Research Article: Carnosine induces intestinal cells to secrete exosomes that activate neuronal cells

Date Published: May 28, 2019

Publisher: Public Library of Science

Author(s): Yuka Sugihara, Shiori Onoue, Kosuke Tashiro, Mikako Sato, Takanori Hasegawa, Yoshinori Katakura, Tohru Minamino.


Recently, we showed that imidazole dipeptide such as carnosine contained abundantly in chicken breast meat improves brain function in a double-blind randomized controlled trial. However, the underlying molecular mechanisms remain unknown. Here, we investigated whether carnosine activates intestinal epithelial cells and induces the secretion of factors that activate brain function. We focused on exosomes derived from intestinal epithelial cells as mediators of brain-gut interaction. Results showed that exosomes derived from Caco-2 cells treated with carnosine significantly induced neurite growth in SH-SY5Y cells. To clarify the molecular basis of this finding, we performed integrated analysis of microRNAs (miRNAs) with altered expression in exosomes in response to carnosine treatment and mRNAs with altered expression in target cells in response to exosome treatment to identify related miRNAs and their target genes. The combination of miR-6769-5p and its target gene ATXN1 was found to be involved in the exosome-induced activation of neuronal cells.

Partial Text

Carnosine, an imidazole dipeptide, has been reported to exert anti-fatigue, anti-oxidant, and exercise performance-enhancing effects [1,2]. Recently, we reported that carnosine and its related peptide anserine improved brain function, as evidenced by experiments using a mouse model of Alzheimer’s disease [3] and a double-blind randomized controlled trial [4]. The expression of inflammatory cytokine CCL24 was suppressed in peripheral blood mononuclear cells from elderly individuals who had ingested carnosine/anserine, suggesting that the latter is a key molecule responsible for the observed effect [5]. Notably, we further demonstrate that anserine/carnosine supplementation preserves brain structure and function in elderly individuals carrying APOE4 [6].

Numerous food components have been reported to possess the ability to affect cognitive function and emotion; these include omega-3 fatty acids, curcumin, flavonoids, and resveratrol [18]. Several gut hormones and regulators of synaptic plasticity, such as brain-derived neurotrophic factor, have been reported to affect brain function. In this study, we presented a novel mechanism of action of such a “brain food”, namely carnosine. Until now, we showed that carnosine induces the secretion of several cytokines including BDNF, which would result in the activation of brain-gut interaction and its consequent brain function [9]. Here, we demonstrated that carnosine induced the secretion of exosomes from intestinal epithelial cells, and that the resulting exosomes and its miRNA activated neuronal cells, resulting in the activation of brain function.