식이 섬유의 분해, 위장관의 기능 및 운동성 증가로 인한 영양소 흡수 촉진 및 병원균 억제 등 개인의 건강에 미치는 미생물의 영향은 매우 다양합니다. 장은 방어력 유지에 기여하고 위장 점막을 복구합니다 [33]. 단백질 분해와 황 화합물의 감소를 통해 항고혈압 효과가 있는 황화수소를 생성하며[35], 산화질소 및 프로스타글란딘과 중복 작용을 하여 많은 항염증 및 항고혈압 효과를 발휘하는 것으로 보입니다[36].

Bacterial metabolism also degrades plant polysaccharides and generates short-chain fatty acids that represent ≥10% of the calories absorbed daily by an individual [28]. In addition, the microbiota produces other beneficial metabolites such as polyamines [37] and vitamins (B and K). However, it can also produce harmful metabolites such as ammonia from urea and uremic toxins such as trimethylamine N-oxide (TMAO), p-cresyl sulfate (PCS), and indoxyl sulfate (IS), which cause systemic inflammation and other significant effects, such as alterations in the metabolism of drugs due to the inhibition of some isoenzymes, highlighting CYP3A4, which are extremely important in the metabolism of approximately 40% of drugs and would partly explain the variability between individuals with kidney failure [38].

The intestinal microflora is regarded as crucial for the health status of the host. In homeostasis, the relationship between the host and the microbiota is mutualistic. However, a breakdown of this balance, known as dysbiosis, could contribute to the development of the disease [39]. The gut microbiota has a crucial function in the energy and metabolic regulation of the human being since it provides up to 10% of our calories consumed daily [39]. Through the fermentation of food, the microbiota releases metabolites and short-chain fatty acids, which have anti-inflammatory properties and contribute to intestinal homeostasis [40]. The microbiota is considered, together with environmental, genetic, and immunological factors [41], an essential element in the development of inflammatory bowel disease, either as a mechanism that predisposes or protects against the development of intestinal inflammation [29,42]. To sum up, the gut microbiota performs several functions, such as regulating various nutrients and regulating the immune system, which can prevent and treat intestinal inflammation [43].

박테리아 대사는 또한 식물 다당류를 분해하고 개인이 매일 흡수하는 칼로리의 ≥10%를 차지하는 단쇄 지방산을 생성합니다[28]. 또한 미생물총은 폴리아민[37] 및 비타민(B와 K)과 같은 다른 유익한 대사산물을 생성합니다. 그러나 요소에서 암모니아와 같은 유해한 대사산물과 트리메틸아민 N-옥사이드(TMAO), p-크레실 설페이트(PCS), 인독실 설페이트(IS)와 같은 요독 독소를 생성하여 전신 염증 및 기타 심각한 영향을 유발할 수 있습니다, 일부 동종 효소의 억제로 인한 약물 대사의 변화와 같이 약물의 약 40%의 대사에 매우 중요하며 신부전 환자 간의 변동성을 부분적으로 설명할 수 있는 CYP3A4를 강조합니다[38].



장내 미생물은 숙주의 건강 상태에 매우 중요한 것으로 간주됩니다. 항상성에서 숙주와 미생물총의 관계는 상호 작용합니다. 그러나 이러한 균형이 깨지면 불균형증으로 알려진 질병이 발생할 수 있습니다[39]. 장내 미생물은 매일 섭취하는 칼로리의 최대 10%를 제공하기 때문에 인간의 에너지 및 대사 조절에 중요한 기능을 합니다[39]. 미생물총은 음식물의 발효를 통해 항염증 작용을 하고 장의 항상성에 기여하는 대사산물과 단쇄 지방산을 방출합니다[40]. 미생물총은 환경적, 유전적, 면역학적 요인[41]과 함께 장내 염증을 유발하거나 예방하는 메커니즘으로서 염증성 장 질환의 발병에 필수적인 요소로 간주됩니다[29,42]. 요약하면, 장내 미생물은 다양한 영양소를 조절하고 면역 체계를 조절하는 등 여러 기능을 수행하여 장 염증을 예방하고 치료할 수 있습니다[43].

면역 체계의 자극[10,33,34], 식이 섬유의 분해, 위장관의 기능 및 운동성 증가로 인한 영양소 흡수 촉진 및 병원균 억제 등 개인의 건강에 미치는 미생물의 영향은 매우 다양합니다. 장은 방어력 유지에 기여하고 위장 점막을 복구합니다 [33]. 단백질 분해와 황 화합물의 감소를 통해 항고혈압 효과가 있는 황화수소를 생성하며[35], 산화질소 및 프로스타글란딘과 중복 작용을 하여 많은 항염증 및 항고혈압 효과를 발휘하는 것으로 보입니다[36].

5. Diseases Related to the Alteration of Intestinal Permeability

5.1. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) involves several chronic remitting diseases, of which Crohn’s disease (CD) and ulcerative colitis (UC) are probably the most common. The two differ mainly in the area of the intestine they affect: the first can appear throughout the gastrointestinal tract, although it mainly affects the ileum and cecum, and the second appears mainly in the colon and rectum [44]. Although the etiology of IBD is unknown, a high level of intestinal inflammation is associated with an alteration of the tight junctions. In addition, it has been observed that patients have higher intestinal permeability than healthy subjects [21]. On the one hand, active UC is associated with a decrease in claudin-1, claudin-4, claudin-7, and occludin and an increase in claudin-2. The CD is associated with decreased claudin-3, claudin-5, and claudin-8, as well as increased expression‎ of claudin-2 [45]. For all these reasons, barrier dysfunction in patients with these diseases is related to inflammatory responses and TJ alteration [23].

염증성 장 질환(IBD)에는 여러 가지 만성 완화 질환이 포함되며, 그 중 크론병(CD)과 궤양성 대장염(UC)이 가장 흔합니다. 이 두 질환은 주로 영향을 미치는 장 부위가 다릅니다. 첫 번째는 주로 회장과 맹장에 영향을 미치지만 위장관 전체에 나타날 수 있고 두 번째는 주로 결장과 직장에 나타납니다 [44]. IBD의 원인은 알려져 있지 않지만 높은 수준의 장 염증은 단단한 접합부의 변화와 관련이 있습니다. 또한 환자는 건강한 피험자보다 장 투과성이 더 높은 것으로 관찰되었습니다 [21]. 한편으로 활성 UC는 클라우딘-1, 클라우딘-4, 클라우딘-7 및 오클루딘의 감소와 클라우딘-2의 증가와 관련이 있습니다. CD는 클라우딘-3, 클라우딘-5, 클라우딘-8의 감소와 클라우딘-2의 발현 증가와 관련이 있습니다[45]. 이러한 모든 이유로 이러한 질환 환자의 장벽 기능 장애는 염증 반응 및 TJ 변경과 관련이 있습니다 [23].

