Key elements determining the intestinal region-specific environment of enteric neurons in type 1 diabetes

Abstract

Diabetes, as a metabolic disorder, is accompanied with several gastrointestinal (GI) symptoms, like abdominal pain, gastroparesis, diarrhoea or constipation. Serious and complex enteric nervous system damage is confirmed in the background of these diabetic motility complaints. The anatomical length of the GI tract, as well as genetic, developmental, structural and functional differences between its segments contribute to the distinct, intestinal region-specific effects of hyperglycemia. These observations support and highlight the importance of a regional approach in diabetes-related enteric neuropathy. Intestinal large and microvessels are essential for the blood supply of enteric ganglia. Bidirectional morpho-functional linkage exists between enteric neurons and enteroglia, however, there is also a reciprocal communication between enteric neurons and immune cells on which intestinal microbial composition has crucial influence. From this point of view, it is more appropriate to say that enteric neurons partake in multidirectional communication and interact with these key players of the intestinal wall. These interplays may differ from segment to segment, thus, the microenvironment of enteric neurons could be considered strictly regional. The goal of this review is to summarize the main tissue components and molecular factors, such as enteric glia cells, interstitial cells of Cajal, gut vasculature, intestinal epithelium, gut microbiota, immune cells, enteroendocrine cells, pro-oxidants, antioxidant molecules and extracellular matrix, which create and determine a gut region-dependent neuronal environment in diabetes.

Keywords: Enteric neurons; Neuronal environment; Gut region specificity; Type 1 diabetes, Hyperglycemia; Microbiota-gut interactions

Core Tip: Diabetes-related intestinal motility disturbances result from multifactorial damage to the enteric nervous system. However, the diversity of the neuronal environment in different gut segments basically determines the regionality of diabetic enteric neuropathy. Therefore, in this review, we highlight the role of enteric glial cells, gut circulation, intestinal epithelium, gut microbiota, immune and enteroendocrine cells, pro-oxidants, antioxidant defence and extracellular matrix, which have great impact on the formation and maintenance of a region-specific enteric neuronal environment in diabetes.