The impact of the gut microbiota on the gastrointestinal tract in a mouse model of amyotrophic lateral sclerosis

• Grant number: 25/12395-7
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: January 10, 2026
• End date: July 09, 2026
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Renata de Britto Mari
• Grantee: Isabelly Cristina Correia dos Santos de Oliveira
• Supervisor: Keith Alexander Sharkey
• Host Institution: Instituto de Biociências (IB-CLP). Universidade Estadual Paulista (UNESP). Campus Experimental do Litoral Paulista. São Vicente , SP, Brazil
• Institution abroad: University of Calgary, Canada
• Associated to the scholarship: 24/06551-3 - TEBUCONAZOLE TOXICITY ON INTESTINAL HOMEOSTASIS: AN INTEGRATED ASSESSMENT OF BIOMARKERS IN WISTAR RATS, BP.MS

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons, leading to severe motor impairment and reduced life expectancy. Notably, ALS exhibits sexual dimorphism in both human patients and animal models, with males generally showing earlier onset and faster disease progression. The transgenic TDP43 (A315T) mouse model recapitulates these sex-dependent differences, along with hallmark features of ALS pathology, including motor neuron loss and muscle atrophy. Emerging evidence highlights the gut microbiota as a critical modulator of neurophysiological and immunological processes through the microbiota-gut-brain axis (MGBA). Dysbiosis, or microbial imbalance, has been implicated in the onset and progression of various neurodegenerative diseases, including ALS, by promoting systemic inflammation, compromising the intestinal barrier, and exacerbating neuroinflammatory responses. Intriguingly, recent studies in TDP43 mice demonstrate that gut microbiota depletion shortens lifespan and abolishes sex-specific disease differences, suggesting that microbiota composition influences both disease trajectory and sexual dimorphism in ALS. This project aims to investigate how gut microbiota modulation affects intestinal homeostasis, enteric neurodegeneration, and gastrointestinal motility in TDP43 mice, with a specific focus on sex differences. The experimental design includes fecal microbiota transplantation (FMT) across sex and genotype in germ-free and antibiotic-treated TDP43 mice, with microbiota sourced from donors at different disease stages. Post-transplantation, animals will be evaluated for neurodegenerative phenotypes, intestinal motility, and enteric nervous system integrity using immunohistochemical markers for neurons and glial cells. This research will be conducted in collaboration with Dr. Keith Sharkey's laboratory at the University of Calgary, an internationally recognized center for neurogastroenterology research, and in partnership with Dr. Minh Dang Nguyen, a leading ALS researcher. The internship will provide access to advanced methodologies in microbiome analysis, FMT, and enteric neurobiology, fostering international collaboration and skill development. This multidisciplinary approach will enhance understanding of the interplay between gut microbiota, sexual dimorphism, and ALS progression, with potential translational implications for the development of microbiota-targeted interventions in neurodegenerative diseases.