5.2. Irritable Bowel Syndrome and Other Intestinal Disorders

Irritable bowel syndrome (IBS) is a functional digestive disorder characterized by frequent abdominal pain related to shifts in the frequency and formation of bowel actions [44]. Intestinal permeability has also been associated with the pathogenesis of IBS. Specifically, IBS patients showed lower levels of the protein zonula occludens (ZO)-1 and occludin in intestinal tissue. They studied the production of cytokines in peripheral blood mononuclear cells PBMCs), and these patients (most notably those with diarrhea) showed elevated basal levels of TNF-α, IL-1β, and IL-6 in serum [4].

As we have already indicated, various diseases have been related to dysbiosis of the intestinal microbiota, microbial translocation, and dysfunction of the intestine’s barrier function. Among them, we can highlight obesity, chronic heart failure, Alzheimer’s disease, cancer, diabetes, and autoimmune diseases. The function of our immune system is to defend ourselves against infections and other diseases. However, in immune disorders, our body becomes the aggressor and attacks the body’s cells, causing damage [46]. Type 1 diabetes and celiac disease are examples of autoimmune diseases that are discussed further.

과민성 대장 증후군(IBS)은 배변 활동의 빈도 및 형성의 변화와 관련된 잦은 복통을 특징으로 하는 기능성 소화 장애입니다[44]. 장 투과성은 또한 IBS의 발병과 관련이 있습니다. 특히, 과민성 대장 증후군 환자는 장 조직에서 단백질 조눌라 오클루덴스(ZO)-1과 오클루딘 수치가 낮은 것으로 나타났습니다. 연구팀은 말초혈액 단핵세포 PBMC에서 사이토카인 생성을 연구했는데, 이러한 환자(특히 설사 환자)는 혈청 내 TNF-α, IL-1β, IL-6의 기저 수치가 높게 나타났습니다[4].

이미 언급했듯이 다양한 질병이 장내 미생물 군집의 불균형, 미생물 전위, 장의 장벽 기능 장애와 관련이 있습니다. 그중에서도 비만, 만성 심부전, 알츠하이머병, 암, 당뇨병, 자가면역질환 등을 꼽을 수 있습니다. 면역 체계의 기능은 감염 및 기타 질병으로부터 우리 몸을 방어하는 것입니다. 그러나 면역 장애에서는 우리 몸이 공격자가 되어 우리 몸의 세포를 공격하여 손상을 일으킵니다[46]. 제1형 당뇨병과 체강 질병은 자가 면역 질환의 예이며, 이에 대해 더 자세히 설명합니다.

5.3. Obesity

Obesity is a chronic illness distinguished by an overabundance of adipose tissue in the body. According to the WHO (World Health Organization), obesity is defined when the BMI (Body Mass Index) is equal to or greater than 30 kg/m2 [47]. Obesity has been associated with increased intestinal permeability. In genetically obese mouse models, there is an increase in intestinal permeability and plasma endotoxins and proinflammatory cytokines, such as interleukin one beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (INFγ), and tumor necrosis factor (TNF-α), compared to wild-type mice. On the other hand, obesity induced by a high-fat diet (diet-induced obesity, DIO) is linked to changes in the population of intestinal bacteria related to inflammation and increased intestinal permeability due to the reduction in gene expression‎ linked to TJs, including ZO-1 and occludin. All this indicates that obesity-induced inflammation may be associated with changes in the integrity of the tight junctions and the intestinal microbiota [48,49].

5.4. NASH and NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a liver disease caused by excessive accumulation of fats within liver cells, not primarily caused by alcohol consumption. On the other hand, in nonalcoholic steatohepatitis (NASH), the patient, in addition to fat, can present other alterations in the liver, such as inflammation and scars [50]. Changes in the gut microbiota composition in NAFLD patients increased LPS in circulating plasma, subsequently triggering inflammation [51]. These plasma LPS and proinflammatory cytokines simultaneously increase intestinal permeability [51]. The increased permeability in NAFLD patients is mainly caused by ZO-1 translocation in the crypt and bacterial overgrowth in the small intestine. In general, NASH and NAFLD are highly associated with impaired TJ integrity [23].

5.5. Chronic Heart Disease

Heart failure is the inability of the heart to pump enough blood to the body, so it cannot deliver the necessary oxygen and nutrients to the rest of the body. Chronic heart failure is the most common and develops gradually over months or years [52]. Patients with chronic heart failure showed a 35% increase in small bowel permeability with the lactulose/mannitol test and a 210% increase in large bowel permeability with the sucralose test. These increases in permeability were associated with disease severity, venous blood congestion, and serum C-reactive protein (CRP). In addition, high levels of endotoxins and inflammatory cytokines such as TNF and STNF-R1 were found. A study of the gut microbiota in such patients showed that they had massive amounts of pathogenic bacteria such as Campylobacter, Salmonella, and Candida compared to healthy subjects. All this indicates that an alteration of the barrier function in patients with CHF can induce translocations of bacteria and trigger the generation of cytokines, thus contributing to a deterioration of cardiac function [53].

5.6. Celiac Disease

Celiac disease is a disease of autoimmune origin with a hereditary component caused by the ingestion of cereals that contain gluten. After the ingestion of gluten in celiac patients, gliadin, a glycoprotein present in cereals, crosses the epithelium and reaches the macrophages of the intestinal submucosa, where a response is initiated by proinflammatory molecules that recognize the protein as a cytotoxic agent and cause intestinal inflammation and increased permeability [54]. This response can cause structural alterations in the TJs. It has been shown that the increase in intestinal permeability is due to an increase in the protein zonulin, which modulates tight junctions and paracellular permeability. Although gluten can trigger the release of zonulin in both healthy individuals and celiacs, the amount of zonulin produced is much higher in the latter. Celiac disease increases intestinal permeability and, consequently, induces a reorganization of the cytoskeleton through PKC and the disruption of the integrity of the tight junctions [55].

5.7. Type 1 Diabetes Mellitus

Diabetes mellitus is a chronic disease caused by an inability of the body to synthesize insulin or by the appearance of insulin resistance. Type 1 diabetes is characterized by an autoimmune response against the host’s pancreatic β cells, leading to insufficient insulin production [56]. Certain studies indicate that there could be a relationship between intestinal barrier dysfunction and type 1 diabetes mellitus. Firstly, studies in humans with type 1 diabetes mellitus show impaired intestinal barrier function, even before the onset of the disease, and increased intestinal permeability due to the production of zonulin. On the other hand, recent studies indicate that microbial translocation contributes to the development of type 1 diabetes. Together, the results suggest an essential role of intestinal permeability in the progression of type 1 diabetes [57].

