The exchange of small molecules, or metabolites, between organisms and their environment gives rise to the complexity of life on Earth1. One of the examples of such complexity is ourselves, our body and the full array of microorganisms (microbiota) that live on and in us, humans.
Just like us, stony corals (Scleractinia) also live in a symbiosis with associated microorganisms. These include bacteria, archea, fungi, viruses, and single-cellular algae called Symbiodinium.
Under normal conditions, these algal cells provide 90 to 95% of the energy required for stony corals to live happily1. The algae provide lipids, carbohydrates, amino acids, and O2 to Scleractinia. In return, the algae get to recycle nitrogen and other inorganic compounds from the coral, that they can use to fuel their own cell metabolism.
Climate change causes a rise in water temperatures; and, this form of environmental heat stress, disrupts the symbiotic relationship between corals and its algae, which results in coral bleaching.
Researchers have now discovered that heat stress destabilizes this basic nutrient exchange between corals and their algae; and, this turn of events happens long before the bleaching process becomes obvious.
In fact, Rädecker and his colleagues2 at the Red Sea Research Centre, discovered that heat stress causes the coral to need more energy, which swings the coral-algae symbiosis from a nitrogen- to a carbon-limited state. This actually ends up reducing the movement and recycling of carbon, and creates an animosity between these life partners.
The coral starts disliking the algae, because the algae it’s not fully doing its work – recycling carbon. As such, the stony coral starts thinking that sheltering such lazy algae is not beneficial anymore. On top of that, the poor coral needs to catabolically degrade more aminoacids, to compensate for the increased energy demands triggered by the warmer waters. Such demanding “cooking tasks” from the coral side, create fury, and actually increase the release of ammonium; which in turn, promote the algae to grow. So, not only does the algae not clean the building properly, but calls its algal friends and they move in.
Under stress, the coral kicks the algae out. But since this marriage is essential to its life support, the Scleractinia cannot feed itself properly anymore. The stony coral goes hungry, and slowly dies out….
1 Williams, A. et al. Metabolomic shifts associated with heat stress in coral holobionts. Science Advances7, eabd4210, doi:doi:10.1126/sciadv.abd4210 (2021).
2 Rädecker, N. et al. Heat stress destabilizes symbiotic nutrient cycling in corals. Proceedings of the National Academy of Sciences118, e2022653118, doi:10.1073/pnas.2022653118 (2021).
When we mention the word Serotonin (5-hydroxytryptamine, 5-HT), we immediately think of the brain and the Central Nervous System (CNS). People tend to associate serotonin to depression, or mood, or feelings of well-being1.
Although that is correct, truth be told, the majority of the serotonin in the human body is actually produced in the gut. In fact, 95% of total serotonin is manufactured by the Enterochromaffin cells (or, Kulchitsky cells) in the gastro-intestinal tract (GI)2,3. These cells live next to the gut epithelium, that covers the cavity of the GI tract, playing a crucial role in the regulation of bowel movements and secretions. If you think that the gut is almost 9 meters (or 30 feet) long, then that’s a lot of cells producing serotonin.
When in the 50’s, Betty M. Twarog and Irvine H. Page discovered that the brain produced its own serotonin4; then, the gut-made serotonin got reduced to its “Aschenputtel” origins, and relinquished to the favela quarters of the body. As such, brain-derived serotonin always got more attention than its gut-derived counterpart – like a rich vs. poor-cousin type of reputation.
Platelets, also called thrombocytes, are small un-nucleated fragment of cells that, when activated, form blood clots (thrombus) and prevent bleeding.
Platelets do not make serotonin, butcan take it up as they circulate through the gut, and carry it along the blood stream6,7. As such, the serotonin produced in the intestine can be carried all over the body. As the chemical messenger serotonin is, it can influence any other cell, in whatever other location, as long as it has a serotonin receptor on it. As such, peripheral serotonin has now discovered its path back into the limelight, and recent research has strengthened the influence that gut-made serotonin has in other parts of the body, functioning as an intestinal-derived hormone.
