Abstract
Tumour necrosis factor alpha (TNFα) is essential in neuroinflammatory modulation. Therefore, the goal of this study is to reveal the effects of chronic hyperglycaemia and insulin treatment on TNFα expression in different gut segments and intestinal wall layers. TNFα expression was mapped by fluorescent immunohistochemistry and quantitative immunogold electron microscopy in myenteric ganglia of duodenum, ileum and colon. Tissue TNFα levels were measured by enzyme-linked immunosorbent assays in muscle/myenteric plexus-containing (MUSCLE-MP) and mucosa/submucosa/submucous plexus-containing (MUC-SUBMUC-SP) homogenates. Increasing density of TNFα-labelling gold particles is observed in myenteric ganglia from proximal to distal segments and TNFα tissue levels are much more elevated in MUSCLE-MP homogenates than in MUC-SUBMUC-SP samples in healthy controls. In the diabetics, the number of TNFα gold labels is significantly increased in the duodenum, decreased in the colon and remained unchanged in the ileal ganglia, while insulin does not prevent these diabetes-related TNFα changes. TNFα tissue concentration is also increased in MUSCLE-MP homogenates of diabetic duodenum, while decreased in MUC-SUBMUC-SP samples of diabetic ileum and colon. These findings support that type 1 diabetes has region-specific and intestinal layer-dependent effects on TNFα expression, contributing to the regional damage of myenteric neurons and their intestinal milieu.
Highlights
The primary goal of the present study is to evaluate the intestinal region-dependent effects of chronic hyperglycaemia and immediate insulin treatment on TNFα expression in myenteric ganglia of different gut segments
The weight of the animals significantly increased in all groups during the experiment, but the final body weight of diabetic rats was less elevated compared to the control and the insulin-treated diabetic animals
Diabetes-related induction of the heme oxygenase (HO) system and an elevated number of HO1-immunoreactive myenteric neurons was demonstrated [39], which may contribute to the decrease in TNFα expression in ganglia of this gut segment
Summary
Distinct structure and function as well as genetic and developmental features fundamentally define the appropriate intestinal milieu in the small and large intestine and even in their subregions [1,2], and pathological stimuli differently affect this regional molecular environment. Type 1 diabetes has strictly region-specific effects on the microbial composition [3,4], antioxidant defence or oxidative status [5] of different gut segments. These all contribute to region-dependent nitrergic enteric neuropathy [6,7], that is markedly involved in gut motility disturbances [6,8,9] suffered by diabetic patients worldwide
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