Is There a Brain Microbiome?

The concept of a brain microbiome
Implications of a brain microbiome
Scientific controversy and challenges
Potential mechanisms and pathways
Future directions in research
References and further reading

Microbiome (a term used to describe the microorganisms present within an area) is typically associated with organs in the human body, like the gut, skin, or nasal cavities. However, an emerging body of evidence suggests the presence of a brain microbiome.

This article will describe the findings leading to this idea alongside potential pathways for its use in research and the controversy this theory has since created.

Image Credit: Vitalii Vodolazskyi/Shutterstock.com

The concept of a brain microbiome

A microbiome is a community of bacteria, fungi, and viruses living within a habitat. Thus the hypothesis that the brain contains a microbiome postulates that bacteria, viruses, and/or fungi exist normally within the brain.

The initial suggestion of native bacterium present in the brain came from a study in 2013, initially investigating whether microbial infiltration into the brain was observed in patients with HIV/AIDS. This study by Branton et al. observed non-human RNA sequences aligning with over 170 bacteria and phages.¹

Critically this study also transplanted the human brain tissue into immunocompromised mice, where after, the same bacterial sequences were detected. These sequences were not detected in a parallel group of mice in which the transplanted tissue was heat-treated.¹

The appearance of microbial RNA in control brains (where the immune system should be fully functional) is not in line with the belief that the brain is a sterile organ. Further to this, the detection of microbial RNA in the non-heat-treated group suggests that the detected bacteria were living. ²

Current techniques for detecting the presence of microorganisms in the brain rely on the recovery and reading of foreign RNA or DNA within the brain, such as in 16S RNA amplification or metagenomic high throughput sequencing.

Implications of a brain microbiome

The brain microbiome may also play a role in brain disease, alongside its presence in healthy individuals. Microorganisms have been implicated in the pathogenesis of Alzheimer’s disease (AD). One study comparing samples from control brains vs brains with AD found an overabundance of bacteria and fungi species in the AD samples.³

Traditionally, the brain has been considered a sterile environment, meaning not containing living microorganisms. Previously, microorganism infiltration of the brain was thought of only in the context of infection, such as the Herpes Simplex Virus-1.⁴

The blood-brain barrier (BBB) is considered one of the largest contributors to the brain's immune privileged status. Under normal conditions, the BBB is near-impermeable to most large molecules, such as microorganisms.⁵ Therefore, conventionally, it was thought that in individuals with a healthy BBB, microorganisms such as bacteria, should not be found in the brain.

Scientific controversy and challenges

One of the main critiques of the brain microbiome concept arises from the potential that the observed microbial sequences are a product of contamination. ^6–8 This contamination may arise from the recovery of the tissue.² This potential for detected microorganisms to be artifacts (false positives created during the study) has led to skepticism regarding the existence of the brain microbiome.

The methodology of studies linking a potential brain microbiome with neurodegenerative disorders has been criticized for potential confounding factors that may lead to the observations of these studies.

In these studies, due to the nature of neurodegenerative disorders, participants are often older. Deterioration of the BBB leading to “leakage” is linked to increasing age in adults, with strong evidence of disruption in AD.^9,10

Additionally, the strength of the immune system decreases with age.¹¹ Thus, there is the potential that microbes observed in patients with neurodegenerative disorders are secondary to infiltration after degeneration, rather than the driver of the neurodegenerative changes.²

Current methods used for the detection of microorganisms in the brain rely on prior knowledge of DNA/RNA sequences of microorganisms. Therefore, there is the possibility for many unknown microorganisms to be missed. Potentially meaning the brain microbiome is larger than currently hypothesized in terms of species.²

Potential mechanisms and pathways

Although a unified theory for microbial colonization of the brain has not been formed, multiple research groups have suggested ways this occurs. Weber et al noted that specific species of bacteria identified in studies exploring the brain microbiome in AD are normally found in the oral microbiome.¹²

Therefore, they hypothesized, that pathogenic changes in the oral cavity (often seen in AD) may damage connective tissues. This tissue destruction releases bacteria from the oral cavity, allowing for nervous system infection. Some of these bacteria can create a biofilm, through the production of amyloid proteins.¹²

These bacterial amyloids share similarities to the disease-causing versions.¹³ These amyloids may then allow other native amyloid proteins to aggregate and form colonies, beginning the pathogenesis of AD.¹²

Future directions in research

The concept of the brain microbiome is still in its infancy. Whilst important steps have been made to elucidate this concept further, a true overview of the brain microbiome is still to be provided. As this field is still developing, there are still necessary steps future research should take to verify these results.

