Epithelial biology in the gastrointestinal system: insights into normal physiology and disease pathogenesis

The gastrointestinal system comprises a multifaceted collection of organs whose coordinated functions are essential for life. The gut, and the organs that drain into it, subserve the dual imperative of digesting and absorbing nutrients while preventing the uptake of toxins and pathogens. These functions were critical to the development of multicellular life-forms. Much of the physiology of the gastrointestinal system revolves around the biology of the columnar epithelia that line its hollow organs. The intestinal epithelium, in particular, represents a massive contiguous interface with the outside world that, in an adult human, exceeds the surface area of a tennis court. Thus, there is substantial reserve capacity for the digestion and absorption of dietary components but also a vast surface that must be defended against potential invaders, as well as surplus capacity for fluid and electrolyte transport that can contribute to life-threatening dehydration in certain severe diarrhoeal diseases. Indeed, many digestive diseases are common, and the pathogenesis of several can be traced, at least in part, to epithelial dysfunction.

There have been numerous recent advances in our understanding, at a molecular level, of the components and signals that regulate the transport, barrier and proliferative properties of GI epithelia. Similarly, crosstalk between the epithelium and the enteric nervous system, as well as components of the mucosal immune system, has now been defined along with functional implications. Another defining characteristic of the intestinal epithelium that distinguishes it from most other epithelia is its essentially life-long symbiotic interaction with a complex microbial community known as the intestinal microbiome. Shortly after birth, the intestine becomes colonized with a large number of commensal bacteria that usually pose no threat to the host – on the contrary, evidence is accumulating that an appropriate microbiome can confer significant benefits and contribute to digestive health as well as nutrient salvage. However, if the integrity of the epithelium is compromised, even commensal bacteria, and/or their products, can gain access to subepithelial compartments and trigger immune and inflammatory responses that may further derange mucosal homeostasis.

In this special issue of The Journal of Physiology, several experts discuss novel facets of epithelial biology in various digestive organs, and suggest how the insights gained may ultimately translate to new approaches to therapy for digestive disorders, such as liver cirrhosis, inflammatory bowel diseases, cancer and gastrointestinal infections. Taking first the mechanisms that specify epithelial development, differentiation and proliferation, and with a particular focus on the stomach, Merchant (2012) describes emerging information about the pivotal role of Hedgehog signalling. Discovery of the Hedgehog pathway in 1978 contributed to a Nobel prize in 1995 for Eric Wieschaus and Christiane Nusslein-Volhard, and the pathway has been shown to be involved in a huge array of developmental processes since its identification as a regulator of Drosophila segmentation. Professor Merchant reviews not only the role of the Hedgehog pathway in gastrointestinal development, but more recent data that indicate that this critical signalling cascade may also play a role in adult tissues. In particular, Hedgehog signalling is required for the physiological response of gastric acid secretion, and may also play important roles in neoplastic transformation that involves crosstalk between the epithelium and mesenchyme. If the details of the latter intercellular communication can be fully elucidated by ongoing work, they may offer the prospect of targets via which to intervene in gastrointestinal carcinogenesis.

Continuing the theme of communication, in their article Molecular basis of host-pathogen interactions in the gut and role in the pathogenesis of infectious diarrhoea,Hodges & Hecht (2012), from the University of Illinois at Chicago, address the novel molecular mechanisms devised by pathogens to communicate with intestinal epithelial cells. These pathways allow bacteria to regulate epithelial functions, presumably to the benefit of the invading microorganism. A range of intestinal pathogens have developed sophisticated methods to deliver toxins and other effector molecules directly into the cytosol of intestinal epithelial cells during the millennia over which they have co-evolved with their hosts. Perhaps the most striking example is the type three secretion system, a molecular ‘syringe’ that is assembled from a number of different bacterial products and which can ‘inject’ bacterial effectors that can regulate epithelial transport and barrier properties, as well as bacterial survival. These mechanisms are likely to contribute to the diarrhoeal symptoms that accompany infection with enteropathogenic E. coli as well as non-typhoidal Salmonella spp., in part by activating transcriptional and post-translational mechanisms that either suppress the expression, or alter the localization, of critical absorptive membrane transporters. The loss of water and electrolytes that results may represent a mechanism for dissemination of the infection to additional hosts, but also could be considered a primitive defence mechanism that ‘flushes’ the offending bacteria from the lumen, thereby limiting systemic spread of the bacteria and septic complications. In any event, additional insights in this area may be useful in countering the scourge of infectious diarrhoea, which remains a critical cause of infant mortality in developing countries as well as in the setting of natural disasters.

