The remarkable complexity of the brain microbiome in health and disease

Abstract

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.‎

Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer's disease: Research outline and call for collaboration

“…A recently reported development is the use of longer probes: the electronic Tree of Life (eToL) method uses a net of much longer (64-mer) probes, prefiltered against human sequences, to identify (by homology; non-exact matches are detected) all non-human rRNA sequences in a given dataset. The method may be less prone to false positives because it refilters matches against human sequences and is relatively insensitive to single-nucleotide changes [54,55], and is being explored as a potential diagnostic method on patient samples.…”

“…Over recent decades multiple studies on post-mortem AD brain have reported that diverse pathogens are present, ranging from bacteria to fungi to viruses [45][46][47][48][49][50][51][52][53]. Archaea, Chloroplastida, and Holozoa have also been reported in brain [54,55]. There are multiple potential routes of entry to the brain (Figure 2).…”

“…For example, a microbe can be present but asymptomatic: most HSV1-infected individuals do not develop coldsores or other lesions, and many people infected with Mycobacterium tuberculosis do not develop tuberculosis. However, two recent studies identified potential differences in the microbiota of AD and age-matched brains [53,55]. One possible explanation is that dementias such as AD can have diverse etiologies in the same way that pneumonia can be caused by a variety of organisms.…”

Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease

“…Microbial titres increase with age in the hippocampus of both cognitively normal humans as well as in macaque (Appendix S7, Fig. S3), consistent with age‐related decline of the immune system, and there is growing evidence that AD brain contains elevated levels of diverse microbes versus control brain (MacDonald, 1986; Miklossy, 2011; Branton et al ., 2013; Itzhaki, 2014; Pisa et al ., 2015; Emery et al ., 2017; Balin et al ., 2018), as recently confirmed (Hu et al ., 2022, 2023).…”

Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer's disease

“…Over recent decades multiple studies on post mortem AD brains have reported that diverse pathogens are present, ranging from bacteria to fungi to viruses 45–53 . Archaea, Chloroplastida, and Holozoa have also been reported in the brain 54,55 . There are multiple potential routes of entry to the brain (Figure 2).…”