Once again, the “Aschenputtel” storycomes into mind, but this time through its “Cinderella” version. Let’s take a look…
For example, gut-derived serotonin can directly regulate the liver and mediate liver regeneration8. In Non-Alcoholic Fatty Liver Disease (NAFLD), a group of conditions that are characterized by excessive fat accumulation in the liver and closely track the global public health problem of obesity, researchers showed that inhibiting gut-derived serotonin synthesis could resolve hepatic fat accumulation8,9.
Peripheral serotonin can also be a negative regulator of bone density, by specifically inhibiting osteoblast formation and leading to osteoporosis10 – a common feature in patients with inflammatory bowel disease (IBD). This happens through the action of a common receptor: the low-density Lipoprotein Receptor-related Protein 5(LRP5), which is expressed in both osteoblasts and enterochromaffin cells11. LRP5 inhibits the expression of an important ingredient for serotonin production (Tryptophan hydroxylase-1, Tph1); as such, when LRP5 is deficient or inactivated due to inflammation or disease, blood levels of serotonin are elevated decreasing osteoblast formation; and, consequently, reducing bone mass1,11.
Epidemiologic data suggests a role of serotonin, or Selective Serotonin-Reuptake Inhibitors (typically used as antidepressants, SSRIs) in the development of venous thrombosis12. In fact, patients with depression were reported to have higher incidences of venous thromboembolism in general13; and, the use of SSRIs is associated with an increased venous thromboembolism risk14. No wonder, serotonin and platelets are “brothers in arms”, ready to block any blood vessel along their way….
Serotonin and its receptors are also present in the immune system, where evidence suggests it contributes to both innate and adaptive responses. There is now clear evidence of a straight communication between the immune system, the gut and the brain via serotonin15,16.
On top of all and because we are not alone, our gut microbiota plays a critical role in regulating our colonic serotonin. Indigenous spore-forming bacteria (Sp) promote serotonin biosynthesis in our enterochromaffin cells, and with that they can significantly modulate GI movements and platelet function – together with many aspects of our physiology17,18. We now know that the microbiota colonizes the GI tract after birth, with a continuous maturation during the first years of life19. Researchers have now showed in animal models that this developing gut microbiota regulates the development of the adult enteric nervous system via intestinal serotonin networks20. What this actually means, is that the actions of our intestinal bugs during the beginning of our life are determinant for the development of our “gut brain”, our second brain. How about that?…
If we ruminate about it, when we “think” with our gut, we are actually listening to our bugs. By directly signalling our cells to produce serotonin and develop a network of neurons as soon as we are born, our gut-bugs are actually finding a way to communicate with us – the host – in the serotonin language.
Now, we just need to understand what are they telling us…
1 Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes20, 14-21, doi:10.1097/MED.0b013e32835bc703 (2013).
2 Bellono, N. W. et al. Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways. Cell170, 185-198.e116, doi:10.1016/j.cell.2017.05.034 (2017).
3 Yaghoubfar, R. et al. Modulation of serotonin signaling/metabolism by Akkermansia muciniphila and its extracellular vesicles through the gut-brain axis in mice. Scientific Reports10, 22119, doi:10.1038/s41598-020-79171-8 (2020).
4 Twarog, B. M. & Page, I. H. Serotonin Content of Some Mammalian Tissues and Urine and a Method for Its Determination. American Journal of Physiology-Legacy Content175, 157-161, doi:10.1152/ajplegacy.19220.127.116.11 (1953).
5 Zilla, P. et al. Scanning electron microscopy of circulating platelets reveals new aspects of platelet alteration during cardiopulmonary bypass operations. Tex Heart Inst J14, 13-21 (1987).
6 Morrissey, J. J., Walker, M. N. & Lovenberg, W. The absence of tryptophan hydroxylase activity in blood platelets. Proc Soc Exp Biol Med154, 496-499, doi:10.3181/00379727-154-39702 (1977).
7 Hughes, F. B. & Brodie, B. B. The mechanism of serotonin and catecholamine uptake by platelets. J Pharmacol Exp Ther127, 96-102 (1959).
