Evaluation of the citral action in the intestinal permeability and metabolic endotoxemia in obese mice fed with high-fat diet

• Grant number: 20/15225-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): April 01, 2021
• Effective date (End): February 28, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Ethnopharmacology
• Principal Investigator: Clélia Akiko Hiruma Lima
• Grantee: Maycon Tavares Emílio Silva
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated scholarship(s): 21/11110-8 - Investigation of the citral effect on the fecal microbiota of C57BL/6J mice fed with a high-fat diet, BE.EP.DR

Abstract

Obesity is a chronic disease that is growing worldwide, due to distinct etiological factors. The High-Fat Diet (HFD) ingestion leads to a progressive increase in fat tissue and triggers metabolic changes. Possibly, this is caused by a change in the microbiota of the gastrointestinal tract (gut), characterized as a condition of intestinal dysbiosis. This change promotes an increase in lipopolysaccharide (LPS) levels, a component of the cell wall of Gram-negative bacteria, which sensitizes macrophages present in the gut and induces the production of pro-inflammatory mediators, such as Tumor Necrosis Factor (TNF)-±. This phenomenon impairs the action of intercellular junction proteins, the occludin, and claudins, which trigger changes in the integrity of the mucosal barrier. The increase in intestinal permeability induces greater extravasation of LPS from the intestinal lumen into the systemic circulation. Metabolic endotoxemia in obese individuals raises the sensitization of circulating macrophages and causes the production of new pro-inflammatory mediators such as; TNF-±, interleukin-6 (IL-6), and the hormone leptin, considered systemic biomarkers of Obesity. Therefore, high levels of LPS associated with a low-grade chronic inflammation characteristic of Obesity are related to the greater involvement of these patients in chronic diseases such as Type 2 Diabetes Mellitus and cardiovascular diseases. The search for drugs that act on microbiota modulation and intestinal permeability may contribute to the discovery of new, more effective, and safer approaches to the treatment of Obesity. Products of plant origin are an important source of biomolecules with pharmacological action, such as citral, a monoterpene that has effective anti-inflammatory, antipyretic, antihyperlipidemic, and gastroprotective action, effects portrayed in previous studies. Our studies have already demonstrated the effective action of citral in reducing serum levels of TNF-± and leptin in obese mice induced to systemic inflammation with LPS. Therefore, our general objective is to characterize the action of citral in the gut microbiota and to evaluate its action in intestinal permeability (in vivo and in vitro), and consequently, to evaluate its action in metabolic endotoxemia in obese mice fed with a High-Fat Diet (HFD). We will evaluate gene expression and protein markers for inflammatory process and intestinal and systemic permeability through PCR and Western blotting, respectively. Also, the intestinal microbiota profile will be evaluated by sequencing genes present in the feces of eutrophic and obese animals. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OHARA, RIE; DARIO, FELIPE LIMA; EMILIO-SILVA, MAYCON TAVARES; ASSUNCAO, RENATA; RODRIGUES, VINICIUS PEIXOTO; BUENO, GABRIELA; RAIMUNDO, PRISCILA ROMANO; DA ROCHA, LUCIA REGINA MACHADO; HIRUMA-LIMA, CLELIA AKIKO. Citral Modulates MMP-2 and MMP-9 Activities on Healing of Gastric Ulcers Associated with High-Fat Diet-Induced Obesity. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 5, p. 15-pg., 2023-03-01. (18/09873-0, 20/07384-2, 20/15225-1)