Citation: Pérez-Valero, Á.; Magadán-Corpas, P.; Ye, S.; Serna-Diestro, J.; Sordon, S.; Huszcza, E.; Popło ´ nski, J.; Villar, C.J.; Lombó, F. Antitumor Effect and Gut Microbiota Modulation by Quercetin, Luteolin, and Xanthohumol in a Rat Model for Colorectal Cancer Prevention. Nutrients 2024, 16, 1161. https:// doi.org/10.3390/nu16081161 Academic Editors: Yi-Wen Liu and Ching-Hsein Chen Received: 13 March 2024 Revised: 9 April 2024 Accepted: 11 April 2024 Published: 13 April 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article Antitumor Effect and Gut Microbiota Modulation by Quercetin, Luteolin, and Xanthohumol in a Rat Model for Colorectal Cancer Prevention Álvaro Pérez-Valero 1,2,3 , Patricia Magadán-Corpas 1,2,3 , Suhui Ye 1,2,3 , Juan Serna-Diestro 1,2,3 , Sandra Sordon 4 , Ewa Huszcza 4 , Jarosław Popło ´ nski 4 , Claudio J. Villar 1,2,3 and Felipe Lombó 1,2,3, * 1 Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain; sernadjuan@uniovi.es (J.S.-D.); cjvg@uniovi.es (C.J.V.) 2 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006 Oviedo, Spain 3 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain 4 Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland; sandra.sordon@upwr.edu.pl (S.S.); ewa.huszcza@upwr.edu.pl (E.H.); jaroslaw.poplonski@upwr.edu.pl (J.P.) * Correspondence: lombofelipe@uniovi.es Abstract: Colorectal cancer stands as the third most prevalent form of cancer worldwide, with a notable increase in incidence in Western countries, mainly attributable to unhealthy dietary habits and other factors, such as smoking or reduced physical activity. Greater consumption of vegetables and fruits has been associated with a lower incidence of colorectal cancer, which is attributed to their high content of fiber and bioactive compounds, such as flavonoids. In this study, we have tested the flavonoids quercetin, luteolin, and xanthohumol as potential antitumor agents in an animal model of colorectal cancer induced by azoxymethane and dodecyl sodium sulphate. Forty rats were divided into four cohorts: Cohort 1 (control cohort), Cohort 2 (quercetin cohort), Cohort 3 (luteolin cohort), and Cohort 4 (xanthohumol cohort). These flavonoids were administered intraperitoneally to evaluate their antitumor potential as pharmaceutical agents. At the end of the experiment, after euthanasia, different physical parameters and the intestinal microbiota populations were analyzed. Luteolin was effective in significantly reducing the number of tumors compared to the control cohort. Furthermore, the main significant differences at the microbiota level were observed between the control cohort and the cohort treated with luteolin, which experienced a significant reduction in the abundance of genera associated with disease or inflammatory conditions, such as Clostridia UCG-014 or Turicibacter. On the other hand, genera associated with a healthy state, such as Muribaculum, showed a significant increase in the luteolin cohort. These results underline the anti-colorectal cancer potential of luteolin, manifested through a modulation of the intestinal microbiota and a reduction in the number of tumors. Keywords: flavonoid; intraperitoneal; colorectal cancer; rat model; gut microbiota 1. Introduction Cancer, a global health challenge, encompasses a group of disorders arising from abnormal and uncontrolled cell proliferation with invasive characteristics [1,2]. Colorectal cancer (CRC) stands as the third most prevalent malignancy worldwide, with over 1.93 mil- lion newly reported cases and 935,173 deaths in 2020, securing its place as the third leading cause of mortality in both, males and females, globally [3–5]. Notably, CRC has emerged as a predominant cancer in Western countries, contributing to 10% of worldwide cancer incidence and 9.4% of cancer-related deaths [3]. This higher prevalence of CRC in Western countries is attributed to the aging popula- tion and the prevalence of unhealthy dietary practices, including high intakes of saturated Nutrients 2024, 16, 1161. https://doi.org/10.3390/nu16081161 https://www.mdpi.com/journal/nutrients