6. Factors That Influence Intestinal Permeability

6.1. Dysbiosis

The dynamic interactions between the gut microbiota and the immune system are significant for maintaining intestinal homeostasis and inhibiting inflammation, as well as for understanding the importance of dysbiosis [58]. They have been attributed several functions to the microbiota related to the regulation of intestinal permeability, including the control of the proliferation of pathogenic bacteria, the stimulation of the immune system, the production of short-chain fatty acids, which modulate the host immune system and serve as a carbon source for colonocytes, and fermentation of amino acids and glucosaccharides [59]. The imbalance in intestinal microbiota alters the tight intercellular junctions (TJ) that allow access to pathogens and toxins (bacterial lipopolysaccharides, LPS). Additionally, it induces stimulation of mucosa-associated lymphatic tissue (MALT) with the activation of the inflammatory cascade (leukocytes, cytokines, and TNF-α), the establishment of a chronic inflammation process and, consequently, massive tissue damage [60].

Among the thousands of bacterial species identified in the healthy human intestine, 90% belong to Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. A dysbiotic microbiota can be produced by the increase in pathobionts such as Proteobacteria phylum, Escherichia, Vibrio, Yersinia, Helicobacter, and Salmonella, and the decrease in commensals such as Clostridium group IV and XIVa, Bacteroides, Bifidobacterium or Faecalibacterium prausnitzii [61]. The composition of the microbiota changes continuously throughout life, and many factors influence its composition. Thus, it mainly varies according to factors such as diet, age, genes, drugs ingested, and environmental, physical, and psychological stress [49].

장내 미생물과 면역 체계 간의 역동적인 상호 작용은 장내 항상성을 유지하고 염증을 억제할 뿐만 아니라 불균형 증식의 중요성을 이해하는 데 중요합니다[58]. 장내 미생물은 병원성 박테리아의 증식 조절, 면역 체계 자극, 숙주 면역 체계를 조절하고 대장 세포의 탄소 공급원 역할을 하는 단쇄 지방산 생산, 아미노산 및 포도당 발효 등 장 투과성 조절과 관련된 여러 기능을 하는 것으로 알려져 있습니다[59]. 장내 미생물의 불균형은 병원균과 독소(박테리아성 지질다당류, LPS)에 대한 접근을 허용하는 단단한 세포 간 접합부(TJ)를 변화시킵니다. 또한 염증성 캐스케이드(백혈구, 사이토카인, TNF-α)의 활성화, 만성 염증 과정의 확립, 결과적으로 대규모 조직 손상과 함께 점막 관련 림프 조직(MALT)의 자극을 유도합니다[60].



건강한 사람의 장에서 확인된 수천 종의 박테리아 중 90%는 프로테오박테리아, 펌미쿠테스, 액티노박테리아, 박테로이데테스과에 속합니다. 프로테오박테리아 속, 대장균, 비브리오, 예르시니아, 헬리코박터, 살모넬라와 같은 병원성 세균이 증가하고 클로스트리디움 그룹 IV 및 XIVa, 박테로이데스, 비피도박테리움 또는 페칼리박테리움 프라우스니치[61]와 같은 공생균이 감소하면 이상 미생물이 생성될 수 있습니다. 미생물총의 구성은 일생 동안 지속적으로 변화하며 많은 요인이 그 구성에 영향을 미칩니다. 따라서 주로 식단, 연령, 유전자, 섭취한 약물, 환경적, 신체적, 심리적 스트레스와 같은 요인에 따라 달라집니다 [49].

6.2. Infections

Infections can also play a role in disrupting the intestinal barrier. For example, Helicobacter pylori infect the human stomach. This bacterium is known to increase intestinal permeability due to the redistribution of the ZO-1 protein from the TJ [62]. Additionally, it has been found that bacteriophages, which were not generally considered mammalian pathogens, may have some impact on the leaky gut [57]. The pathological effect of these bacteriophages manifested as an increase in intestinal permeability and the translocation of bacterial components and products. Bliss translocation is considered among the main triggers of various polyetiological diseases associated with chronic inflammation and leaky gut. However, due to the possible association of bacteriophages with leaky gut, it may be caused by phages found in the intestinal microenvironment to which humans are continuously exposed. The infection of the microbiota by bacteriophages represents a new group of viral diseases in mammals. Even so, further studies should be carried out to confirm‎ the effect of bacteriophages on the intestinal microbiota and eval‎uate its implications in the different human pathologies [63].

6.3. Antibiotics and Drugs

The gut microbiota can also be affected by antibiotics or other drugs. A study on the effects of antibiotics with different modes of action on the composition of the human microbiota showed that antibiotic treatment could increase or decrease certain species of the intestinal microbiota [64]. Macrolides are among the most widely used antibiotics in children and adults. It has been shown that consumption of antibiotics, for a prolonged time, in children led to an alteration in the intestinal microbiota, which decreased Actinobacteria and increased Bacteroides and Proteobacteria. On the other hand, clarithromycin, the first antibiotic used to eradicate Helicobacter pylori, showed a decrease in actinobacteria and firmicutes, with an increase in Bacteroides and Proteobacteria after H. pylori eradication. Some studies showed that vancomycin decreased fecal microbiota diversity due to reduced Firmicutes and increased Proteobacteria. Ciprofloxacin was found to reduce Firmicutes and Actinobacteria (specifically Bifidobacterium) and increased Bacteroides, while clindamycin decreased Lactobacillus and Bifidobacteriaceae [65]. In addition, other drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or paracetamol damage the gastric and intestinal mucosa and are associated with gastrointestinal complications. Patients who are long-term users of these drugs may show a decrease in absorption capacity and a possible increase in bowel permeability [66].

6.4. Alcohol

Animal studies have shown that alcohol could cause increased intestinal permeability, depending on the dose and time of administration of alcohol, and decreases in the hydrophobicity of the mucosal surface (a physiological marker of mucosal barrier function) associated with increased levels of free fatty acids in the intestinal lumen. These results suggest that alcohol can cause loss of intestinal barrier function by extracting and dissolving intestinal mucosal lipids with a resulting decrease in the hydrophobicity of the mucosal surface, which is a critical component of intestinal barrier function [67]. Human studies support the inhibition of beneficial bacteria and the dysbiosis produced after high consumption of alcohol. Alcohol consumption has been shown to alter the mucosa-associated microbiota composition in the sigmoid colon biopsies [68].

6.5. Stress

On certain occasions, stress can affect the development of the intestinal barrier and be associated with increased gut permeability [69]. An example of this type of stress is burns and alcohol consumption, which we have referred to in the previous section. Burn injury, mediated by myosin light-chain (MLC) kinase activity, results in an increase in gut permeability. In addition, MLC phosphorylation or activation of other kinases triggers the opening of TJ proteins (including ZO-1 and claudin-1), which can be reversed by adding an inhibitor of MLC phosphorylation [57]. The effects of stress on intestinal permeability are not simple and possibly involve the brain, apart from the gut. Corticotropin-releasing factor (CRF) and its receptors (CRFR1 and CRFR2) play a key role in permeability dysfunction in the stress-induced gut. In response to an acute stressor, paracellular permeability is associated with visceral hypersensitivity. In turn, stress in early life enhances plasma corticosterone in rat pups. It is associated with increased intestinal permeability and bacterial translocation to the liver and spleen, predominating the effect in the colon [70]. Human studies also confirm‎ that acute stress can affect gut permeability [70]. A stressor such as public speaking produces an increase in intestinal permeability with an increase in cortisol levels. Another stress factor, pain due to cold, produces increased permeability to albumin, although it is only found in women [70]. The stress factor is also relevant in the prenatal period since babies of mothers with high stress reported high concentrations of salivary cortisol during pregnancy and had a significantly higher relative abundance of Proteobacteria and a relative abundance of minor lactic acid bacteria (Lactobacillus, Lactococcus, Aerococcus, and Bifidobacteria). Likewise, babies with an altered composition of the microbiota showed a higher incidence of gastrointestinal symptoms and allergic reactions in children, highlighting the functional consequences of aberrant colonization patterns in the early years of life [70].

