Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation

• Grant number: 18/15313-8
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: May 01, 2019
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Marco Aurélio Ramirez Vinolo
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 12/10653-9 - Role of short chain fatty acids and their receptor (GPR43) in the immune response to anaerobic bacteria in vivo and in vitro, AP.JP
• Associated research grant(s): 20/04583-4 - Impact of intestinal microbiota and its metabolites on SARS-CoV-2 infection, AP.R
• Associated scholarship(s): 21/10478-1 - Analysis of the role of microbiota and TLRs signaling in epigenetic modifications of intestinal epithelial cells in DSS-induced inflammation, BP.DR; 21/09155-3 - Analysis of the role of the FFAR2 receptor in neutrophil functionality and myelopoiesis, BP.DR; 20/13689-0 - The role of histone crotonylation in intestinal stem cells, BP.DR; + associated scholarships 20/00311-0 - Role of ³´ T cells in adaptations of intestinal epithelium induced by inulin diet, BP.DD; 20/02685-4 - Investigation of the effect of gut dysbiosis on histone post-translational modifications in neutrophils, BP.PD; 20/02919-5 - Effect of inulin and Short-Chain Fatty Acids (SCFAs) on Hypoxia-Inducible Factor 1 (HIF-1) and its target genes in epithelial cells and intestinal stem cells, BP.PD; 20/00465-7 - Relevance of SCFAs-induced histone acylation in neutrophils production of inflammatory mediators, BP.DD; 20/02312-3 - Study of the effect of short-chain fatty acids on the tissue regeneration process during experimental colitis, BP.DD; 19/14342-7 - Comparison of gamma variant tropism and pathogenicity versus original SARS CoV-2 in humanized K18-ACE2 mice: role of gut microbiota, BP.DR; 19/11662-0 - Participation of the FFAR2 receptor in the inflammation in a DSS-induced colitis model, BP.MS - associated scholarships

Abstract

How the microbiota communicates with the host and contributes to health is a key question for progress in this research field. Bacterial metabolites called short chain fatty acids (SCFAs), which are generated by fermentation of non-digestible carbohydrates, constitute a link between microbiota and host cells. Previous studies demonstrated that these metabolites regulate host metabolism and immunity. However, the molecular mechanisms are not totally defined. The aim of this project is to investigate this by examining 1) activation of the SCFA receptor FFAR2 (GPR43) and 2) modification of the pattern of histone acylations (mainly, acetylation and crotonylation) in neutrophils and intestinal epithelial cells (IECs) and their biological relevance in inflammatory models. For this, we will 1) characterize, using cell-specific knockout mice, the role of FFAR2 in neutrophil and IEC functions, and its participation in inflammasome activation and relevance during intestinal inflammation and; 2) investigate the effect of SCFAs on the pattern of histone acylation in intestinal epithelial cells and neutrophils and how this affects their transcriptional and effector responses during inflammation. With this, we will contribute to the understanding of the molecular mechanisms of microbial-host interaction and identification of new biomarkers and therapeutic targets for inflammatory diseases. (AU)

Scientific publications

(15)

(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)

HIRABARA, SANDRO MASSAO; GORJAO, RENATA; MARZUCA-NASSR, GABRIEL NASRI; VITZEL, KAIO FERNANDO; VINOLO, MARCO AURELIO RAMIREZ; MASI, LAUREANE NUNES. Editorial: Molecular and cellular mechanisms involved in inflammation, metabolism and oxidative stress induced by coronaviruses. FRONTIERS IN MICROBIOLOGY, v. 14, p. 3-pg., 2023-03-22. (18/15313-8, 18/09868-7)

