The human element: moving beyond animal models to study the neuronal regulation of intestinal electrolyte transport

The intestine has the dual and sometimes conflicting roles of absorbing the nutrients, electrolytes and water essential for life, and providing a barrier for the exclusion of bacteria, bacterial products, wastes and toxins from the underlying lamina propria. Vectorial electrolyte transport across the epithelium drives both the efficient absorption of water to maintain fluid balance and the secretion of water to hydrate mucus and contribute to the epithelial barrier. The primary regulator of epithelial electrolyte and water transport is the submucosal plexus of the enteric nervous system. This complex, ganglionated network of intrinsic primary afferent and secretomotor efferent neurons coordinates the release of neurotransmitters that drive the cellular machinery controlling the ion pumps, channels and transporters that regulate transepithelial water movement. Disturbances in this complex regulatory network arise in diseases that affect billions of people world-wide: enteric infections, food allergies and sensitivities, drug side effects, functional bowel disorders and intestinal inflammation can all result in debilitating diarrhoeal disease. The neural regulation of intestinal electrolyte and water transport by the gastrointestinal epithelium has been the subject of study since the late 19th century, with our biggest advances occurring during the 1970s and 1980s (Cooke, 1989). Our current knowledge has been based primarily on work in animals, especially guinea pigs, rats and, more recently, mice. Guinea pigs and rats were commonly used as these were the first species in which the chemical coding of enteric neurotransmission was elucidated. The advent of genetically modified mouse models has necessitated the solidification of our knowledge of enteric neural function in this species (Nurgali et al. 2004). While these approaches have vastly improved our general understanding of neural control of mucosal function, the species-to-species variation in the chemical coding and wiring of the enteric nervous system, as well as the imperfect nature of animal models of human GI disease, limits direct applicability to human physiology and pathophysiology. This is particularly relevant today as we learn more about the pitfalls of the biases inherent in many animal studies, especially as they relate to drug development for human application (Sena et al. 2007). Studies of the neural regulation of electrolyte and water transport in the human GI tract have been reported over the decades, but these have been hampered by several factors. First, not all centres have ready access to live resected tissue from patients. Second, such studies require cooperation among researchers, technicians, surgeons, pathologists and others, which makes these approaches more logistically cumbersome. Third, biopsies obtained during endoscopy or colonoscopy are most often restricted to the mucosa, and therefore lack the submucosal plexuses involved in the neural regulation of epithelial function. Finally, studying humans in the clinical setting is fraught with confounding variables: genetics, diet, disease activity, medications, a diverse microbiome and other factors all mean that the sample sizes typical of mouse studies, where all of these variables can be carefully controlled, render data that are almost impossible to interpret with confidence when applied to studies of human tissue. These confounding factors have been admirably addressed in the paper of Krueger et al. (2016) in this issue of The Journal of Physiology. This group has studied the regulation of electrolyte flux in GI tissue in over 2200 resection samples from 435 patients, a sample unparalleled in the field. Using the well-established Ussing chamber technique, the authors were able to study various electrophysiological parameters (notably tissue resistance and short-circuit current under voltage-clamp conditions) while manipulating enteric neurotransmission with electrical field stimulation and pharmacological approaches. In addition, they were able to contrast and compare responses in tissues from different regions of the GI tract in several disease states. The result has been the most comprehensive analysis yet of the regulation of ion transport in the human GI tract. Several important observations arise from this study. First, neither sex nor age had any effect on basal or neurally evoked electrophysiological parameters. This is important since various studies have reported age- and sex-related differences in physiology or susceptibility to diseases like colorectal cancer, inflammatory bowel disease or irritable bowel syndrome. The data provided here suggest this is not the case for basal or neurally regulated secretory function. Second, the underlying disease leading to surgery did not alter basal state or stimulated parameters. This is interesting since tissues from uninvolved regions of gut are often considered poor controls; it is assumed that the disease state has pathophysiological effects in tissues that appear macroscopically normal. The data presented by Krueger et al. suggest that uninvolved tissue does reflect a ‘normal’ state, at least for the diseases they have studied. Third, this study has confirmed the key neurotransmitters that drive electrogenic ion transport in small and large intestine. Specifically, acetylcholine, vasoactive intestinal polypeptide and nitric oxide are all major players, but in different proportions compared with earlier studies in animal models. Indeed, the demonstration of neurally derived nitric oxide as a major secretagogue in the human colon is a novel finding. Krueger et al. have reinforced the value of a multidisciplinary, translational approach to studying human physiology in health and disease, and that the establishment of effective and consistent pipelines for patient tissue, potentially from multiple centres, is necessary to obtain the sample sizes required to provide statistically meaningful data from patient samples. Furthermore, their work emphasizes the fact that modern approaches using organoid systems and transgenic mouse models still require validation with an integrative physiological approach at the human tissue level. This translational approach, while potentially challenging, will provide the necessary bridge linking basic discovery to therapeutic benefit for patients suffering from GI diseases. None declared.

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