경우에 따라 스트레스는 장 장벽의 발달에 영향을 미치고 장 투과성 증가와 관련이 있을 수 있습니다[69]. 이러한 유형의 스트레스의 예로는 이전 섹션에서 언급한 화상과 음주를 들 수 있습니다. 미오신 경쇄(MLC) 키나아제 활성에 의해 매개되는 화상 손상은 장 투과성을 증가시킵니다. 또한, MLC 인산화 또는 다른 키나아제의 활성화는 TJ 단백질(ZO-1 및 클라우딘-1 포함)의 개방을 유발하며, 이는 MLC 인산화 억제제를 추가하여 되돌릴 수 있습니다[57]. 장 투과성에 대한 스트레스의 영향은 단순하지 않으며 장 외에도 뇌와 관련이 있을 수 있습니다. 코르티코트로핀 방출 인자(CRF)와 그 수용체(CRFR1 및 CRFR2)는 스트레스에 의한 장의 투과성 기능 장애에 중요한 역할을 합니다. 급성 스트레스 요인에 대한 반응으로, 세포 투과성은 내장 과민증과 관련이 있습니다. 결과적으로, 생애 초기의 스트레스는 쥐 새끼의 혈장 코르티코스테론을 강화합니다. 이는 장 투과성 증가 및 간과 비장으로의 박테리아 전좌와 관련이 있으며 결장에서의 효과가 우세합니다 [70]. 인간 연구에서도 급성 스트레스가 장 투과성에 영향을 미칠 수 있음을 확인했습니다 [70]. 대중 연설과 같은 스트레스 요인은 코티솔 수치의 증가와 함께 장 투과성을 증가시킵니다. 또 다른 스트레스 요인인 감기로 인한 통증은 알부민에 대한 투과성을 증가시키지만, 이는 여성에게서만 발견됩니다 [70]. 스트레스가 높은 산모의 아기는 임신 중 타액 코티솔 농도가 높고 프로테오박테리아의 상대적 풍부도와 마이너 유산균(락토바실러스, 락토코커스, 에어로코커스, 비피도박테리아)의 상대적 풍부도가 훨씬 더 높았기 때문에 스트레스 요인은 태아기에도 관련이 있습니다. 마찬가지로, 미생물 군집의 구성이 변경된 아기는 소아에서 위장 증상과 알레르기 반응의 발생률이 더 높았으며, 이는 생후 초기에 비정상적인 식민지화 패턴의 기능적 결과를 강조합니다 [70].

6.6. Diet

The diet strongly influences the microbial composition and functions of the gut. Diet has a dominant role in the configuration of the intestinal microbiota since dietary components can significantly alter gastrointestinal functions, compromising the intestinal barrier’s integrity [71]. The consumption of carbohydrates and lipids can affect intestinal permeability, leading to bowel syndrome permeable [7]. Additionally, the different eating habits in different countries are reflected in the incidence rates of intestinal diseases. The intestinal hyperpermeability cases tend to be located in countries with a Western culture, where a diet rich in fats and refined carbohydrates predominates [72]. The carbohydrates and liquids induce cellular inflammation through intestinal dysbiosis and affect both the metabolism of the gastrointestinal tract of the host and immune homeostasis [73]. Long-chain fatty acids are critical components of living cells and have been shown to influence intestinal permeability due to the alteration of TJs and the acetylation of histones. Several studies showed that fructose, glucose, and sucrose are implicated in increased intestinal permeability and dysfunction of TJs [7].

On the other hand, some carbohydrates, such as galactooligosaccharides, can support the growth of beneficial bacteria, and dietary fiber has been shown to positively affect intestinal permeability [7]. The dietary fiber is digested by enzymes and microorganisms fermenting short-chain fatty acids such as butyrate and propionate, which are key factors in the protection of the intestine [73]. Additionally, food additives have been related to permeable bowel syndrome. A recent review describes the ability of additives to increase intestinal permeability by interfering with TJs, promoting the passage of antigens immunogenic to the organism [74]. A potentially beneficial diet would focus on avoiding products such as fruits abundant in fructose, food additives, and oils that contain ALA and GLA. On the other hand, patients with LGS should consume a greater amount of dietary fiber and less sugars and fats (Figure 5) [7].

식단은 장내 미생물 구성과 기능에 큰 영향을 미칩니다. 식이 성분이 위장 기능을 크게 변화시켜 장 장벽의 완전성을 손상시킬 수 있기 때문에 식단은 장내 미생물 구성에 지배적인 역할을 합니다[71]. 탄수화물과 지질의 섭취는 장 투과성에 영향을 미쳐 장 증후군 투과성을 유발할 수 있습니다 [7]. 또한 국가마다 다른 식습관은 장 질환의 발병률에 반영됩니다. 장 투과성 장 질환은 지방과 정제 탄수화물이 풍부한 식단이 주를 이루는 서구 문화권 국가에서 많이 발생하는 경향이 있습니다[72]. 탄수화물과 액체는 장내 미생물을 통해 세포 염증을 유발하고 숙주의 위장관 대사와 면역 항상성 모두에 영향을 미칩니다 [73]. 장쇄 지방산은 살아있는 세포의 중요한 구성 요소이며 TJ의 변화와 히스톤의 아세틸화로 인해 장 투과성에 영향을 미치는 것으로 나타났습니다. 여러 연구에 따르면 과당, 포도당 및 자당은 장 투과성 증가 및 TJ 기능 장애와 관련이 있는 것으로 나타났습니다 [7].



반면에 갈락토올리고당과 같은 일부 탄수화물은 유익한 박테리아의 성장을 지원할 수 있으며 식이 섬유는 장 투과성에 긍정적 인 영향을 미치는 것으로 나타났습니다 [7]. 식이 섬유는 장 보호의 핵심 요소인 부티레이트 및 프로피오네이트와 같은 단쇄 지방산을 발효하는 효소와 미생물에 의해 소화됩니다 [73]. 또한 식품 첨가물은 투과성 장 증후군과 관련이 있습니다. 최근의 한 연구에서는 첨가물이 TJ를 방해하여 장 투과성을 높이고 유기체에 면역원성이 있는 항원의 통과를 촉진하는 기능을 설명합니다[74]. 잠재적으로 유익한 식단은 과당이 풍부한 과일, 식품 첨가물, ALA 및 감마리놀렌산이 함유된 오일과 같은 제품을 피하는 데 초점을 맞출 수 있습니다. 반면에 LGS 환자는 더 많은 양의 식이 섬유를 섭취하고 설탕과 지방은 적게 섭취해야 합니다(그림 5) [7].

