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.


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.


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).

Stroke or heart infarct?

According to a recent study by Daghlas and colleagues1, compared to sleeping 6 to 9 h/night, short sleepers have a 20% higher risk of having a heart attack; but, if you are a long sleeper (i.e., sleeping >9h/night), than your chances are even worse, because your risk increases to 34%. Even though the researchers don’t know the underlying cause for such susceptibilities, they claim sleeping too much or too little boosts inflammation in the body, which is associated with the development of heart disease. If you have a genetic predisposition for heart disease, this study found that sleeping between 6-9h, actually reduces your risk of having a heart attack by 18%, which is actually very good news, since not only diet and exercise can help you keep your heart healthy. More and more data, supports the evidence that we should consider sleep to be an adjustable and controllable risk factor for our good heath status2.

Speaking of diet, another study published recently in the Journal of the American Heart Association by Hyunju Kim and his team3, showed that healthy plant‐based diets, which are higher in whole grains, fruits, vegetables, nuts, legumes, tea, and coffee, and lower in animal foods, were associated with a lower risk of cardiovascular disease mortality and all‐cause mortality. Of course, they didn’t explore if the quality of plant foods (either healthy plant foods, or less-healthy plant foods) within the “framework of plant‐based diets” would be associated with cardiovascular disease and all‐cause mortality in the general population.

But, what is intriguing is that, another recent study by Tammy Tong and colleagues4, examined the associations of vegetarianism with risks of ischemic heart disease (i.e., coronary artery disease) and stroke. The results of this study showed that vegetarians had 20% higher rates of total stroke than meat eaters – which was equivalent to 3x more cases of stroke over 10 years; and, the associations for stroke did not soothe after adjustments to other disease risk factors. As the authors of the study say, vegetarian and vegan diets have become increasingly popular in recent years, partly due to perceived health benefits, as well as concerns about the environment and animal welfare; but, what the evidence suggests, is that vegetarians might have different disease risks compared with non-vegetarians. The study group of vegetarians and vegans in this cohort had lower circulating levels of several nutrients (e.g., vitamin B12, vitamin D, essential amino acids, and long chain n-3 polyunsaturated fatty acids), and differences in some of these nutritional factors could contribute to the increased stroke risk. Not only that, but a number of studies in Japan5, 6, showed that individuals with very low intake of animal products, also had an increased incidence and mortality from hemorrhagic and total stroke, implying that some factors connected with animal food intake might be protective for stroke. 

Its like Yin and Yang from ancient Chinese philosophy. Rather than opposing, or standing at the sides, our health and life is made of complementary forces that interact to form a dynamic system. It’s all about balance and balancing the sides (and diets).

All in life is balance
Balancing life’s way


1.         Daghlas I, Dashti HS, Lane J, Aragam KG, Rutter MK, Saxena R and Vetter C. Sleep Duration and Myocardial Infarction. Journal of the American College of Cardiology. 2019;74:1304-1314.

2.         Tobaldini E, Fiorelli EM, Solbiati M, Costantino G, Nobili L and Montano N. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat Rev Cardiol. 2019;16:213-224.

3.         Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J and Rebholz CM. Plant-Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality in a General Population of Middle-Aged Adults. J Am Heart Assoc. 2019;8:e012865.

4.         Tong TYN, Appleby PN, Bradbury KE, Perez-Cornago A, Travis RC, Clarke R and Key TJ. Risks of ischaemic heart disease and stroke in meat eaters, fish eaters, and vegetarians over 18 years of follow-up: results from the prospective EPIC-Oxford study. BMJ. 2019;366:l4897.

5.         Kinjo Y, Beral V, Akiba S, Key T, Mizuno S, Appleby P, Yamaguchi N, Watanabe S and Doll R. Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan. J Epidemiol. 1999;9:268-74.

6.         Sauvaget C, Nagano J, Allen N, Grant EJ and Beral V. Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study. Int J Epidemiol. 2003;32:536-43.

Underwater banquet!

Cabal, is a term defined in the Merriam-Webster dictionary, as the contrived scheme of a group of persons secretly united in a plot (as to overturn a government, for example). 

But, if you talk in terms of Biology, cabals are also a series of synergistic venom peptides essential for the capture of prey. One animal venom can be a complex mixture of 10-200+ short chains of amino acids linked by bonds (peptides), working in a concerted mode to regulate physiological function, with very potent and precise molecular targets1.

For example, cone snails, a small venomous marine mollusk that hunts fish and worms, has ~850 species identified, with each expressing many thousands of unique peptides that selectively target a diverse range of voltage- and ligand-gated ion-channels, transporters and G-protein couple receptors2

These tiny wonders of nature have the ability to switch between predatory and defensive venom regimes. For example, if they just want to stunt a predator causing a flaccid paralysis, they will produce venom that has high levels of muscle blockers (motor cabal), and that inhibit sodium channels and nicotinic acetylcholine receptors. But, if in the mean time, they change their minds and intend to eat the prey, they use a combination of peptides that cause a rigid paralysis. This lightning-strike cabal has excitatory peptides that inhibit potassium channels and delay inactivation of sodium channels, causing the prey to lie “dead” until it is happily digested in an underwater banquet.

But, how does the cone snail decide whether it is fear or hunger that it’s “feeling” in that moment?

The simple neuronal circuit of the cone snail shifts from a contented state of inertia, to an active motion, stimulated by internal hunger and an appetite stimulus – just like us, slushing from the couch to the fridge looking for our night prey… The hunting activity of the Conus is then organized by a basic set of behavioral transitions. Once the cone snail detects a fish, through sensory signals, it becomes much more active and moves towards the fish extending its rostrum– a massive funnel formed by the muscular walls of the snail sheath; and, a long, thin trunk extends out in the open, where a harpoon-like tooth shoots out to pierce the skin of the fish3 – imagine if we could actually do the same to that bag of cookies that is lying in the shelve right next to the couch.

The active feeding of the cone snail tends to inhibit the avoidance, and the snail changes to a prevention mood once its appetite is satisfied4

Cone snail


1.         Angell Y, Holford M and Moos WH. Building on Success: A Bright Future for Peptide Therapeutics. Protein Pept Lett. 2018;25:1044-1050.

2.         Himaya SWA, Mari F and Lewis RJ. Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals. Sci Rep. 2018;8:330.

3.         Olivera BM, Seger J, Horvath MP and Fedosov AE. Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution. Brain Behav Evol. 2015;86:58-74.

4.         Gillette R and Brown JW. The Sea Slug, Pleurobranchaea californica: A Signpost Species in the Evolution of Complex Nervous Systems and Behavior. Integr Comp Biol. 2015;55:1058-69.