8 Wang, L. et al. Gut-Derived Serotonin Contributes to the Progression of Non-Alcoholic Steatohepatitis via the Liver HTR2A/PPARγ2 Pathway. Frontiers in Pharmacology11, doi:10.3389/fphar.2020.00553 (2020).
9 Choi, W. et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nature Communications9, 4824, doi:10.1038/s41467-018-07287-7 (2018).
10 Lavoie, B. et al. Gut-derived serotonin contributes to bone deficits in colitis. Pharmacol Res140, 75-84, doi:10.1016/j.phrs.2018.07.018 (2019).
11 Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell135, 825-837, doi:10.1016/j.cell.2008.09.059 (2008).
12 Rieder, M., Gauchel, N., Bode, C. & Duerschmied, D. Serotonin: a platelet hormone modulating cardiovascular disease. J Thromb Thrombolysis52, 42-47, doi:10.1007/s11239-020-02331-0 (2021).
13 Takeshima, M. et al. Prevalence of Asymptomatic Venous Thromboembolism in Depressive Inpatients. Neuropsychiatr Dis Treat16, 579-587, doi:10.2147/NDT.S243308 (2020).
14 Parkin, L. et al. Antidepressants, Depression, and Venous Thromboembolism Risk: Large Prospective Study of UK Women. J Am Heart Assoc6, doi:10.1161/jaha.116.005316 (2017).
15 Baganz, N. L. & Blakely, R. D. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci4, 48-63, doi:10.1021/cn300186b (2013).
16 Jacobson, A., Yang, D., Vella, M. & Chiu, I. M. The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunology14, 555-565, doi:10.1038/s41385-020-00368-1 (2021).
17 Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell161, 264-276, doi:10.1016/j.cell.2015.02.047 (2015).
18 Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. Faseb j29, 1395-1403, doi:10.1096/fj.14-259598 (2015).
19 Bäckhed, F. et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host Microbe17, 690-703, doi:10.1016/j.chom.2015.04.004 (2015).
20 De Vadder, F. et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci U S A115, 6458-6463, doi:10.1073/pnas.1720017115 (2018).
The gut microbiome is a community of microorganisms that lives in our gastrointestinal tract. It is so far, the most studied microbial community in healthy humans, because of its known role in a range of functions and diseases, like Inflammatory Bowel Disease (IBD)1,2.
To gain perspective on the magnitude of the bacterial presence inside of us, and potential effects on our bodies, the human body expresses 20,000 eukaryotic genes while the gut microbiome expresses 3.3 million prokaryotic genes. This suggests that the genetic contribution of the microbiome to humans may be many hundreds of times greater than the genetic contribution from the human genome.
Most of the microbes in the microbiome do not cause disease. In fact, we need them to perform many important functions that we cannot do ourselves. Microbes digest food to generate nutrients for host cells, synthesize vitamins, help to absorb nutrients and minerals, produce short-chain fatty acids, metabolize drugs, detoxify carcinogens, stimulate renewal of cells in the gut lining, and activate and support the immune system1.
The fermentation by-products acetate, propionate, and butyrate are important for gut health; and, provide energy for epithelial cells, enhance the integrity of the epithelial barrier, and provide immunomodulation and protection against pathogens1.
Current investigations explore resident bacterial gene function, and the potential role it might have in human health and metabolism. Each individual has its own microbiome, and no one common microbe is present in all body sites or all individuals.
Researchers identified the composition of different individual microbiomes, but they also identified the metabolic pathways of the microbial communities found in different body sites (e.g., skin, colon, liver…). What is interesting is that microbial membership diverges greatly between healthy individuals; but, the metabolic pathways of our own microbiomes is very similar, with common ‘housekeeping’ properties that maintain cell function and a functional body site ecosystem3,4.