Figure 5. Effect of various components of the diet on the permeability of the intestinal epithelium. The components that decrease intestinal permeability appear on the upper part of the figure and those that increase it appear on the lower part of the figure.

7. Ingredients That Help Treat Leaky Gut

7.1. FODMAP

FODMAP is a collective term that consists of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [75]. Intestinal permeability has also been associated with the pathogenesis of irritable bowel syndrome (IBS), which is treated with FODMAP. IBS patients showed lower protein zonula occludens (ZO)-1 and occludin in intestinal tissue. They showed an increase in the production of cytokines in peripheral blood mononuclear cells (PBMCs), and these patients (most notably those with diarrhea) showed basal levels of elevated serum TNF-α, IL-1β, and IL-6 [4]. The first study demonstrating the function of a low-FODMAP diet in handling gastrointestinal problems was clinical trials with IBS and fructose malabsorption on a low-fructose/fructan diet [75]. Fructans and galactooligosaccharides have well-documented prebiotic actions [76].

Nevertheless, fructose over glucose, lactose, sorbitol, mannitol, fructans (fructooligosaccharides, inulin), and galactooligosaccharides have shown osmotic action, increasing small bowel and lumen water content. Slow or no absorption of FODMAPs results in an increase in osmotic action, resulting in increased luminal water content and subsequent distention of the small intestine, leading to IBS symptom induction [76]. Malabsorption of FODMAPs results in their delivery to the large intestine, allowing exposure to the microbiota and subsequent fermentation, resulting in gas production and luminal distention of the large intestine, leading to IBS symptom induction. The low-FODMAP diet has been recommended to provide irritable bowel syndrome patients with a treatment approach that can effectively relieve most symptoms in most patients and is now supported by high-quality evidence, including randomized controlled trials [77].

FODMAP consumption affects multiple gastrointestinal effects. Some of them may be beneficial, such as increased fecal bolus volume, improved calcium absorption, and increased production of short-chain fatty acids. Selective stimulation of some components of the microbiota, such as bifidobacterium, is also described, as well as a positive effect on the growth and function of the intestinal microbiota [77].

7.2. Probiotics

Probiotics are viable microorganisms with physiological or beneficial therapeutics. Probiotics are found both in foods and as supplements, with the most common foods being yogurt and kefir [78]. Among the main effects of the administration of probiotics are the maintenance of homeostasis and intestinal integrity, regulation of intestinal transit, the production of short-chain fatty acids and vitamins, and providing enzyme digestion activities for the degradation of undigested fibers and the neutralization of xenobiotics. Probiotics could also help modulate intestinal permeability affecting the mucus, epithelium and microbiota (Figure 6).

Figure 6. Effects of probiotic bacteria on intestinal epithelial barrier function. Figure adapted from Ohland and MacNaughton (2010) with modifications.

Probiotics can exhibit anti-inflammatory properties against TNF-α or IL-6 [79]. They can also strengthen the mucosal barrier [80] and reduce intestinal permeability, upregulating TJS proteins [81]. The advantageous effect of probiotics in pouchitis is associated with the homeostasis of the mucosal barrier [82]. Another possible mechanism of action is the addition of butyrate-producing species [83]. These factors combine to result in greater integrity of the intestine, making probiotics a fantastic therapy for reducing leaky gut [84]. Table 1 illustrates the major intestinal epithelial homeostasis and health benefits of probiotics.

Table 1. Major probiotics that help leaky gut.

Various species of Lactobacillus exert effects on the expression‎ and secretion of mucins. Intestinal mucins are the mucus’s main protein component that covers the gastrointestinal tract’s epithelium. These glycosylated macromolecules (up to 80% w/w) are synthesized by goblet cells or goblet cells. They are located in the cell membrane or secreted into the intestinal lumen to form the mucosal layer. Of the 18 mucin-like glycoproteins expressed by humans, the mucin MUC2 is the predominant glycoprotein found in the mucus of the small and large intestines. The NH2 and COOH termini are not glycosylated to the same extent but are rich in cysteine residues that form intra- and intermolecular disulfide bonds. These glycan groups confer proteolytic resistance to the mucins, while the disulfide bonds form a matrix of glycoproteins that is the backbone of the mucosa. This layer protects the epithelium against antigens and potentially harmful molecules and acts as a lubricant for intestinal motility. The mucus is the first barrier intestinal bacteria encounter, and pathogens must penetrate it to reach epithelial cells during infection. Microorganisms have developed various mechanisms to degrade mucus, such as mucin disulfide bond reduction, proteolytic activity, and glucosidase valuable activity to invade or absorb nutrients derived from mucus. On the other hand, the colon’s mucosal layer is thinner in areas of inflammation, allowing greater adherence and bacterial infiltration.

In vitro studies show that various species of Lactobacillus, such as L. plantarum 299v, L. rhamnosus GG, and L. acidophilus DDS-1, may increase mucin expression‎ and secretion by goblet cells as a mechanism to enhance barrier function and pathogen exclusion by limiting bacterial movement through of the mucosal layer [1,115,116].

Another positive effect of some probiotic microorganisms on the epithelium is the increase in the expression‎ and secretion of defensins. α-defensins (HD-5 and HD-6), expressed mainly by Paneth cells in the small intestine, and β-defensins (hBD1 to hBD-4), expressed by epithelial cells throughout the intestine, possess antimicrobial activity against a wide range of variety of bacteria, fungi, and some viruses and are constitutively expressed to prevent pathogens from reaching the epithelium. For its part, the decrease in the production of defensins has been associated with the development of inflammatory bowel disease and greater susceptibility to bacterial infections [1]. Various species of the Lactobacillus genus and commercial probiotic preparations have shown in in vitro studies with Caco-2 cells and in vivo studies with humans that they can regulate the expression‎ and secretion of β-defensin hBD-2. Increased defensin expression‎ and mucus secretion by epithelial cells may prevent the proliferation of commensals and pathogens, thus also contributing to barrier integrity [117,118]. Patients who received the commercial preparations twice daily for three weeks showed a significant increase in fecal levels of hBD-2 protein, while individuals treated with a placebo showed no change [118]. These levels were maintained for 9 weeks after cessation of probiotic treatment, although to a lesser extent [118].

