Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function

At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.

Evaluating the involvement of cerebral microvascular endothelial Na+/K+-ATPase and Na+-K+-2Cl– co-transporter in electrolyte fluxes in an in vitro blood–brain barrier model of dehydration

The blood–brain barrier (BBB) is involved in brain water and salt homeostasis. Blood osmolarity increases during dehydration and water is osmotically extracted from the brain. The loss of water is less than expected from pure osmotic forces, due to brain electrolyte accumulation. Although the underlying molecular mechanisms are unresolved, the current model suggests the luminally expressed Na+-K+-2Cl− co-transporter 1 (NKCC1) as a key component, while the role of the Na+/K+-ATPase remains uninvestigated. To test the involvement of these proteins in brain electrolyte flux under mimicked dehydration, we employed a tight in vitro co-culture BBB model with primary cultures of brain endothelial cells and astrocytes. The Na+/K+-ATPase and the NKCC1 were both functionally dominant in the abluminal membrane. Exposure of the in vitro BBB model to conditions mimicking systemic dehydration, i.e. hyperosmotic conditions, vasopressin, or increased [K+]o illustrated that NKCC1 activity was unaffected by exposure to vasopressin and to hyperosmotic conditions. Hyperosmotic conditions and increased K+ concentrations enhanced the Na+/K+-ATPase activity, here determined to consist of the α1 β1 and α1 β3 isozymes. Abluminally expressed endothelial Na+/K+-ATPase, and not NKCC1, may therefore counteract osmotic brain water loss during systemic dehydration by promoting brain Na+ accumulation.

A Comparison Between Mechano-Electrochemical and Biphasic Swelling Theories for Soft Hydrated Tissues

Biological tissues like intervertebral discs and articular cartilage primarily consist of interstitial fluid, collagen fibrils and negatively charged proteoglycans. Due to the fixed charges of the proteoglycans, the total ion concentration inside the tissue is higher than in the surrounding synovial fluid (cation concentration is higher and the anion concentration is lower). This excess of ion particles leads to an osmotic pressure difference, which causes swelling of the tissue. In the last decade several mechano-electrochemical models, which include this mechanism, have been developed. As these models are complex and computationally expensive, it is only possible to analyze geometrically relatively small problems. Furthermore, there is still no commercial finite element tool that includes such a mechano-electrochemical theory. Lanir (Biorheology, 24, pp. 173–187, 1987) hypothesized that electrolyte flux in articular cartilage can be neglected in mechanical studies. Lanir’s hypothesis implies that the swelling behavior of cartilage is only determined by deformation of the solid and by fluid flow. Hence, the response could be described by adding a deformation-dependent pressure term to the standard biphasic equations. Based on this theory we developed a biphasic swelling model. The goal of the study was to test Lanir’s hypothesis for a range of material properties. We compared the deformation behavior predicted by the biphasic swelling model and a full mechano-electrochemical model for confined compression and 1D swelling. It was shown that, depending on the material properties, the biphasic swelling model behaves largely the same as the mechano-electrochemical model, with regard to stresses and strains in the tissue following either mechanical or chemical perturbations. Hence, the biphasic swelling model could be an alternative for the more complex mechano-electrochemical model, in those cases where the ion flux itself is not the subject of the study. We propose thumbrules to estimate the correlation between the two models for specific problems.

Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease.

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.