Genome Dynamics in the Brain-Gut Axis

The biology of the neurological and gastrointestinal systems are tightly interconnected, interacting with and influencing each other through multiple bidirectional signaling pathways. The human microbiome strongly influences the physiology of all organs including the central nervous system (CNS), and the CNS in turn modulates gut function. It is well established that the 10th cranial nerve facilitates communication between the gut and the brain. Additional avenues of communication between the gut and brain are mediated by host exosomes and microbial vesicles containing regulatory substances including neurotransmitters and small regulatory RNAs. The human gut microbiome produces vast amounts of neurotransmitters, with effects on both human local neuronal cells and on brain activity. Ultimately, a fraction of the neurotransmitters are packaged into exosomes, cross the blood-brain barrier and may influence brain function. Therefore, imbalance in the brain-gut axis could correlate with incipient pathology in the CNS and/or the gastrointestinal tract.

We asked if and how the gut microbiome modulates susceptibility to progressive neurodegenerative Alzheimer’s disease (AD). The proteomic expression profile was tested in post-mortem human brain biopsies and gut mucosal biopsies, and the gut microbiome profile was defined in selected subjects. In terms of DNA repair, predominant base excision repair (BER) was expressed in brain tissue, while nucleotide excision repair (NER) was more highly expressed in the gut mucosa. This differential expression pattern reflects local stress and organ environments, both the nature of non-replicating versus replicating cells as well as the state of a sterile organ versus that of an organ with a rich microbiome. Different DNA repair responses were evident in the prodromal versus late stages of AD. We have previously shown that signature reactions in BER patterns in brain appear before AD pathology is evident. These studies elucidate how DNA repair and the gut microbiome may impact on AD.