Marie-Claire Arrieta

Alterations in intestinal permeability

The goal of this review is to describe barrier function of the intestine, the structure of the tight junction, methods to evaluate intestinal permeability, and most importantly the relevance of abnormal permeability to disease. In this context, we will also present an emerging paradigm regarding the genesis of autoimmune diseases and describe the data that supports this from the perspective of both human disease and animal models. While this is a complicated area there are several points worth remembering: From the lower oesophageal sphincter to the anus, the gastrointestinal tract has a single contiguous layer of cells that separates the inside of the body from the external environment. Separation is important as there are a wide variety of environmental agents in the lumen of the bowel that can initiate or perpetuate mucosal inflammation if they cross the epithelial barrier. While the epithelial lining of the intestine plays a critical role in preventing access of these agents, it is not the only component of what is termed barrier function. Also important are secreted products such as immunoglobulin, mucous, defensins, and other antimicrobial products. The importance of epithelial barrier function in normal homeostasis can be appreciated from experiments performed in the early 1990s where cell wall extracts from luminal bacteria were injected into the colonic wall of rats.1 This simple manoeuvre of bypassing the epithelial barrier and placing luminal compounds directly into the colonic wall initiated an …

The intestinal microbiome in early life: health and disease

Human microbial colonization begins at birth and continues to develop and modulate in species abundance for about 3 years, until the microbiota becomes adult-like. During the same time period, children experience significant developmental changes that influence their health status as well as their immune system. An ever-expanding number of articles associate several diseases with early-life imbalances of the gut microbiota, also referred to as gut microbial dysbiosis. Whether early-life dysbiosis precedes and plays a role in disease pathogenesis, or simply originates from the disease process itself is a question that is beginning to be answered in a few diseases, including IBD, obesity, and asthma. This review describes the gut microbiome structure and function during the formative first years of life, as well as the environmental factors that determine its composition. It also aims to discuss the recent advances in understanding the role of the early-life gut microbiota in the development of immune-mediated, metabolic, and neurological diseases. A greater understanding of how the early-life gut microbiota impacts our immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age.

Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse

Background: Defects in the small intestinal epithelial barrier have been associated with inflammatory bowel disease but their role in the causation of disease is still a matter of debate. In some models of disease increased permeability appears to be a very early event. The interleukin 10 (IL10) gene-deficient mouse spontaneously develops colitis after 12 weeks of age. These mice have been shown to have increased small intestinal permeability that appears early in life. Furthermore, the development of colitis is dependent upon luminal agents, as animals do not develop disease if raised under germ-free conditions. Aims: To determine if the elevated small bowel permeability can be prevented, and if by doing so colonic disease is prevented or attenuated. Methods: IL10 gene-deficient (IL10−/−) mice) were treated with AT-1001 (a zonulin peptide inhibitor), a small peptide previously demonstrated to reduce small intestinal permeability. Small intestinal permeability was measured, in vivo, weekly from 4 to 17 weeks of age. Colonic disease was assessed at 8 weeks in Ussing chambers, and at 17 weeks of age inflammatory cytokines and myeloperoxidase were measured in the colon. Colonic permeability and histology were also endpoints. Results: Treated animals showed a marked reduction in small intestinal permeability. Average area under the lactulose/mannitol time curve: 5.36 (SE 0.08) in controls vs 3.97 (SE 0.07) in the high-dose AT-1001 group, p<0.05. At 8 weeks of age there was a significant reduction of colonic mucosal permeability and increased electrical resistance. By 17 weeks of age, secretion of tumour necrosis factor α (TNFα) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 17.51) pg/ml in controls, p<0.01). All other markers also demonstrated a clear reduction of colitis in the treated animals. Additional experiments were performed which demonstrated that AT-1001 was functionally active only in the small intestine. Conclusions: This work suggests that increased intestinal permeability may be an important aetiological event in the development of colitis in IL10−/− mice.

