# Instant Cascara Beverage as a Neuroimmune Modulator of the Brain–Gut Axis: Sex-Dependent Effects in Healthy Rats

## TL;DR

A coffee byproduct drink called Instant Cascara may affect brain-gut communication differently in male and female rats, with subtle effects on gut sensitivity and immune responses.

## Contribution

This study reveals sex-dependent neuroimmune effects of Instant Cascara in healthy rats, highlighting its potential as a brain–gut axis modulator.

## Key findings

- IC increased locomotor activity and somatic sensitivity in female rats.
- IC-treated females showed higher glial cell density and lower CGRP-positive fibers in the colon.
- IC reduced macrophage numbers in male colons but increased them in females compared to males.

## Abstract

Instant Cascara (IC), a beverage obtained from dried coffee cherry pulp, represents a sustainable hydration option rich in bioactive phytochemicals, such as caffeine, chlorogenic acids, and melanoidins, which may provide effects beyond basic nutrition. This study evaluated the impact of three weeks of IC consumption on somatic and visceral sensitivity, and on neural and immune markers in the colon of male and female healthy Wistar rats. Behavioral tests showed that IC increased locomotor activity and somatic sensitivity in females (p < 0.05). Although control females were more sensitive to visceral pain than males (p < 0.05), IC intake did not significantly alter pain sensitivity in either sex. Histological and immunohistochemical analyses in the colonic myenteric plexus revealed higher enteric glial cell density and glia-to-neuron ratio (p < 0.01), but lower calcitonin gene-related peptide (CGRP)-positive fiber density (p < 0.001) in IC-treated compared to control females. Macrophages decreased in IC-treated compared with control males in the colon wall (p < 0.05), whereas their number increased in IC-treated females compared to IC-treated males (p > 0.0001). Visceral pain responses are associated with complex sex-dependent neuroimmune changes in the colon. Interestingly, IC effects appear mild under healthy conditions, possibly due to compensatory mechanisms exerted by its different phytochemicals. Further investigation is needed to determine the effects of IC in pathological situations involving visceral hypersensitivity, such as brain–gut axis disorders.