The interactions between the gut microbiota and our bodies immune system begins at birth4. The microbiota shapes the development of the immune system; and, in turn, the immune system shapes the composition of the microbiota. This cross-talk between the microbes and our bodies is transmitted through a vast array of signaling pathways that involve many different classes of molecules, and extend upon multiple organs such as the gut, liver, muscle, and the brain. This creates axes of metabolic pathways, or highways of chemical communication, between the gut and the different organs in our bodies.
Because the gut microbiome is highly malleable, it can be altered throughout our lifespan by environmental factors, such as diet, stress and medication. What we have seen during the last 60 years, is an increaseincidence of gut dysbiosis, which is an imbalance in the intestinal bacteria that leads to disease.
As such, there is much interest in developing new therapeutic tools for manipulating the composition of the gut microbiota to benefit our health. A better understanding of how variations in this symbiotic relation within us, supraorganisms, will contribute to disease risk and health sustainability; and, will point the way to new therapeutic interventions and disease prevention strategies.
Danone, a leading yogurt multinational food corporation, is developing “precision probiotics”, for example. Researchers at Danone aim to tailor probiotics to an individual’s diet, phenotype, lifestyle, age, gender, genetics and microbiome. The intention it’s to bring to the gut activities or functions that are not provided by our own gut microbiome, or our own genes.
It’s funny that around 1920’s, Isaac Carasso, the creator of Danone, first started selling yogurt in pharmacies, using ferments isolated from the Institute Pasteur, and label it as health-food. It’s like going full circle.
It’s funny that this pandemic can prove all anti-evolutionists wrong.
Nothing like seeing Charles Darwin natural selection right in front of your eyes at the speed of light. Just look at the SARS-CoV-2 viral evolution…
In his book “On the origin of species” written in 1859, Charles Darwin defined natural selection as the “principle by which each slight variation of a trait, if useful, is preserved”. What does this mean (?), it means the individuals best adapted to their environments are more likely to survive and reproduce.
What we are seeing now, is that the mutations of SARS-CoV-2 that better promote spreading, are the ones that are becoming more common among the population, even when derived in different locations. The virus is changing and evolving to spread more rapidly, because natural selection will optimize the level of virulence that maximizes pathogen fitness – expressed as the basic reproductive number (R0)1,2.
On average, comparative data from previous studies tell us that, low-virulence infections have a greater chance of successfully establishing transmission cycles in humans than virus with higher mortality3. As such, as before, the virus actually just wants to spread and not kill.
But, since the environment also affects transmissibility, there are more factors on the equation “when will this madness end” than we would have wished for.
For example, in the evolutionary trade-off between virulence and transmissibility, because intra-host virus replication is needed to allow inter-host transmission, it is almost impossible for natural selection to optimize all traits simultaneously1 and give us some peace.
For example, in the case of the Myxoma virus (MYXV) in rabbits, this evolutionary trade-off leads to an ‘intermediate’ virulence being more advantageous to the virus than a higher virulence1,4. This happens because the rabbit host dies before inter-host transmission, in the case of higher virulence; and, with lower virulence the virus goes absolutely nowhere, because it does not increase virus transmission rates. A similar trade-off model has been proposed to explain the evolution of HIV virulence1,5.
Unfortunately, experimental studies in some viruses have shown that high virulence can promote certain advantages, as in the case of malaria, where a higher virulence was shown to provide the Plasmodium parasites with a competitive advantage within hosts1,6. Or, in the case of the rabbit haemorrhagic disease virus (RHDV), where there is evidence that virulence has increased through time, probably because virus transmission often occurs through flies that feed on animal carcasses, making host death selectively favourable1,7.
Let’s thank the Gods that SARS-CoV-2 is NOT transmissible through flies.
So, current evolutionary theory tells us that it is possible to anticipate the direction of virulence evolution, if the key relationship between virulence and transmissibility, and hence viral fitness, is understood1. Crucial to this is the analysis of the intersection between genomics and evolutionary studies, what is called phylogenomics.
This field of science provides a way to understand virulence evolution, and creates a number of hypotheses that can be tested using appropriate experimental cell assays and bioinformatic tools8,9.
