Irradiation Induces Tuft Cell Hyperplasia and Myenteric Neuronal Loss in the Absence of Dietary Fiber in a Mouse Model of Pelvic Radiotherapy

Abstract

Pelvic radiotherapy is associated with chronic intestinal dysfunction. Dietary approaches, such as fiber enrichment during and after pelvic radiotherapy, have been suggested to prevent or reduce dysfunctions. In the present paper, we aimed to investigate whether a diet rich in fermentable fiber could have a positive effect on radiation-induced intestinal damage, especially focusing on tuft cells and enteric neurons. Male C57BL/6 mice were fed either a purified non-fiber diet or the same purified diet with 5% or 15% oat fiber added, starting two weeks prior to sham-irradiation or irradiation with four fractions of 8 Gray. The animals continued on the diets for 1, 6 or 18 weeks, after which the gross morphology of the colorectum was assessed together with the numbers of enteric neurons, tuft cells and crypt-surface units. The results showed that dietary fiber significantly affected the intestinal morphometrics, both in the short and long-term. The presence of dietary fiber stimulated the re-emergence of crypt-surface unit structures after irradiation. At 18 weeks, the animals fed with the non-fiber diet displayed more myenteric neurons than the animals fed with the dietary fibers, but irradiation resulted in a loss of neurons in the non-fiber fed animals. Irradiation, but not diet, affected the tuft cell numbers, and a significant increase in tuft cells was found 6 and 18 weeks after irradiation. In conclusion, dietary fiber intake has the potential to modify neuronal pathogenesis in the colorectum after irradiation. The long-lasting increase in tuft cells induced by irradiation may reflect an as yet unknown role in the mucosal pathophysiology after pelvic irradiation.

The Aging Enteric Nervous System

“…These cells communicate with luminal bacteria and interact with the afferent and efferent nerve terminals in the lamina propria by activated chemosensory receptors [95]. Though ECC comprises only 1% of intestinal epithelial cells, they produce and release 90% of the body's 5-HT [96,97]. Chen et al demonstrated that under environmental stress, epithelial cells released interleukin-33, which binds to suppression of tumorigenicity 2 receptors on ECC.…”

“…This suggests the potential of a bidirectional communication with the ENS (Figure 3). Tuft cells and submucosal and myenteric neurons express the SCFA receptor (FFAR3, free fatty acid receptor 3), the stimulation of which may modulate neuronal activity [97]. Both tuft cells and myenteric excitatory neurons express ChAT [97], and reduced ChAT signaling from enteric neurons appears to provoke an increase in tuft cells to maintain cholinergic homeostasis [102].…”

“…Tuft cells and submucosal and myenteric neurons express the SCFA receptor (FFAR3, free fatty acid receptor 3), the stimulation of which may modulate neuronal activity [97]. Both tuft cells and myenteric excitatory neurons express ChAT [97], and reduced ChAT signaling from enteric neurons appears to provoke an increase in tuft cells to maintain cholinergic homeostasis [102]. Tuft cells were reported to lack both vesicular acetylcholine transporters and high-affinity choline transporters, which are needed for the synaptic release of acetylcholine [103].…”