The gut - microbiota - brain connection: Bacillus subtilis DG101 regulates the aging-related insulin-IGFR1-FOXO route and the oxidative stress-related p38MAPK-Nrf2 signaling to protect against Parkinson’s and Alzheimer’s diseases

Title : The gut - microbiota - brain connection: Bacillus subtilis DG101 regulates the aging-related insulin-IGFR1-FOXO route and the oxidative stress-related p38MAPK-Nrf2 signaling to protect against Parkinson’s and Alzheimer’s diseases

Abstract:

Neurodegenerative diseases (Parkinson and Alzheimer’s diseases) represent a pandemic that affects millions of humans around the globe, and for which there is no cure or effective treatments or medications. The gut microbiota, the trillions of microorganisms inhabiting the intestinal lumen, connect with the central nervous system and affects its functioning. One member of the gut microbiota, the bacterium Bacillus subtilis natto (BSN) DG101, is recognize for its beneficial (probiotic) effects on human health. Here, we present our recent investigations in the animal model Caenorhabditis elegans colonized by biofilm-forming BSN DG101 against the onset and progression of PD and AD. C. elegans is resistant to oxidative injury of dopaminergic neurons caused by treatment with the neurotoxin 6-hydroxydopamine (6-OHDA). Biofilm-forming BSN DG101-colonized C. elegans display dopamine-dependent behaviors indistinguishable from those of 6-OHDA-untreated worms colonized by gut commensal E. coli OP50. Life expectancy is longer and dopaminergic neurons are more strongly protected in biofilm-forming BSN DG101-colonized C. elegans dat-1p::CAT-2 worms, which exhibit early dopaminergic decay, than in biofilm-deficient BSN DG101- or E. coli OP50-colonized dat-1p::CAT-2 worms. Increases in healthy life expectancy and behavioral fitness are also observed in biofilm-forming BSN DG101-colonized worms overexpressing human alpha-synuclein and Parkin synthesis-deficient worms. The BSN DG101-controlled insulin/IGF-1 signaling (ILS), whose downregulation prevents aging-related PD, is not involved in protecting against oxidative damage-related PD. We demonstrate that biofilm-forming BSN DG101 activates PMK-1 (p38 MAPK)/SKN-1 (Nrf2) signaling, which exerts antioxidant effects to protect C. elegans from oxidative injury-induced PD. Additionally, transgenic C. elegans model of AD (i.e., worms expressing the toxic forms of human Aβ-amyloid peptide) colonized by BSN DG101, but not worms colonized by gut commensal E. coli OP50, were fully protected and displayed cognitive responses and life expectancies indistinguishable from the behavior and life span of wild-type C. elegans. This research points to the important role of the microbial gut biofilm in neuroprotection and opens the possibility of novel strategies against PD, AD and other neurodegenerative diseases involving the gut – brain connectome and the human probiotic BSN DG101.

Biography:

Biochemist and PhD in Biological Sciences (Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, UNR); International Master's Degree in Human Microbiota (Technological University of Spain); Professor of the Diploma Program in Microbiota and Nutrigenomics at the University of Mendoza; advanced studies in Philosophy (Faculty of Humanities and Arts, UNR). Postdoctoral Fellow in Molecular Biology of Signal Transduction in Bacteria (The Scripps Research Institute, Department of Molecular and Experimental Medicine, San Diego, California, USA). Former university professor and researcher, Latin American Fellow of the Pew Charitable Trust in Biological Sciences (San Francisco, USA); Fulbright International Scholar (Washington, DC, USA). With 43 years of experience in scientific research; recipient of more than 20 national and international awards for his teaching and scientific career; Director of over 40 scientific research projects funded by national and international government agencies and private companies. He has published over 50 original articles in prestigious journals and given over 150 presentations at scientific conferences, supervised dozens of postgraduate and doctoral theses, trained over 50 professionals in science, and been a visiting professor at more than 15 universities and research institutes worldwide (France, Spain, Germany, India, Japan, Brazil, Cuba, Chile, USA, UK). He has founded and/or catalyzed the creation of half a dozen biotechnology companies, including Kyojin S.A. in Argentina and Juventas 4life SL in Spain. He is a member of the EURECAT-Barcelona / Metrofood EU 2024-2025 program; the Health Start Madri+D 2025-2026 program; and the Madrid Science Park Foundation (Complutense and Autonomous Universities of Madrid) 2026-. Current Research Topic: Role of Microbiota and Probiotics in Neuroprotection, Antitumor Therapies and Healthy Longevity.