The collaboration of public health and research teams worldwide has now allowed the publication of 620,338 SARS-CoV-2 genomes in GISAID (http://www.gisaid.org/) (as of February 25, 2020)9. At the same time, a dynamic nomenclature system for SARS-CoV-2 has been described to facilitate real-time epidemiology revealing links between global outbreaks that share similar viral genomes10. At the root of the phylogeny are two lineages, A and B; where, A is likely ancestral, as it shares two distinguishing variants with the closest known bat viruses. Further linage designations link new variants to geographically distinct populations, B.1 in the Italian outbreak, then other parts of Europe and the world; and, B.1.1 being the major European lineage which was spread throughout the world. However, many of the major lineages are now present in most countries, and recapitulate the global diversity of SARS-CoV-2, indicating that most local epidemics were seeded by a large number of independent introductions of the virus.
The current evolutionary tree of SARS-CoV-2 shows multiple introductions of different variants across the globe, with introductions from distant locations seeding local epidemics, where infections sometimes went unrecognized for several weeks and allowed wider spread11. The tree topology actually indicates that SARS-CoV-2 viruses have not diverged significantly since the beginning of the pandemic11. These results show that, so far, SARS-CoV-2 has evolved through a non-deterministic, noisy process; and, that random genetic drift has played the dominant role in disseminating unique mutations throughout the world11.
There remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to contain and mitigate the spread; and, the virus’s surface S (Spike) protein continues to be an attractive vaccine target,because it plays a key role in mediating virus entry into the cells, and is known to be immunogenic.
Of course, the virus was only recently identified in the human population with a short time frame relative to the adaptive processes that can take years to occur.
But, the most recent findings show us that the SARS-CoV-2 viruses that are currently circulating, constitute a homogeneous viral population, to which the current vaccines available will be sufficient to mitigate the spread.
Soon, SARS-CoV-2 will become just another viral acquaintance during the winter, like a common cold
1 Geoghegan, J. L. & Holmes, E. C. The phylogenomics of evolving virus virulence. Nature Reviews Genetics19, 756-769, doi:10.1038/s41576-018-0055-5 (2018).
2 Bull, J. J. & Lauring, A. S. Theory and empiricism in virulence evolution. PLoS Pathog10, e1004387, doi:10.1371/journal.ppat.1004387 (2014).
3 Geoghegan, J. L., Senior, A. M., Di Giallonardo, F. & Holmes, E. C. Virological factors that increase the transmissibility of emerging human viruses. Proc Natl Acad Sci U S A113, 4170-4175, doi:10.1073/pnas.1521582113 (2016).
4 Kerr, P. J. et al. Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype. Proceedings of the National Academy of Sciences114, 9397-9402, doi:10.1073/pnas.1710336114 (2017).
5 Fraser, C., Hollingsworth, T. D., Chapman, R., de Wolf, F. & Hanage, W. P. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A104, 17441-17446, doi:10.1073/pnas.0708559104 (2007).
6 de Roode, J. C. et al. Virulence and competitive ability in genetically diverse malaria infections. Proc Natl Acad Sci U S A102, 7624-7628, doi:10.1073/pnas.0500078102 (2005).
7 Di Giallonardo, F. & Holmes, E. C. Viral biocontrol: grand experiments in disease emergence and evolution. Trends Microbiol23, 83-90, doi:10.1016/j.tim.2014.10.004 (2015).
8 Stern, A. et al. The Evolutionary Pathway to Virulence of an RNA Virus. Cell169, 35-46.e19, doi:10.1016/j.cell.2017.03.013 (2017).
9 Sjaarda, C. P. et al. Phylogenomics reveals viral sources, transmission, and potential superinfection in early-stage COVID-19 patients in Ontario, Canada. Scientific Reports11, 3697, doi:10.1038/s41598-021-83355-1 (2021).
10 da Silva Filipe, A. et al. Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland. Nat Microbiol6, 112-122, doi:10.1038/s41564-020-00838-z (2021).
11 Dearlove, B. et al. A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains. bioRxiv, 2020.2004.2027.064774, doi:10.1101/2020.04.27.064774 (2020).