Effects of Antibiotics on Human Microbiota and Subsequent Disease

Although antibiotics have significantly improved human health and life expectancy, their disruption of the existing microbiota has been linked to significant side effects such as antibiotic-associated diarrhea, pseudomembranous colitis, and increased susceptibility to subsequent disease. By using antibiotics to break colonization resistance against Clostridium, Salmonella, and Citrobacter species, researchers are now exploring mechanisms for microbiota-mediated modulation against pathogenic infection, revealing potential roles for different phyla and family members as well as microbiota-liberated sugars, hormones, and short-chain fatty acids in regulating pathogenicity. Furthermore, connections are now being made between microbiota dysbiosis and a variety of different diseases such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, atopy, and obesity. Future advances in the rapidly developing field of microbial bioinformatics will enable researchers to further characterize the mechanisms of microbiota modulation of disease and potentially identify novel therapeutics against disease.

Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model

Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide. However, the aetiology of the disease remains unknown and no animal model exists to date, the creation of which would aid in understanding this complex disease. Here we demonstrate that early-life consumption of a moderately malnourished diet, in combination with iterative oral exposure to commensal Bacteroidales species and Escherichia coli, remodels the murine small intestine to resemble features of EE observed in humans. We further report the profound changes that malnutrition imparts on the small intestinal microbiota, metabolite and intraepithelial lymphocyte composition, along with the susceptibility to enteric infection. Our findings provide evidence indicating that both diet and microbes combine to contribute to the aetiology of EE, and describe a novel murine model that can be used to elucidate the mechanisms behind this understudied disease.

Human Microbiota-Associated Mice: A Model with Challenges

Human microbiota-associated (HMA) mice have been used extensively in gut microbiome research. Here we discuss ecological and evolutionary aspects of the mammalian-gut microbiome interrelationship that confound the application of HMA mice, and propose experimental designs that increase the likelihood for obtaining meaningful findings.

A fresh look at the hygiene hypothesis: How intestinal microbial exposure drives immune effector responses in atopic disease

There currently is no consensus on which immunological mechanisms can best explain the rise in atopic disease post industrialization. The hygiene hypothesis lays groundwork for our understanding of how altered microbial exposures can drive atopy; yet since its introduction increasing evidence suggests the exposure of our immune system to the intestinal microbiota plays a key role in development of atopic disease. As societal change shifts our microbial exposure, concordant shifts in the tolerant and effector functions of our immune systems give rise to more hypersensitive responses to external antigens. This is contrasted with the greater immune tolerant capabilities of individuals still living in regions with lifestyles more representative of our evolutionary history. Recent findings, buoyed by technological advances in the field, suggest a direct role for the intestinal microbiota-immune system interplay in the development of atopic disease mechanisms. Overall, harnessing current mechanistic studies for translational research into microbiota composition and function in relation to atopy have potential for the design of therapeutics that could moderate these diseases.

Gastrointestinal Microbiota–Mediated Control of Enteric Pathogens

The gastrointestinal (GI) microbiota is a complex community of microorganisms residing within the mammalian gastrointestinal tract. The GI microbiota is vital to the development of the host immune system and plays a crucial role in human health and disease. The composition of the GI microbiota differs immensely among individuals yet specific shifts in composition and diversity have been linked to inflammatory bowel disease, obesity, atopy, and susceptibility to infection. In this review, we describe the GI microbiota and its role in enteric diseases caused by pathogenic Escherichia coli, Salmonella enterica, and Clostridium difficile. We discuss the central role of the GI microbiota in protective immunity, resistance to enteric pathogens, and resolution of enteric colitis.

The Commensal Microbiota Drives Immune Homeostasis

For millions of years, microbes have coexisted with eukaryotic cells at the mucosal surfaces of vertebrates in a complex, yet usually harmonious symbiosis. An ever-expanding number of reports describe how eliminating or shifting the intestinal microbiota has profound effects on the development and functionality of the mucosal and systemic immune systems. Here, we examine some of the mechanisms by which bacterial signals affect immune homeostasis. Focusing on the strategies that microbes use to keep our immune system healthy, as opposed to trying to correct the immune imbalances caused by dysbiosis, may prove to be a more astute and efficient way of treating immune-mediated disease.

Intestinal Permeability in Children with Food Allergy on Specific Elimination Diets

Children with food allergy have been shown to have increased small intestinal permeability (IP) following ingestion of the offending food as well as during elimination diets. We investigated IP in asymptomatic food allergic children during an elimination diet to identify clinical characteristics associated with altered IP.