Probiotics can increase the levels of immunoglobulin A (IgA)-producing cells in the lamina propria and promote the secretion of secretory IgA (sIgA) in the luminal layer of the mucosa. These antibodies limit epithelial colonization by binding to bacteria and their antigens, contributing to intestinal homeostasis. Some studies show that certain microorganisms can increase the levels of total and pathogen-specific IgAs after infection, without increasing probiotic-specific IgAs. Galdeano and Perdigón (2006) [119] showed that the administration of L. casei to mice significantly increased the number of IgA- and IL-6-producing cells, which can stimulate class switching to IgA in B cells within the lamina propria of the mouse. In addition, they did not find specific antibodies against L. casei, which indicates the lack of response of the intestinal immune system to this beneficial bacterium [119].

Different tests have experimented with the effectiveness of various species of probiotics in intestinal permeability, including Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus Plantarum, Bifidobacterium infantis, Bifidobacterium animalis lactis BB-12, and Escherichia coli Nissle 1917 [120] (Table 1). Table 1 details the role of probiotics in major epithelial intestinal modulations and possible mechanisms of actions in the intestinal barrier that eventually can potentially provide health benefits for leaky gut syndrome-related diseases. Comprehending the mechanism of action of the dietary nutrients may assist in delivering knowledge about the potential of the ingredient and how it affects intestinal barrier dysfunctions. Nevertheless, the probiotic application is still limited, and their mechanisms of action are not fully understood.

7.3. Vitamins

For the most part, vitamins A and D play critical functions in regulating gastrointestinal homeostasis [121]. In clinical trials, these vitamins impacted the components of the mucosal barrier, including epithelial integrity, immune system, and gut microbiota. It is suggested that vitamins A and D’s effects on gut microbiota composition are indirect [122]. In animal studies, these vitamins reduce microbial diversity and increase the Proteobacteria phylum [123], which are potentially pathogenic in patients with inflammatory bowel disease (IBD) [124]. In human studies, vitamin A-sufficient children have more diverse microbial communities when compared to vitamin A-deficient children [125]. In the intestinal epithelium, in vitro studies show that vitamin A and vitamin D improve the tight junctions (ZO-1, occludin, and several claudins) [126,127]. Vitamins A and D are necessary for the integrity of the epithelium and gut microbiota and modulate immune responses at different levels. Both vitamins can inhibit T-cell IFN-γ production [128] and inhibit Th17 cells in vitro. In vitro models, these vitamins can generate IL-10 production and FOXP3 protein, which is implicated in immune system reactions [129]. Retinoic acid can stimulate the production of antibacterial peptides such as Reg3β and Reg3γ in enterocytes [130]. These and other results indicate that the theoretically advantageous effects of vitamins A and D may be because of the regulation of different elements of the mucosal barrier. Nevertheless, only a few studies or clinical trials are available in the literature, and more research is encouraged.

7.4. Fibers and Short-Chain Fatty Acids

Among carbohydrates, dietary fibers (DF) are appropriate for anti-inflammation properties and intestinal barrier regulation. Accordingly, the microbiota ferments DF and produces short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate. In particular, the beneficial species of Bifidobacterium bacteria and Lactobacilli are related to the production of SCFA and the immunostimulation and inhibitory effects on the growth of harmful bacteria [131]. The SCFA constitutes the primary energy source for the colonocyte’s epithelial cells. Butyrate is the most critical substrate the colonocyte prefers, providing between 60 and 70% of the energy requirements [132]. SCFAs are critical in metabolism, immunity, and intestinal barrier functions. For instance, butyrate can improve paracellular permeability by modulating hypoxia-inducible factor-1 and epithelial tight junction CLDN1 [133]. In addition, butyrate regulates the central element of the colonic mucus layer, goblet-cell-specific mucin MUC2 expression‎ in human goblet cell-like LS174T cells [134]. Regarding its anti-inflammatory properties, SCFAs modulate the chemotaxis of immune cells and release reactive oxygen species (ROS) and cytokines. SCFAs could have a binding regulatory effect on inflammatory diseases by controlling the migration of immune cells towards the site of inflammation and modulating their activity, allowing the rapid elimination of pathogens by activating ROS. The above binding process can contribute to the reduction in damage to the host, which could allow not only its survival but also the production of SCFA by intestinal bacteria [135].

The deficiency of SCFAS and dietary fibers can compromise epithelial and mucus barrier functions by increasing gut permeability. In mice, the deficiency in consumption of dietary fibers and SCFAS production can harm intestinal barrier integrity by inhibiting Akkermansia muciniphila [136]. This bacterium uses mucus glycans as a nutrient source without dietary fibers. This alteration can cause damage to the colonic mucus barrier and result in the development of colitis caused by the enteric pathogen Citrobacter rodentium [136]. Yamada et al. (2015) [137] eval‎uated changes in SCFAs in 140 patients diagnosed with severe systemic inflammatory response syndrome (SIRS) and compared them with healthy volunteers; they found a significant decrease in the concentration of butyric, propionic, and acetic acids and a significant increase in pH; both the total concentration of organic acids and SCFA were significantly lower in patients with gastrointestinal dysmotility [137]. In this study, regarding the healthy volunteers, the authors reported in inflammatory response syndrome patients a significantly lower count of obligate anaerobic bacteria (Bacteroidaceae, Bifidobacterium, and Enterobacteriaceae) and a significantly higher count of facultative anaerobic microorganisms (Enterococcus, Staphylococcus, Pseudomonas, and Candida). The mechanisms by which SCFA decrease in critically ill patients are not precise. Although more studies are needed, the decrease in obligate anaerobic bacteria may affect their concentration in the long term [138]. The fermentation substrates necessary for SCFA production in these patients may be decreased [139]. An increase in intestinal permeability and a decrease in pH has been reported in critically ill patients [140].

7.5. Glutamine

Dietary glutamine is not subject to significant acid hydrolysis in the stomach and upper duodenum and is, therefore, effectively available in the small intestine for absorption and metabolic utilization. In accompaniment to its essential function in absorption, secretion, and digestion, amino acids are critical to nourishing gut health as a barrier to the permeability of pathogens, allergens, and toxins into the epithelium. Glutamine is considered a crucial amino acid capable of regulating the expression‎ of tight junction proteins, allowing the membrane of intestinal cells to remain impermeable. Preclinical studies have indicated that adding glutamine improves fibrosis and intestinal inflammation [141,142]. In T and B-lymphocytes and epithelial cells, glutamine improves anti-inflammatory IL-10 levels and decreases the production of pro-inflammatory IL-6 and IL-8 [143]. Since IL-10 is vital in sustaining intestinal mucosal homeostasis, this amino acid is considered a regulator of the innate and adaptive immune response system [144]. Glutamine with probiotics can have beneficial effects when treating intestinal permeability in patients with severe disorders. This combination could generate a synergistic effect by increasing the amount of Lactobacillus, slowing down the growth of Gram-negative bacteria, improving the structure of the intestinal flora, and restoring damage to the colonic barrier. In addition, it can effectively reduce the intestinal mucosa’s permeability and the intestinal endotoxin level, restoring the mechanical damage of the intestinal barrier and thus reducing intestinal bacteria’s translocation [145]. However, research eval‎uating the impact of glutamine on the intestinal barrier in preclinical models is restricted. It is recommended to demonstrate that nutritional intervention can impact the clinic by approaching treatment on time and avoiding surgical complications. In addition, it is essential to implement a guide on the perioperative nutritional management (encompasses preoperative, intraoperative, and postoperative care) of patients with gastrointestinal disorders, detailing the importance of using glutamine, dosage, and probiotics strains. A Randomized Clinical Trial (RCT) with a larger sample size is suggested to confirm‎ the positive benefits of using probiotics and glutamine. Even though multiple in vitro, in vivo, and clinical studies reveal that glutamine has an advantageous function in the maintenance of the mucosal barrier, larger randomized trials are required to eval‎uate the advantageous effects of glutamine.

