“I’m Gonna Make Him an Offer He Can’t Refuse.” -Don Vito Corleone
It could be a quote from a dialogue between the host microbiota and the host immune system… Let’s figure it out step by step.
Did you know that beneficial microorganisms live in and on our bodies? An adult human body consists of approximately 30 trillion human cells, but about 39 trillion bacterial cells. Our microbiome has coevolved with us over years, in sickness and in health, and it regulates a lot of metabolic processes in our body. Furthermore, microbial composition and products can influence the gene expression, development, and activity of the immune system during health and disease. Are you still sure that you are in charge of your own body?
In my imagination, our microbiome is the Don Vito Corleone and misunderstandings with him could be critical for the whole “mafia”.
What will happen when Don Vito is not at home?
Research led by Erny, Dokalis, and Mezo has recently shown how microbiota can influence the metabolic fitness of the microglia in mouse models.
Microglia are tissue macrophages of the central nervous system, and they act as key immune players by clearing dead neurons and cell debris. Hence, their dysfunction could lead to neurodegenerative and neuroinflammatory disorder. Their condition is strongly dependent on different environmental factors including commensal microbiota. Gut bacteria continuously modulate microglial maturation and function by the production of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. However, the precise mechanisms behind these processes are still enigmatic.
To analyze the role of SCFAs in microglia maturation and function, the authors compared germ-free mice with specific pathogen-free mice. They found that, while specific pathogen free mice contained mature microglia, the germ-free mice predominantly carried immature microglia having altered morphology and reduced anti-viral response. This was due to epigenetic changes caused by histone methylation (H3K4me3) or acylation (H3K9ac) on metabolic genes. Histones are proteins that are critical in the packing of- the otherwise extremely long- DNA into chromatins. Adding methyl or acetyl groups to the histones can activate or inhibit gene expression. Epigenetic modifications due to absence of host microbiome were associated with increased mitochondrial density and specific respiratory chain dysfunctions resulting in excessive generation of reactive oxygen species.
Why are mitochondria so important for the immune system?
To fight bacteria, viruses, cancer cells and other invaders, we need energy, A LOT of energy. The world (including our microbiota) knows who provides energy to our cells! Mitochondria– the “powerhouse of the cell”– generates ATP contributing to TCA cycle, purine metabolism, arginine-proline-metabolism, oxidative phosphorylation, fatty acid oxidation, and glycolysis during activation of microglia. Could you imagine that these sophisticated mechanisms are controlled by gut microbiota? Mitochondrial quantity, mass, and reactive oxygen species were observed to be significantly affected in the microglia of germ-free mice. How can disorders associated with microglial metabolism and mitochondrial changes be prevented?
“An offer he can’t refuse”
Do you think that all we need is love? Well, unfortunately, love may not cure neurological diseases, but SCFAs from the gut microbiome can! SCFAs can translocate from the intestine to the systemic circulation and cross the blood-brain barrier. In this study, acetate was the most abundant SCFA in the brain of SPF mice and was significantly reduced in the brain of GF mice. Acetate was seen to be essential in driving microglia maturation and regulating the homeostatic metabolic state. Yes, acetate is exactly “the offer” from the microbiome that the immune system can’t refuse to maintain homeostasis in the central nervous system. Supplying GF mice with acetate fixed the impaired microglia function during homeostatic conditions. But what happens during the pathological conditions?
Can the absence of the Don be beneficial for the house?
Sometimes, too much of a good thing, can be a bad thing (as in the case of autoimmunity). During multiple sclerosis, propionate (another SCFA) protects the nerves from attack by the unnecessarily activated immune system, by regulating mitochondrial function in regulatory T cell subpopulation. Having a healthy microbiome producing propionate would thus serve as a therapy against multiple sclerosis. On the contrary, germ-free mouse models for Alzheimer’s disease experienced a reduction in the load of amyloid-beta (peptide that accumulates and aggregates to trigger the progression of Alzheimer’s. In this case, the results indicated that microbiome released metabolites may be acting against the host.
Gut bacteria may accelerate microglia exhaustion, worsening Alzheimer’s and Parkinson’s disease. To support this, Erny, Daniel, Mezo and colleagues showed that acetate can rapidly progress these diseases by decreasing microglial phagocytosis of amyloid-beta. Future therapeutics may aim to reduce acetate levels to ameliorate the course of Alzheimer’s disease.
Microbiota can clearly be designated as ‘the Godfather’ of the immune system, right?
Erny, Daniel & Mezö, Charlotte & Dokalis, Nikolaos & Castoldi, Angela & Mossad, Omar & Staszewski, Ori & Frosch, Maximilian & Villa, Matteo & Fuchs, Vidmante & Mayer, Arun & Neuber, Jana & Sosat, Janika & Tholen, Stefan & Schilling, Oliver & Vlachos, Andreas & Blank, Thomas & Gomez de Agüero, Mercedes & Macpherson, Andrew & Prinz, Marco. (2021). Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metabolism. 13. https://doi.org/10.1016/j.cmet.2021.10.010
Article author: Taras Baranovskyi. Taras is a medical doctor at Immunotherapy Clinic in Kyiv, Ukraine. His research is focused on developing new approaches for overcoming the antimicrobial resistance of Klebsiella pneumoniae. Also, Taras is a part of a team which spreads knowledge of immunology through the ‘Cup of Immunology’ project.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “Host microbiota affects the brain’s innate immune system“.Tweet