Interactions with bacteria, albeit commensals rather than pathogens, also feature prominently in the article contributed by Raybould (2012) from the University of California at Davis. Her article develops the thesis that changes in the commensal microbiome, leading to alterations in gut epithelial function, can perturb the homeostatic humoral and neural pathways that control food intake. Thus, ultimately, derangements in the microbiome might lead to obesity, a growing epidemic in developed countries with serious impacts for a range of health outcomes. In responding to a meal, the gut must sense the nutrients delivered to the lumen, activate a range of secretory and motility responses, and ultimately generate signals that indicate satiety and trigger the cessation of food intake. In both experimental animals and human subjects, obesity has been associated with alterations in the make-up of the gut microbiome and the microbiome may similarly be necessary to mediate the adverse effect of chronically ingesting a high fat diet, at least in mice and rats. The latter response appears to reflect specific recognition of bacterial products by the epithelium, or by enteroendocrine cells, and generation of a leaky gut as well as a chronic state of low-grade inflammation and endotoxaemia. These responses also seem to be accompanied by alterations in the function of enteric nerve terminals that would otherwise signal satiety, with the consequence of impaired intestinal feedback and hyperphagia. Genetic factors specific to the host appear also to control this crosstalk, providing an explanation for the variable expression of obesity seen in either animals or humans consuming similar diets. More information is needed on the precise sequence of events that link the microbiome to the development of obesity (for example, it is not clear whether the presence of specific microbial species reflects a cause or a consequence of the development of an obese phenotype). Nevertheless, it is evident that elucidation of underlying mechanisms may allow intervention to prevent the failure of intestinal homeostatic mechanisms that match nutrient uptake to energy requirements, and thus offer a way to offset the myriad health consequences of being overweight.

The article from Seki & Schnabel (2012) from the University of California, San Diego, offers insights into another disease state where inappropriate penetration of bacterial products across the wall of the intestine may lead to pathology, namely liver fibrosis. The liver is strategically placed to filter and retain toxins and other substances originating in the gut lumen, because it has a unique circulation in which it derives the majority of its blood supply as portal venous blood that drains the gut. In health, this is advantageous because it protects the rest of the body from substances or even bacteria themselves that may potentially be injurious, but if intestinal permeability is upregulated, the associated increase in the flux of pathogen-associated molecules to the liver may trigger innate immune responses from a variety of resident cell types and ultimately trigger fibrosis. Further, there is evidence that in liver disease, such as that caused by chronic alcohol ingestion or bile duct obstruction, the altered composition of bile and thus intestinal contents may change expression of antibacterial and other regulatory factors in the gut, perhaps thereby contributing to the overgrowth of injurious members of the microbiota and/or bacterial translocation. As we saw for the relationship between changes in the microbiome and obesity, the precise delineation of cause and consequence when considering how the microbiome might feature in chronic liver disease still requires additional study. Nevertheless, given the clinical impact of liver disease, and the propensity of liver fibrosis and cirrhosis to progress to hepatocellular carcinoma, these new paradigms may offer hope of additional and more effective therapies for an important set of disorders that have multiple physiological effects.

Finally, returning more specifically to the intestinal epithelium, a forthcoming article in The Journal from the group of Joerg-Dieter Schulzke of the Charite Hospital in Berlin, related to those published in this issue, addresses the molecular basis of epithelial barrier function (Hering et al. 2012)). The authors describe the diversity of molecules that make up and regulate tight junctions between neighbouring epithelial cells, or at tricellular contacts. Our understanding of the tight junction has exploded in recent years with the identification of dozens of molecules known as claudins, which provide either junctional sealing or specific pore pathways through the junction. Further, the authors discuss the relevance of changes in tight junctional make-up for the pathogenesis of digestive diseases, taking as a particular example the inflammatory bowel diseases of Crohn's disease and ulcerative colitis. Schulzke and others have shown that inflammatory cytokines, as well as the types of bacterial interactions discussed above, can induce downregulation of ‘sealing’ claudins and/or upregulation of pore-forming claudins, and thus a perturbation of intestinal barrier function that clearly contributes to the vicious cycle of intestinal inflammation that characterizes the diseases. It is likely that similar mechanisms underpin the barrier dysfunction identified as pivotal in the pathogenesis of both obesity and hepatic fibrosis, as discussed above.

In summary, therefore, our understanding of epithelial biology in the gastrointestinal tract is coalescing around a number of common themes. These include identification of the growth factors and signalling pathways that regulate differentiation and proliferation, communication of the epithelium with partners both in the lamina propria and lumen, the protean effects of molecules released by both pathogenic and commensal microorganisms for epithelial integrity and transport properties, and the systemic consequences and disease states than can emerge in the setting of intestinal dysbiosis and barrier dysfunction. Additional work in this area is eagerly anticipated given the potential for insights to lead meaningfully to the development of new therapies for diseases of the intestine and beyond, as well as the restoration of the normal physiological role of the intestinal mucosa.