7.6. Arginine

Unlike glutamine, just a few studies indicate the protective effects of arginine on intestinal epithelium integrity. In an intestinal obstruction model, arginine decreased intestinal paracellular permeability (400 Da molecule) and E. coli translocation [146]. Similarly, l-arginine (4 mM) moderately inverted the increase in paracellular permeability of Lucifer Yellow (457.25 Da) and the reduction in TEER (transepithelial electrical resistance) generated by heat stress [147]. Protective effects of L-arginine have been reported on the intestinal epithelial barrier under heat-stress conditions in rats and the IEC-6 cell line [148]. In IPEC-J2 cells, arginine improved hypoxia-induced paracellular inulin permeability, decreased TEER, and moderation ZO-1 [149]. In the small intestine of nonalcoholic steatohepatitis rodents, arginine regulates occludin and ZO-1 and promotes plasma levels of bacterial endotoxins [150]. Arginine enhances the intestinal barrier function of birds fed a reduced protein diet under stress conditions [151]. Similarly, arginine demonstrated favorable effects in overall growth, intestinal integrity, and morphology in broilers subjected or not to the Eimeria challenge. In the intestinal skin of mice, arginine increased the Bacteroidetes population and the production of mucin-2, mucin -4, TNF-α, IL-1β, IFN-γ, paneth antimicrobials, and secretory immunoglobulin A [152]. Well-designed clinical trials must be addressed to confirm‎ the potential observed in preclinical trials.

7.7. Polyphenols

To date, the mechanisms of action regarding polyphenols with intestinal permeability have not been well understood. Nevertheless, polyphenols are involved in a direct/indirect matter with intestinal permeability by NF-κB inactivation, a pathway identified as among the most significant arbitrators of cytokines, interleukins, and inflammation. Furthermore, the NF-κB activation is related to impairing the epithelial barrier function by TJ disassembly. Luescher et al. (2017) [153] have reported that polyphenols inactive NF-κB by containing degraded proteasome of IκB and interfering with IκB kinase phosphorylation [153]. Another essential aspect potentially engaged in improving intestinal epithelium functions is the inhibition of several protein kinases, including activated protein kinase, phosphoinositide-3-kinase, tyrosine kinase, mitogen-activated protein kinase, myosin light-chain kinase, protein kinase C and adenosine monophosphate [154]. Some epigallocatechin 3-gallate, curcumin, and quercetin have been reported to decrease intestinal permeability by inhibiting protein kinase C and myosin light-chain kinase involved in the phosphorylation of inflammatory proteins [155,156,157].

Initially, the beneficial effects of polyphenols were attributed to their ability to eliminate ROS, that is, antioxidants. There is increasing evidence that its benefits are strongly related to the ability to interfere with redox signaling pathways [32]. it is considered that oxidative stress could be involved in the etiology of intestinal permeability; polyphenols, due to their properties, are proposed for treating the disease. Research suggests that the diet’s consumption of polyphenols contributes to restoring redox homeostasis and increasing the activity of antioxidant enzymes (SOD, CAT, GPx, and GR). The expression‎ of these enzymes is regulated by a nuclear erythroid-derived factor 2 (Nrf2). Nrf2 is activated at the cellular level by ROS and translocates to the nucleus, where it regulates the transcriptions of various genes encoding the aforementioned antioxidant enzymes. The antioxidant activity of polyphenols is associated with the ability to activate Nrf2 and, therefore, regulate antioxidant enzymes [158].

A critical aspect that must be highlighted in this broad group of metabolites is their bioavailability since it is essential to eval‎uate their biological properties. It is reported that, after ingesting polyphenols, only a percentage between 1 and 10% of the total is detected in urine and plasma samples. Although this group of compounds generally has low oral bioavailability, some subgroups of the highest classification differ in this parameter. For example, bioavailability is particularly low for flavones, while it is higher for flavanones and soy isoflavones. Thus, consuming 10–100 mg of simple polyphenol results in a plasma concentration rarely exceeding 1 μM. However, the low bioavailability of polyphenols may not be a problem in intestinal diseases since several studies suggest that the highest levels of polyphenols in the human body are concentrated in the intestine [32,159].

Polyphenols have been shown to enhance tight junction integrity, increase mucus secretion, and decrease intestinal barrier permeability, thereby generally improving the intestinal defense mechanism [156,160]. In addition to, the involvement of polyphenols in multiple inflammatory signaling pathways, they also exert beneficial effects by acting on the intestinal epithelium. Table 2 illustrates the polyphenols’ primary intestinal epithelial homeostasis and regulations and health benefits. Table 2 details the role of polyphenols in possible mechanisms of actions that can potentially provide health benefits for intestinal permeability-related illnesses. Recent studies indicate that a polyphenol-rich diet lowers the risk of intestinal barrier dysfunctions. Polyphenols such as quercetin, epigallocatechin gallate, catechin, epicatechin, berberine, resveratrol, and curcumin have been studied intensely to provide health benefits in leaky gut-related diseases.

Table 2. Major polyphenols that help leaky gut.