CORREA, RENAN OLIVEIRA; CASTRO, POLLYANA RIBEIRO; FACHI, JOSE LUIS; NIRELLO, VINICIUS DIAS; EL-SAHHAR, SALMA; IMADA, SHINYA; PEREIRA, GABRIEL VASCONCELOS; PRAL, LAIS PASSARIELLO; PEREIRA ARAUJO, NATHALIA VITORIA; FERNANDES, MARIANE FONT; et al. Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium. MICROBIOME, v. 11, n. 1, p. 25-pg., 2023-04-26. (16/23142-3, 21/06572-2, 19/06372-3, 19/16113-5, 19/02640-3, 18/15313-8, 20/02919-5, 17/16280-3, 20/14071-0, 21/00393-9, 17/06577-9, 20/13689-0, 21/05269-4, 20/02312-3, 18/10165-0, 20/00311-0)

HEUMEL, SEVERINE; RODOVALHO, VINICIUS DE REZENDE; URIEN, CHARLOTTE; SPECQUE, FLORIAN; RODRIGUES, PATRICIA BRITO; ROBIL, CYRIL; DELVAL, LOU; SENCIO, VALENTIN; DESCAT, AMANDINE; DERUYTER, LUCIE; et al. Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection. GUT MICROBES, v. 16, n. 1, p. 29-pg., 2024-12-31. (22/02058-5, 18/15313-8, 19/14342-7)

FACHI, JOSE L.; PRAL, LAIS. P.; ASSIS, HELDER C.; OLIVEIRA, SARAH; RODOVALHO, VINICIUS R.; DOS SANTOS, JEFFERSON A. C.; FERNANDES, MARIANE F.; MATHEUS, VALQUIRIA A.; SESTI-COSTA, RENATA; BASSO, PAULO J.; et al. Hyperbaric oxygen augments susceptibility to C. difficile infection by impairing gut microbiota ability to stimulate the HIF-1α-IL-22 axis in ILC3. GUT MICROBES, v. 16, n. 1, p. 26-pg., 2024-12-31. (17/06577-9, 18/15313-8)

FACHI, JOSE L.; DE OLIVEIRA, SARAH; TRSAN, TIHANA; PENATI, SILVIA; GILFILLAN, SUSAN; CAO, SIYAN; CASTRO, POLLYANA RIBEIRO; FERNANDES, MARIANE FONT; HYRC, KRZYSZTOF L.; LIU, XIULI; et al. Article Fiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection. CELL HOST & MICROBE, v. 33, n. 2, p. 25-pg., 2025-02-12. (21/09155-3, 18/15313-8, 23/00393-4, 17/06577-9)

RODRIGUES, PATRICIA BRITO; RODOVALHO, VINICIUS DE REZENDE; SENCIO, VALENTIN; BENECH, NICOLAS; CRESKEY, MARYBETH; ANGULO, FABIOLA SILVA; DELVAL, LOU; ROBIL, CYRIL; GOSSET, PHILIPPE; MACHELART, ARNAUD; et al. Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in a hamster model of COVID-19. GUT MICROBES, v. 17, n. 1, p. 25-pg., 2025-12-31. (22/02058-5, 18/15313-8, 19/14342-7)

FACHI, J. L.; PRAL, L. P.; DOS SANTOS, J. A. C.; CODO, A. C.; DE OLIVEIRA, S.; FELIPE, J. S.; ZAMBOM, F. F. F.; CAMARA, N. O. S.; VIEIRA, P. M. M. M.; COLONNA, M.; et al. Hypoxia enhances ILC3 responses through HIF-1 alpha-dependent mechanism. MUCOSAL IMMUNOLOGY, v. 14, n. 4, JAN 2021. (15/15626-8, 19/11662-0, 18/22505-0, 18/15313-8, 18/02208-1, 17/06577-9, 19/06372-3, 17/16280-3)

SATO, FABIO TAKEO; YAP, YU ANNE; CRISMA, AMANDA RABELLO; PORTOVEDO, MARIANA; MURATA, GILSON MASAHIRO; HIRABARA, SANDRO MASSAO; RIBEIRO, WILLIAN RODRIGUES; FERREIRA, CAROLINE MARCANTONIO; CRUZ, MAYSA MARIANA; BERTAGLIA PEREIRA, JOICE NAIARA; et al. Tributyrin Attenuates Metabolic and Inflammatory Changes Associated with Obesity through a GPR109A-Dependent Mechanism. CELLS, v. 9, n. 9, SEP 2020. (12/15774-9, 12/10653-9, 18/15313-8)

