The language of serotonin

Or, “What are they saying?

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.

Moving-on…

Platelets, also called thrombocytes, are small un-nucleated fragment of cells that, when activated, form blood clots (thrombus) and prevent bleeding. 

Electron microscopy images of circulating platelets, extracted from Zilla et al, 19875

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” story comes 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… 

Beethoven’s hearing aids, Beethoven House Museum, Bonn.

References:

1          Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 20, 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. Cell 170, 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 Reports 10, 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 Content 175, 157-161, doi:10.1152/ajplegacy.1953.175.1.157 (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 J 14, 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 Med 154, 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 Ther 127, 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 Pharmacology 11, doi:10.3389/fphar.2020.00553 (2020).

9          Choi, W. et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nature Communications 9, 4824, doi:10.1038/s41467-018-07287-7 (2018).

10        Lavoie, B. et al. Gut-derived serotonin contributes to bone deficits in colitis. Pharmacol Res 140, 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. Cell 135, 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 Thrombolysis 52, 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 Assoc 6, 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 Neurosci 4, 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 Immunology 14, 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. Cell 161, 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 j 29, 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 Microbe 17, 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 A 115, 6458-6463, doi:10.1073/pnas.1720017115 (2018).

Let’s get physical!

A healthy lifestyle is the cornerstone of cardiovascular health.

Lifestyle interventions are already a key component of primary prevention in low-risk cardiovascular disease groups, and serve as an important aide to pharmacotherapy in higher-risk groups. 

But according to the new guidelines by the American Heart Association (AHA) and the American College of Cardiology (ACC)1, a first line of therapy for mild to moderate–risk groups are lifestyle-only approaches for a proper blood pressure and blood cholesterol management.

As such, the next time you go to the doctor, you might get an exercise prescription instead of an order to visit the pharmacy. 

This is a major change in the idea of health, promoted by not taking a pill, but having a look at lifestyle in order to improve health – and avoid the numerous side-effects that certain medications can have. 

An exercise prescription is an individualized physical activity program designed using the Frequency (how often?), Intensity (how hard?), Time (how long?), and Type (what kind?), or the FITT principle developed by the American College of Sports Medicine (ACSM). 

Although most health care professionals and patients are aware that physical activity is recommended for good health, the abundance of scientific and lay recommendations for activity can be difficult to distil. As such, framing the exercise prescription by the FITT principle provides clinicians with more structured guidance on how to recommend exercise to their patients. 

The updated FITT exercise recommendations for adults with elevated blood pressure are the following: 

  • Frequency: in most, preferably all days of the week due to the transient Blood Pressure lowering effects that last for up to 24 hours after an exercise session; 
  • Intensity: Moderate, any intensity of exercise has been shown to lower Blood Pressure;
  • Time: >20 to 30 minutes per day to total >90 to >150 minutes per week of continuous or accumulated exercise of any duration;
  • Type: Emphasize aerobic or resistance exercise alone or combined, due to the recent evidence showing the Blood Pressure lowering effects of exercise do not vary by exercise modality2

The updated FITT exercise prescription recommendations propose more exercise options in less time, that hopefully will translate to better exercise adherence.

As a plus, we should be reminded of the advantageous effects of exercise on brain functions. Acute bouts of physical activity can stimulate transient Serotonin, Dopamine and Norepinephrine activity in the brain3

Furthermore, long-term exercise produces changes in the availability of receptors that can control the release of monoamines, like the Serotonin-1A receptor of the Raphe Nuclei4, and Dopamine-2 receptor in the Striatum5

Regular exercise has antidepressant/anxiolytic properties, and results in dramatic alterations in physiological stress responses. 

In addition to antidepressant and anxiolytic properties, the Serotonin system (5-HT) has also been linked to cognitive function; since, a distress of the 5-HT system is associated with cognitive syndromes, such as Alzheimer’s disease6

So, don’t shy away, and take at least a 20 min quick walk today. 

It’s free, and it’s good for you!

My boots were made for walking!

References:

1          Gibbs, B. B. et al. Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How?: A Scientific Statement From the American Heart Association. Hypertension 0, HYP.0000000000000196, doi:doi:10.1161/HYP.0000000000000196.

2          Pescatello, L. S. et al. Physical Activity to Prevent and Treat Hypertension: A Systematic Review. Med Sci Sports Exerc 51, 1314-1323, doi:10.1249/mss.0000000000001943 (2019).

3          Buhr, T. J. et al. The Influence of Moderate Physical Activity on Brain Monoaminergic Responses to Binge-Patterned Alcohol Ingestion in Female Mice. Front Behav Neurosci 15, 639790-639790, doi:10.3389/fnbeh.2021.639790 (2021).

4          Greenwood, B. N. et al. Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J Neurosci 23, 2889-2898, doi:10.1523/jneurosci.23-07-02889.2003 (2003).

5          Clark, P. J. et al. Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors. Behav Brain Res272, 252-263, doi:10.1016/j.bbr.2014.07.006 (2014).

6          Meltzer, C. C. et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 18, 407-430, doi:10.1016/s0893-133x(97)00194-2 (1998).

Feeling anxious or depressed? Might be your microglia…

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 accumbensamygdala 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 prefrontalanterior 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. 

Microglia cell (green) “counselling” a synapse

References:

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

11.       Miller GE, Rohleder N, Cole SW. Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later. Psychosom Med. 2009;71:57-62

12.       Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H, Hashimoto A, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nature communications. 2019;10:5816-5816

13.       Kim J, Yoon S, Lee S, Hong H, Ha E, Joo Y, et al. A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms. Nature Communications. 2020;11:1898