7.8. Medical Herbs

The World Health Organization (WHO) estimated that more than 80% of the world population uses traditional medicine to meet their needs in primary care, using plant extracts or their active ingredients [47]. Herbal medicine can be applied and administered as tea infusions, tea decoctions, alcohol extracts, nonalcohol extractions, percolations (tinctures), elixirs/cordials (pleasant-tasting extractions), capsules, spagyrics, salves, hydrosols, and essential oils [197]. Medical plants have phytochemicals such as organic acids, flavonoids, iridoid glycosides, saponins, chlorogenic acid, secoiridoids, berberine, sesquiterpene, and sesquiterpenoid [197]. These phytochemicals have proven to treat diseases such as obesity, nonalcoholic steatohepatitis, ulcerative colitis, Crohn’s disease, food allergies, inflammatory bowel disease, and irritable bowel syndrome [198]. As noted before, a leaky gut is usually related to diseases such as dysbiosis, immune system imbalance, IBS, and nutritional deficiencies. Herbs are useful for medical therapy and practical nutrition to help leaky gut-associated illnesses [199]. Medical herbs are often used to treat leaky gut-associated autoimmune disorders such as ulcerative colitis, systemic lupus erythematosus, and rheumatoid arthritis [200]; nevertheless, the possible mechanism of action and its effectiveness remain ambiguous. Given the influence of intestinal permeability on numerous illnesses, the integrity of the gut epithelial functions is essential for maintaining intestinal homeostasis. The mechanism of actions in medical plants is broad, including regulating intestinal microbiota and permeability, upregulating both mRNA and protein expressions of claudin-1, lowering extracellular signal-regulated kinase activation in hepatocytes, suppressing MLCK-MLC phosphorylation signaling pathway, and protecting on IECs against LPS-insult [198]. Recent studies suggest that herbs alleviate leaky gut-related diseases in animal studies and clinical trials [198]. Medical herbs can deliver a potential therapeutic approach for gastrointestinal disorders. Table 3 illustrates the most predominant studies concerning medical herbs in leaky gut-related illnesses and its possible mechanisms of actions, modulation and regulation concerning the leaky gut syndrome. Current studies reveal that medical herbs maintain satisfactory gut health, which is related to intestinal disorders.

Table 3. Major herbs that help leaky gut.

7.9. Mushrooms

The use of mushrooms as functional ingredients has grown in the past decade. Mushrooms are a great source of bioactive compounds such as ergosterol, vitamin D, phenolic compounds, terpenes, and terpenoids. In addition, mushrooms are deemed a viable source of prebiotics as they contain different polysaccharides, such as chitin, chitosan, hemicellulose, xylans, mannans, galactans, and α- and β-glucans [228]. For health relevance, mushrooms are considered to pose a critical function in immunoregulating antitumor activities, atherosclerosis, and pneumococcal pneumonia. In leaky gut-related diseases, mushrooms have been demonstrated to potentially treat pancreatitis, nonalcoholic fatty liver disease, colitis, obesity, and diabetes [229]. Mushrooms were found to modulate gut microbiota by stimulating the production of catecholamines, their metabolites, and the inflammatory response. As mentioned, mushroom polysaccharides can also affect SCFAs production mainly butyrate, propionate, and acetate [230]. Many studies have reported within the lower intestinal tract that mushroom polysaccharides contributed to the proliferation of Bacteroidetes, which is liable for most acetate and propionate production [231]. The SCFAs can interact with many receptors to enhance immune-signaling and anti-inflammatory activities. SCFAs can function as signaling molecules with G-protein-associated receptors such as free fatty acid receptor 3 and free fatty acid receptor 2 to discharge GLP-1 and GLP-2 that regulates the tight junctions [232]. Table 4 illustrates the most predominant studies concerning mushrooms in intestinal epithelial homeostasis, health benefits, and gut microbiota regulation. Table 4 is aimed at collecting the health-promoting advantages of edible mushrooms via the gut microbiota. Recent studies showed that mushrooms act as prebiotics to promote a balanced and healthy gut microbiota, granting health benefits to leaky gut-related diseases.

Table 4. Major mushrooms that help leaky gut.

8. Other Foods That Can Potentially Help Treat Leaky Gut

When examining foods in leaky gut-related diseases, the composition of the gut microbiome and gut-derived metabolites produced by functions are intensely interesting. In addition, ingesting functional food such as yogurt can influence the gut microflora, which impacts intestinal epithelial homeostasis [263,264,265]. In food matrixes, the influence of polyphenols, fat, proteins, carbohydrates, and pre/probiotics on microbiota has also been investigated [199,266]. For this reason, we will not repeat the studies performed on macromolecular food components. Rather, we will illustrate the current studies of the food systems in intestinal homeostasis to show the great impact of dietary whole-food consumption on maintaining intestinal integrity.

Recent studies have shown that small-molecular food phytochemicals such as glycyrrhetinic acid and polydatin can protect intestinal epithelium [208,267]. Therefore, there is an urgent need to summarize the detailed effect of foods on intestinal aliments at different stages. Table 5 focuses on the in vivo effects of foods and their phytochemicals and illustrates their effects on every step of the intestinal pathological progression, from intestinal epithelial atrophy to colorectal cancers, to demonstrate their potential as dietary supplements regarding intestinal health. Table 5 details the role of foods and ingredients in possible mechanisms of actions in the intestinal barrier that eventually can potentially provide health benefits for leaky gut syndrome-related diseases. Table 5 describes functional foods and ingredients that promote intestinal epithelial regeneration by exercising intestinal-functions effects, interfering with intestinal inflammation, and improving intestinal flora. Nevertheless, most of these studies are based on preliminary in vitro studies, such as in vitro anti-inflammatory and cytotoxic studies. The results cannot reveal the real potential of foods in modulating human bio-functions. In addition, concerning intestinal diseases, studies on functional foods mainly focus on macromolecules such as prebiotics and polysaccharides. In contrast, the effects of small-molecular constituents of foods are less investigated and should be addressed in future studies.

Table 5. Major foods that help leaky gut.

9. Conclusions

The intestinal microbiota is essential to maintain the intestinal epithelium’s integrity and homeostasis. A qualitative and quantitative imbalance in the composition of the intestinal microbiota or dysbiosis contributes to intestinal barrier dysfunction and leaky gut syndrome. Certain infections, an unhealthy diet, stress, excessive use of antibiotics and other drugs, and alcohol can influence increased intestinal permeability and cause leaky gut syndrome. The intestinal hyperpermeability produced in leaky gut syndrome leads to an alteration of the tight junctions, the entry of toxic agents into the blood, and dysfunction in organs and systems. Leaky gut syndrome therapy should include diet modification avoiding fats, sugars, additives, and ultra-processed foods, and the appropriate supplementation of probiotics/prebiotics, arginine, glutamine, polyphenols, vitamins, fibers, medical herbs, edible mushrooms, and FODMAPs. Several studies have shown that these ingredients influence the modulation of intestinal immunity, regulation of the intestinal epithelial barrier, amelioration of mucosal abnormalities, and growth of epithelial cells. This review delivers recent insights into the critical functions of the dietary ingredients proposed to maintain intestinal barrier functions. Nevertheless, most of the studies are based on animal models, and more well-designed clinical trials are required to address the potential of these ingredients when regulating intestinal barrier dysfunctions.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Ohland, C.L.; MacNaughton, W.K. Probiotic bacteria and intestinal epithelial barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 2010, 298, G807–G819. [Google Scholar] [CrossRef][Green Version]
2. Bischoff, S.C.; Barbara, G.; Buurman, W.; Ockhuizen, T.; Schulzke, J.D.; Serino, M.; Tilg, H.; Watson, A.; Wells, J.M. Intestinal permeability—A new target for disease prevention and therapy. BMC Gastroenterol. 2014, 14, 189. [Google Scholar] [CrossRef] [PubMed][Green Version]
3. Rescigno, M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol. 2011, 32, 256–264. [Google Scholar] [CrossRef] [PubMed]