PRAL, LAIS P.; FACHI, JOSE L.; CORREA, RENAN O.; COLONNA, MARCO; VINOLO, MARCO A. R.. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. TRENDS IN IMMUNOLOGY, v. 42, n. 7, p. 604-621, JUL 2021. (16/23142-3, 17/06577-9, 18/02208-1, 18/15313-8)

ROCHA, ANDREA LIVIA; DE LIMA, TANES IMAMURA; DE SOUZA, GERSON PROFETA; CORREA, RENAN OLIVEIRA; FERRUCCI, DANILO LOPES; RODRIGUES, BRUNO; LOPES-RAMOS, CAMILA; NILSSON, DANIEL; KNITTEL, THIAGO LEITE; CASTRO, POLLYANA RIBEIRO; et al. Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression. SCIENCE ADVANCES, v. 6, n. 49, DEC 2020. (10/52557-0, 17/01184-9, 18/15313-8, 16/23142-3, 17/07975-8, 16/24163-4, 15/01316-7, 16/12294-7)

DARDI, PATRIZIA; COUTINHO, CAMILLE PERELLA; DE OLIVEIRA, SARAH; TEIXEIRA, SIMONE APARECIDA; GACEK, RENAIDE RODRIGUES FERREIRA; PURGATTO, EDUARDO; VINOLO, MARCO AURELIO RAMIREZ; MUSCARA, MARCELO NICOLAS; ROSSONI, LUCIANA VENTURINI. Changes in the intestinal microbiota induced by the postnatal environment and their association with hypertension. PHARMACOLOGICAL RESEARCH, v. 212, p. 16-pg., 2025-01-25. (20/10381-5, 18/15313-8, 23/03813-4, 23/13436-3, 19/08026-5)

DARDI, PATRIZIA; DOS SANTOS-EICHLER, ROSANGELA APARECIDA; DE OLIVEIRA, SARAH; RAMIREZ VINOLO, MARCO AURELIO; SARAIVA CAMARA, NIELS OLSEN; ROSSONI, LUCIANA VENTURINI. Reduced intestinal butyrate availability is associated with the vascular remodeling in resistance arteries of hypertensive rats. FRONTIERS IN PHYSIOLOGY, v. 13, p. 12-pg., 2022-09-29. (19/08026-5, 20/10381-5, 18/15313-8)

CORREA, RENAN OLIVEIRA; CASTRO, POLLYANA RIBEIRO; MOSER, RENE; FERREIRA, CAROLINE MARCANTONIO; QUESNIAUX, VALERIE F. J.; RAMIREZ VINOLO, MARCO AURELIO; RYFFEL, BERNHARD. Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders. FRONTIERS IN NUTRITION, v. 9, p. 16-pg., 2022-10-20. (13/07607-8, 18/15313-8)

IMADA, SHINYA; KHAWALED, SALEH; SHIN, HEAJI; MECKELMANN, SVEN W.; WHITTAKER, CHARLES A.; CORREA, RENAN OLIVEIRA; ALQUATI, CHIARA; LU, YIXIN; TIE, GUODONG; PRADHAN, DIKSHANT; et al. Short-term post-fast refeeding enhances intestinal stemness via polyamines. Nature, v. N/A, p. 28-pg., 2024-08-21. (19/02640-3, 18/15313-8, 16/23142-3)

CHOLLET, LOIC; HEUMEL, SEVERINE; DERUYTER, LUCIE; BOUILLOUX, FABRICE; DELVAL, LOU; ROBERT, VERONIQUE; GEVAERT, MARIE-HELENE; PICHAVANT, MURIEL; SENCIO, VALENTIN; ROBIL, CYRIL; et al. Faecalibacterium duncaniae as a novel next generation probiotic against influenza. FRONTIERS IN IMMUNOLOGY, v. 15, p. 14-pg., 2024-03-12. (22/02058-5, 18/15313-8, 19/14342-7)