Assessment of the impacts of dysbiosis caused by cesarean section on the gut microbiome's capacity to metabolize di(2-etilhexil) phthalate (DEHP).

• Grant number: 23/13458-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 01, 2024
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• Principal Investigator: Juliana Elaine Perobelli
• Grantee: Marcella da Silva Araujo Santiago
• Supervisor: Michael Zimmermann
• Host Institution: Instituto do Mar (IMar). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
• Institution abroad: European Molecular Biology Laboratory, Heidelberg (EMBL), Germany
• Associated to the scholarship: 21/11319-4 - Birth pathway and its influence on the gut microbiota: implications for health and response to environmental pollutants, BP.DR

Abstract

The interaction between the gut microbiota (GM) and the xenobiotics, i.e. man-made chemical compounds that are foreign to the organism, is described as a bidirectional pathway, being one path the ability of the compound to alter the GM composition, and the other the ability of the GM to alter the metabolization of the xenobiotic. Among the xenobiotics, environmental pollutants deserve special attention since they characterize one of the most important challenges of public health worldwide. Phthalates are one of the most studied pollutants nowadays, for their widespread use and, consequently, large-scale exposure. The main project of this proposal aims to investigate, in vivo, if the dysbiosis, i.e., an imbalance in the composition of status of the GM, after the birth by cesarean section - already known for causing dysbiosis - is persistent throughout the individual's life, causing implications for the general health status and for the organism's response to environmental pollutants, being the Di-(2-ethylhexyl) phthalate (DEHP) the pollutant chosen as a model of study. However, the in vivo study has a limitation to elucidate how the GM in a dysbiosis state induced by cesarean, per se, can alter the metabolism and toxicity of an environmental pollutant. This is because, with in vivo models, it is difficult to isolate the impacts of environmental pollutants on GM or the impacts of GM on the metabolism of the pollutant, so that the observed effects can result from a combination of both. Therefore, this subproject aims to evaluate the impacts of birth by cesarean section on the capacity of the GM to metabolize DEHP, using in vitro approaches. To do that, bacterial cultures with the main bacteria found in the GM of rats born via vaginal delivery or cesarean section will be cultured and inoculated with DEHP, aiming to: (i) assess the main bacteria responsible for its metabolization; (ii) which metabolites are generated after its exposure; and (iii) which DNA fragments confer drug metabolic capacity to the host. Still, (iv) a pharmacokinetic model will be constructed to assess the contribution of the host and GM to systemic DEHP and metabolite exposure. These analyses will be conducted in collaboration with the Zimmermann Lab, led by Dr. Michael Zimmermann, at the European Molecular Biology Laboratory (EMBL - Heidelberg), which has extensively studied the ability of GM bacteria to metabolize xenobiotics. With the results obtained in this project, it is expected to identify whether there are bacteria impacted by cesarean section that may be central in the metabolization of xenobiotics and, along with data from the main project under development in Brazil, it will be possible to build a more realistic scenario of the real impact of cesarean section on the vulnerability of individuals to exposure to xenobiotics. Still, it is expected to suggest possible gene therapies with GM as a target for mitigating the impacts of chemical exposures, especially in risk areas.