RNA Viruses, such as the SARS-CoV-2, HIV and Influenza, tend to pick up mutations rather quickly, once they are copied inside the cells of our bodies. This happens because the little cell workers that copy the RNA (called enzymes) are sloppy workers and prone to make errors.
The SARS-CoV-2 virus genetic code has just 30,000 nucleotides blocks of RNA, or letters that can spell at least 29 genes1; and, the most common mutations are single-nucleotide changes between viruses from different people, that have little effect on the overall performance of the virus infection rate, but that allow researchers to track the spread by linking closely-related viruses2.
In fact, sequencing data actually suggests that coronaviruses change more slowly than most other RNA viruses, because they have “proofreading” mechanisms that correct potentially fatal copying mistakes, accumulating only two single-letter mutations per month in its genome — a rate of change about half that of Influenza and one-quarter that of HIV2.
The problem is, that scientists can spot mutations faster than they can make sense of them, or what problems they may cause. Many mutations will have no consequence for the virus’s ability to spread or cause disease, because they do not alter the shape of a protein; whereas those mutations that do change proteins are more likely to harm the virus than improve it2. For example, in the beginning of the pandemic in Singapore, the ∆382 deletion made the infection of the virus milder3. On the contrary, the G614 variant showed a fitness advantage of infection, where individuals had a higher concentration of pseudotyped virions, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity4.
If we think about it, the virus just wants to spread, but not actually kill – because, if it kills, it can no longer spread.
More recently, a new SARS-CoV-2 virus variant showed up in the UK, where multiple spike protein mutations are seen (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H)5. Changes are also seen in other genomic regions, inclusively in the receptor binding domain (N501Y, “Nelly”).
The unusually high number of spike protein mutations suggests that the variant has not emerged through gradual accumulation of mutations6. Instead, one possible explanation for the emergence of the variant, is prolonged SARS-CoV-2 infection in a single patient, potentially with reduced immunocompetence, similar to what has previously been described7,8. Such prolonged infection in immunocompromised patients can lead to accumulation of immune-escape mutations at a higher rate.
This explanation is also suggested to the current SARS-CoV-2 virus variant found in Brazil (P.1)9, and in South Africa (501Y.V2)10.
Unfortunately, this shows that the emergence of successful variants with similar properties is not so rare6; and, just like the need to develop new influenza vaccines every season, that also might be the case for SARS-CoV-2. The persistence of the pandemic, may enable accumulation of immunologically relevant mutations in the population, even as vaccines are developed.
But, because science tries to be one step ahead, this is exactly what manufacturers are already working on, specifically the ones using mRNA technology that can quickly adapt their platforms to the current mutations seen.
1 Naqvi, A. A. T. et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim Biophys Acta Mol Basis Dis1866, 165878-165878, doi:10.1016/j.bbadis.2020.165878 (2020).
3 Young, B. E. et al. Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study. The Lancet396, 603-611, doi:10.1016/S0140-6736(20)31757-8 (2020).
4 Korber, B. et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell182, 812-827.e819, doi:10.1016/j.cell.2020.06.043 (2020).
A macrophage is a hungry immune cell that engulfs and eats all things that don’t have a good reputation in our body (e.g., cellular debris, pathogens…); and, microglia cells are the resident macrophage population of the Central Nervous System (CNS)1. They function as sentinels of local infection in the brain, backing both innate and adaptive immune responses, and account for 10-15% of all cells found in the brain and spinal cord2.
Microglia cells are also involved in the maintenance of brain homeostasis, contributing to mechanisms that underly learning and memory. They constantly survey their local microenvironment – like patrols – extending their motile processes, or hands/legs, to make a brief contact with neuronal synapses. This continuous synaptic plasticity, throughout our lifetime, is essential to control maladaptive learning and memory, such as addiction3. For example, the number of synapses in the brain regions of the nucleus accumbens, amygdala and dorsomedial striatum increase when we expose our brains to addictive substances (such as alcohol, or opiates); and, decrease upon withdrawal due to the action of microglia cells4. As such, microglia cells help to modify and eliminate synaptic structures when they grow too much, or, are on the way to touch too many other neurons5 – because, neurons tend to be touchy and to enjoy a synaptic orgy.
