Citation: Magadán-Corpas, P.; Pérez-Valero, Á.; Ye, S.; Sordon, S.; Huszcza, E.; Popło ´ nski, J.; Villar, C.J.; Lombó, F. Gut Microbiota and Inflammation Modulation in a Rat Model for Ulcerative Colitis after the Intraperitoneal Administration of Apigenin, Luteolin, and Xanthohumol. Int. J. Mol. Sci. 2024, 25, 3236. https://doi.org/10.3390/ijms25063236 Academic Editors: Fernando Santos-Beneit and Rustam I. Aminov Received: 24 January 2024 Revised: 5 March 2024 Accepted: 8 March 2024 Published: 12 March 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/). International Journal of Molecular Sciences Article Gut Microbiota and Inflammation Modulation in a Rat Model for Ulcerative Colitis after the Intraperitoneal Administration of Apigenin, Luteolin, and Xanthohumol Patricia Magadán-Corpas 1,2,3 , Álvaro Pérez-Valero 1,2,3 , Suhui Ye 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; magadanpatricia@uniovi.es (P.M.-C.); apv.moratalla@gmail.com (Á.P.-V.); yesuhui@uniovi.es (S.Y.); cjvg@uniovi.es (C.J.V.) 2 IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain 3 ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 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; Tel.: +34-985103593 Abstract: Ulcerative colitis (UC) is a chronic inflammatory disorder affecting the colon, with symp- tomatology influenced by factors including environmental, genomic, microbial, and immunological interactions. Gut microbiota dysbiosis, characterized by bacterial population alterations, contributes to intestinal homeostasis disruption and aberrant immune system activation, thereby exacerbating the inflammatory state. This study assesses the therapeutic efficacy of intraperitoneal (IP) injected flavonoids (apigenin, luteolin, and xanthohumol) in the reduction of inflammatory parameters and the modulation of the gut microbiota in a murine model of ulcerative colitis. Flavonoids interact with gut microbiota by modulating their composition and serving as substrates for the fermentation into other anti-inflammatory bioactive compounds. Our results demonstrate the effectiveness of luteolin and xanthohumol treatment in enhancing the relative abundance of anti-inflammatory mi- croorganisms, thereby attenuating pro-inflammatory species. Moreover, all three flavonoids exhibit efficacy in the reduction of pro-inflammatory cytokine levels, with luteolin strongly demonstrating utility in alleviating associated physical UC symptoms. This suggests that this molecule is a potential alternative or co-therapy to conventional pharmacological interventions, potentially mitigating their adverse effects. A limited impact on microbiota is observed with apigenin, and this is attributed to its solubility constraints via the chosen administration route, resulting in its accumulation in the mesentery. Keywords: inflammatory bowel disease; gut microbiota; flavonoid; anti-inflammatory 1. Introduction Inflammatory bowel disease (IBD) is a term that encompasses two conditions, Crohn’s disease (CD) and ulcerative colitis (UC), both characterized by chronic inflammation of the gastrointestinal tract. While CD can affect any part of the intestinal tract (from mouth to anus), UC only affects the colon, causing abdominal pain, mucus, diarrhea, and blood stool [1]. IBD represents a group of archetypal complex disorders distinguished by chronic and varied symptoms, influenced by the interplay among environmental, genomic, microbial, and immunological factors [2]. Multiple investigations have corroborated notable distinctions in the composition, diversity, and/or abundance of gut microbiota (dysbiosis) between healthy individuals and those with IBD, leading to the loss of intestinal homeostasis or improper immune Int. J. Mol. Sci. 2024, 25, 3236. https://doi.org/10.3390/ijms25063236 https://www.mdpi.com/journal/ijms