As highlighted earlier, the potential that microorganisms have been detected in brain samples may arise due to subject age and BBB deterioration, suggests studies should focus on exploring multiple age ranges. This may elucidate whether these detected microbes are due to age-related changes or are a true representation of a brain microbiome.²

As the human gut microbiome is potentially unique to the individual, the same thing may be true for the brain microbiome.¹⁴ Therefore, future research may seek to analyze brain samples of individuals in parallel. This would allow researchers to observe whether detected microbes vary between individuals, which would potentially confirm the presence of a brain microbiome.²

As the brain microbiome may play a role in neurodegenerative disorders such as AD, a better understanding of this relationship may better inform future treatments. If microbes do drive or play a part in the associated neurodegenerative changes, there are opportunities to use targeted treatment.

In the case of the hypothesis that bacteria from the oral cavity play a role in the instigation of AD, lactoferrin may represent an important therapeutic. Lactoferrin is a protein native to the oral cavity with antimicrobial properties; typically, lactoferrin helps keep the oral microbiome in homeostasis. However, lactoferrin has also shown promise as a therapeutic in the field of neurodegenerative diseases.¹²

The brain microbiome is a fascinating concept, that is still developing. Whilst there is mounting evidence that a potential brain microbiome plays a role in human health, skepticism surrounding the methodologies used to come to these conclusions is still present. This research may prove to be incredibly important, potentially discovering new treatment routes for neurodegenerative disorders like AD.

References and further reading

1. Branton WG, Ellestad KK, Maingat F, et al. Brain Microbial Populations in HIV/AIDS: α-Proteobacteria Predominate Independent of Host Immune Status. PLoS One. 2013;8(1). doi:10.1371/journal.pone.0054673
2. Link CD. Is There a Brain Microbiome? Neurosci Insights. 2021;16. doi:10.1177/26331055211018709
3. Hu X, Mckenzie C-A, Smith C, Haas JG, Lathe R. The remarkable complexity of the brain microbiome in health and disease. bioRxiv - Prepr. 2023:2023.02.06.527297. doi:10.1101/2023.02.06.527297
4. Marcocci ME, Napoletani G, Protto V, et al. Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection. Trends Microbiol. 2020;28(10):808-820. doi:10.1016/j.tim.2020.03.003
5. Dotiwala A, McCausland C, Samra N. Anatomy, Head and Neck: Blood Brain Barrier. StatPearls Publishing, Treasure Island (FL); 2023. https://www.ncbi.nlm.nih.gov/books/NBK519556/.
6. Lusk RW. Diverse and Widespread Contamination Evident in the Unmapped Depths of High Throughput Sequencing Data. Gilbert T, ed. PLoS One. 2014;9(10):e110808. doi:10.1371/journal.pone.0110808
7. Salter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 2014;12(1):87. doi:10.1186/s12915-014-0087-z
8. Mangul S, Yang HT, Strauli N, et al. ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol. 2018;19(1):36. doi:10.1186/s13059-018-1403-7
9. Verheggen ICM, de Jong JJA, van Boxtel MPJ, et al. Increase in blood–brain barrier leakage in healthy, older adults. GeroScience. 2020;42(4):1183-1193. doi:10.1007/s11357-020-00211-2
10. Sweeney MD, Zlokovic B V. A lymphatic waste-disposal system implicated in Alzheimer’s disease. Nature. 2018;560(7717):172-174. doi:10.1038/d41586-018-05763-0
11. Hirokawa K, Utsuyama M, Kasai M, Kurashima C. Aging and Immunity. Acta Pathol Jpn. 1992;42(8):537-548. doi:10.1111/j.1440-1827.1992.tb03103.x
12. Weber C, Dilthey A, Finzer P. The role of microbiome-host interactions in the development of Alzheimer´s disease. Front Cell Infect Microbiol. 2023;13(June). doi:10.3389/fcimb.2023.1151021
13. Evans ML, Gichana E, Zhou Y, Chapman MR. Bacterial amyloids. Methods Mol Biol. 2018;1779:267-288. doi:10.1007/978-1-4939-7816-8_17
14. Schloissnig S, Arumugam M, Sunagawa S, et al. Genomic variation landscape of the human gut microbiome. Nature. 2013;493(7430):45-50. doi:10.1038/nature11711