The remarkable complexity of the brain microbiome in health and disease

Microbes in human brain and their potential contribution to neurodegenerative conditions such as Alzheimers disease (AD) have long been debated. We recently developed a new method (the electronic tree of life, eToL) based on small subunit ribosomal RNA (rRNA) probes, further confirmed by large subunit rRNA analysis, to comprehensively address the spectrum of microorganisms in control and AD brain. We report a remarkable diversity of brain microbes in control brain. The most abundant are fungi, bacteria, and chloroplastida, and we report detailed identification of representative microbial species. The pattern is substantially conserved across different bilateran species from Drosophila to human. In terms of diversity, the human brain microbiome appears to be a subset (~20%) of the gut microbiome. Adenovirus type C was the major virus found in human brain; other viruses were not well represented. However, the spectrum of brain microbes differed between individuals as well as between brain regions examined from single individuals (amygdala, cingulate cortex, hippocampus, hypothalamus); of these four regions, the highest microbial burden was in cingulate cortex. There was evidence of spreading of pathogens between brain regions in single individuals. Some microbes are over-represented in AD brain according to two measures: (i) absolute number of microbes normalized to endogenous human transcripts, and (ii) the number of brain specimens showing overabundance versus control. Species over-represented in AD brain according to both measures notably include bacteria (Streptococcus, Staphylococcus/Bacillus, Sphingomonas/Ralstonia) and fungi (Acrocalymma/Altenaria/Aureobasidium of the Aspergillus group; Komagataella of the Candida group, Cortinarius of the Schizophyllum group, and Tausonia of the Cryptococcus group), that are all related to known human pathogens. In addition, an uncharacterized chloroplastida (algae-related) species was more abundant in AD brain samples. Although these findings point to diverse microbial species, indicative of multiple causation, similar absolute levels of bacteria and fungi in AD brain samples could suggest synergy between pathogens. However, it is important to stress that not all AD samples were positive for these microbes, but this could be because the affected brain region(s) was not examined. These findings support the contention that infection, perhaps associated with declining immunity with age, may contribute to AD development.