The remarkable complexity of the brain microbiome in health and disease

Microbes in human brain and their potential contribution to neurodegenerative conditions such as ‎Alzheimer's 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.‎ ### Competing Interest Statement The authors have declared no competing interest.