Intestinal Permeability -- A New Target for Disease
Intestinal Permeability -- A New Target for Disease
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
Why do we need a gut barrier? The intestinal barrier covers a surface of about 400 m and requires approximately 40% of the body's energy expenditure. It prevents against loss of water and electrolytes and entry of antigens and microorganisms into the body while allowing exchange of molecules between host and environment and absorption of nutrients in the diet. Specialized adaptations of the mammalian intestinal mucosa fulfill two seemingly opposing functions: firstly to allow a peaceful co-existence with intestinal symbionts without eliciting chronic inflammation and secondly to provide a measured inflammatory and defensive response according to the threat from pathogens. It is a complex multilayer system, consisting of an external "physical" barrier and an inner "functional" immunological barrier. The interaction of these 2 barriers enables equilibrated permeability to be maintained. To understand this complex barrier, not only the functions of its components, but also the processes of interactions of bacterial and other luminal components with cells and receptors of the host needs to be considered. Experimental data showed that disruption of the peaceful co-existence with intestinal symbionts at early life, and possibly even later in life, results in severe immunodeficiency and risk of disease. Such findings support the hypothesis that the breakdown of intestinal barrier control mechanisms means danger and possibly disease.
What is the difference between intestinal barrier and intestinal permeability? The two terms have been used synonymously although they probably do not mean the same thing. A clear definition of such parameters as means to assess them is mandatory to avoid future confusion and to assess their impact for disease prevention and disease. In fact, intestinal permeability is a barrier feature closely linked to the intestinal commensal microbiota as well as to the elements of the mucosal immune system (Figure 1). Many factors can alter intestinal permeability such as gut microbiota modifications, mucus layer alterations, and epithelial damage, resulting in translocation of luminal content to the inner layers of the intestinal wall. Moreover, lifestyle and dietetic factors like alcohol and energy-dense food can increase intestinal permeability such as alcohol and energy-dense Western style diet.
(Enlarge Image)
Figure 1.
Relation between intestinal permeability, intestinal microbiota, and mucosal immunology. For details see text.
What is the clinical significance of the intestinal barrier and intestinal permeability? There is now increasing evidence for the notion that loss of intestinal barrier functions can occur either abruptly, e.g. following a major trauma resulting in gram-negative sepsis and multi-organ failure (MOF), or gradually leading to chronic inflammatory diseases. During the last 30 years, almost 2000 publications appeared according to the PubMed database with a linear increase from approximately 10 publications a year in the eighties of last century to almost 100 at present. Although we learned over the past decade about the link between the intestinal barrier and diseases, the mechanisms are not precisely understood. For example, we have limited knowledge of what causes initially intestinal barrier dysfunction, and what prevents or restores it. The former might involve different events including virus infections, reduced perfusion of the mucosa, drugs, or changes in the microbiota. New data suggest that intestinal barrier and intestinal microbiota play a role in many different diseases such as idiopathic liver fibrosis or intestinal dysbiosis the mechanism of which were largely unclear until recently.
Understanding that the intestinal barrier also means to have clear definitions, clear modes of assessment in vitro and in vivo in animal models and in humans, and clear strategies of how to perform human trials in this field. These topics have been extensively discussed within an expert panel in Frankfurt/Germany in June 2012. The major results are summarized and extended in the following text.
Abstract and Introduction
Abstract
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
Introduction
Why do we need a gut barrier? The intestinal barrier covers a surface of about 400 m and requires approximately 40% of the body's energy expenditure. It prevents against loss of water and electrolytes and entry of antigens and microorganisms into the body while allowing exchange of molecules between host and environment and absorption of nutrients in the diet. Specialized adaptations of the mammalian intestinal mucosa fulfill two seemingly opposing functions: firstly to allow a peaceful co-existence with intestinal symbionts without eliciting chronic inflammation and secondly to provide a measured inflammatory and defensive response according to the threat from pathogens. It is a complex multilayer system, consisting of an external "physical" barrier and an inner "functional" immunological barrier. The interaction of these 2 barriers enables equilibrated permeability to be maintained. To understand this complex barrier, not only the functions of its components, but also the processes of interactions of bacterial and other luminal components with cells and receptors of the host needs to be considered. Experimental data showed that disruption of the peaceful co-existence with intestinal symbionts at early life, and possibly even later in life, results in severe immunodeficiency and risk of disease. Such findings support the hypothesis that the breakdown of intestinal barrier control mechanisms means danger and possibly disease.
What is the difference between intestinal barrier and intestinal permeability? The two terms have been used synonymously although they probably do not mean the same thing. A clear definition of such parameters as means to assess them is mandatory to avoid future confusion and to assess their impact for disease prevention and disease. In fact, intestinal permeability is a barrier feature closely linked to the intestinal commensal microbiota as well as to the elements of the mucosal immune system (Figure 1). Many factors can alter intestinal permeability such as gut microbiota modifications, mucus layer alterations, and epithelial damage, resulting in translocation of luminal content to the inner layers of the intestinal wall. Moreover, lifestyle and dietetic factors like alcohol and energy-dense food can increase intestinal permeability such as alcohol and energy-dense Western style diet.
(Enlarge Image)
Figure 1.
Relation between intestinal permeability, intestinal microbiota, and mucosal immunology. For details see text.
What is the clinical significance of the intestinal barrier and intestinal permeability? There is now increasing evidence for the notion that loss of intestinal barrier functions can occur either abruptly, e.g. following a major trauma resulting in gram-negative sepsis and multi-organ failure (MOF), or gradually leading to chronic inflammatory diseases. During the last 30 years, almost 2000 publications appeared according to the PubMed database with a linear increase from approximately 10 publications a year in the eighties of last century to almost 100 at present. Although we learned over the past decade about the link between the intestinal barrier and diseases, the mechanisms are not precisely understood. For example, we have limited knowledge of what causes initially intestinal barrier dysfunction, and what prevents or restores it. The former might involve different events including virus infections, reduced perfusion of the mucosa, drugs, or changes in the microbiota. New data suggest that intestinal barrier and intestinal microbiota play a role in many different diseases such as idiopathic liver fibrosis or intestinal dysbiosis the mechanism of which were largely unclear until recently.
Understanding that the intestinal barrier also means to have clear definitions, clear modes of assessment in vitro and in vivo in animal models and in humans, and clear strategies of how to perform human trials in this field. These topics have been extensively discussed within an expert panel in Frankfurt/Germany in June 2012. The major results are summarized and extended in the following text.
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