Whenever a neuron starts to freak out that it has too many synapses and it needs help regulating its neuronal “touchy” behaviour, then the synapse extends a greeting “hand” (filopodia) and “Hi5s” the neighbouring microglia cell, telling her that it needs help remodelling. Once “Hi5ed”, the microglia cell starts nibbling on the synapse6 – cutting all the excess – and, avoiding that that specific neuron gets assigned a bad “sexual” reputation. It’s like behaviour counselling, transforming and remodelling, but neuron-wise and with a microglia cell as the counsellor…
Even though microglia cells are essential and extremely helpful; like everything in life, they can also go haywire, ending up pruning too many synapses, and destroying healthy tissue. An uncontrolled activation of the microglia can be directly toxic to neurons, because they can release inflammatory cytokines (IL-1, TNF-alpha, IL-6, Nitric Oxide, Prostaglandine E2, and Superoxide)7, and lead to excessive pruning of neuronal synapses3.
The most recent research in the pathophysiology of depression and anxiety shows that abnormalities in microglia cells have a central role in the development of these diseases8. For example, a neuroimaging study in depressed patients, revealed that stronger depressive symptoms related with microglial activation in brain regions associated with mood regulation (the prefrontal, anterior cingulate, and insular cortices of the brain)9. Additionally, post-mortem studies of depressed suicide victims showed microglial activation and macrophage accumulation within the anterior cingulate cortex brain region10.
Persistent stress activates a chronic low-inflammatory state in our bodies that enhances our inflammatory response to challenges11. Social stress causes the release of inflammatory monocytes into the circulation8, which end up reaching the Blood Brain Barrier (BBB) and its endothelial cells. This low-systemic inflammation that travels through our vessels, encourages the migration of the brain resident microglia cells to the area of the cerebral vessels. In here, microglia cells make physical contact with endothelial cells of the BBB, and “sense” the inflammatory environment that is present in the blood (aka, inflammatory cytokines activate receptors in the microglia cells). If there is sustained inflammation, then some of the microglia cells can “become neurotic” and start nibbling the end-feet of healthy cells, making the BBB more permeable and, consequently, damaging the protective BBB shield function12. This is turn, leaks inflammatory cytokines from the blood into the brain tissue, further activating more microglia cells, that start cutting synapses from healthy neurons.
What this means is that a persistent low-grade inflammation can trigger microglia activation and change the functional connectivity of healthy neurons in major brain emotional centers13. Because our immune system can interact with the neurocircuitry that is involved in emotion regulation and behaviour, a chronic low-inflammation derived from stress can influence the development of various neuropsychiatric disorders, like depression and anxiety.
But, what can we do to avoid falling in this trap?
Eat well, sleep well, do sports and have a good laugh with friends. All things that inhibit inflammation, and make us feel good.
1. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Frontiers in Cellular Neuroscience. 2013;7
2. Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience. 1992;48:405-415
3. Neniskyte U, Gross CT. Errant gardeners: Glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18:658-670
4. Spiga S, Talani G, Mulas G, Licheri V, Fois GR, Muggironi G, et al. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats. Proc Natl Acad Sci U S A. 2014;111:E3745-3754
5. Tremblay M-È, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLOS Biology. 2010;8:e1000527
6. Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nature Communications. 2018;9:1228
7. Kim YS, Joh TH. Microglia, major player in the brain inflammation: Their roles in the pathogenesis of parkinson’s disease. Exp Mol Med. 2006;38:333-347
8. McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of il-1β-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421-1431
9. Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268-275
10. Suzuki H, Ohgidani M, Kuwano N, Chrétien F, Lorin de la Grandmaison G, Onaya M, et al. Suicide and microglia: Recent findings and future perspectives based on human studies. Frontiers in cellular neuroscience. 2019;13:31-31
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