Tag: health

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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).

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Precision: the new Tinder Belle of the Heart

Precision medicine is an emerging approach to medical care.  It takes into account individual variations in genetic make-up, metabolism and other biological and environmental factors, to better determine which treatment and prevention strategies for a particular disease may work better for which groups of people1.

Today, precision medicine is routinely integrated into the care of cancer patients, and has provided substantial increases in cancer free survival2. For example, translational studies investigating signatures within the tumour that promote disease progression, can predict individual responses to standard and targeted chemotherapy regimens2,3.

In the cardiovascular field, even though the prognosis for people with heart failure has improved in recent decades as research studies demonstrate the effectiveness of various medications, precision medicine is still in its infancy.

Some aspects of precision medicine are routinely used by healthcare providers, like the blood level of the biomarker called B-type natriuretic peptide, which is a sensitive indicator of whether heart failure is worsening or if treatments are helping1,4. This biomarker can also help the doctor determine whether shortness of breath symptoms in an individual are due to heart failure, or another medical problem1.

But as it is now, patients diagnosed with heart failure are still offered essentially identical treatments, regardless of whether their disease was caused by coronary artery disease, genetic mutations, or an autoinflammatory processes2. 

Also, historically, clinical trial participants have been predominantly white people with particular genetic variants; but, individuals with different racial and ethnic ancestry have different genetic variants, and therefore, may not have the same response to a certain medication or treatment1.

While this “one-size-fits-all’ approach has led to improvements in clinical outcomes in large populations, the individual response rates continue to vary tremendously; and, it is often difficult to distinguish patients who will achieve a favourable response, from those who will experience disease progression, and ultimately succumb to their illness2.  

As such, in the cardiovascular field, it is urgent to personalize heart failure care by identifying groups of patients more likely to develop heart failure, and tailoring which medications and other therapies could be most effective for them1. Currently, many individuals are left poorly treated, and there is substantial room for improvement2.

Key studies demonstrating selective efficacy of certain drugs in patients harbouring specific genetic variants, indicate a direction where treatment responses can be predicted using individual genetic information. 

Given the recent cost reductions in exome sequencing, for example, this can now be used routinely to identify genetic variants that predict heart failure prognosis, and specific responses to medical and device-based therapies. Such information can further provide critical insights into new disease mechanisms, like Lamin A mutations that display a molecular phenotype that is dramatically distinct from other forms of dilated cardiomyopathy5. 

More and more we come to realize that despite a common surface phenotype or symptomology, certain mutations may actually give rise to distinct diseases that need to be appropriately treated.

As such, researchers need to increase clinical trial diversity, so that optimal treatment approaches can be found for each population group. Also, the power of supercomputing should be used to rapidly predict the outcomes of possible new treatments. And, processes for sharing information across large databases shouldbe put in place with guarantees of patient privacy (e.g., cloud-based platforms), so that clinicians/scientists can quickly collaborate and share data internationally.

Moreover, updated health-wearable devices, artificial intelligence and other deep learning technologies strategies will ultimately be employed to develop testable hypotheses from large datasets, and provide precision-personalized approaches to cardiovascular health care.

Let’s hope Precision will be more than a one night stand on Heart’s Tinder list….

Yayoi Kusama art installation, Berlin Modern Art Museum

References:

1          AHA. Emerging practice of precision medicine could one day improve care for many heart failure patients. Heart.org https://newsroom.heart.org/news/emerging-practice-of-precision-medicine-could-one-day-improve-care-for-many-heart-failure-patients?utm_campaign=sciencenews19-20&utm_source=science-news&utm_medium=phd-link&utm_content=phd09-12-19 (2019).

2          Kory J. Lavine, C. E. C. Precision Medicine for Heart Failure: using “omics” technologies to find the road to personalized care. Heart.org https://professional.heart.org/en/science-news/heart-failure-in-the-era-of-precision-medicine/Commentary (2021).

3          Prasad, V., Fojo, T. & Brada, M. Precision oncology: origins, optimism, and potential. Lancet Oncol. https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(15)00620-8 17, e81-e86, doi:10.1016/s1470-2045(15)00620-8 (2016).

4          Maisel, A. B-Type Natriuretic Peptide Levels: Diagnostic and Prognostic in Congestive Heart Failure. Circulation. https://www.ahajournals.org/doi/10.1161/01.CIR.0000019121.91548.C2 105, 2328-2331, doi:doi:10.1161/01.CIR.0000019121.91548.C2 (2002).

5          Cheedipudi, S. M. et al. Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy. Circ Res. https://pubmed.ncbi.nlm.nih.gov/30739589/ 124, 1198-1213, doi:10.1161/circresaha.118.314177 (2019).

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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).

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Skin microbiome: feed it right for a healthier look!

Dry skin and atopic dermatitis have been associated with changes in the variety of the skin microbiome. 

Our skin, as the largest organ in our body, has a huge array of commensal microbes that support a healthy skin barrier. One of those is Staphylococcus epidermidis, one of the most abundant bacterial species of the skin microbiome1.

This chubby mutualistic, Gram-positive, facultative anaerobe constitutes up to 90% of the aerobic resident flora of our skin, and has been associated with a healthy-looking skin2. It does not like to be lonely, and usually appears in pairs or tetrads on the surface of our skin, like a protecting biofilm.

Dry skin, for example, is associated with an increase in microbial diversity along with a decrease in microbial load in comparison to more sebaceous areas of the skin, that are usually populated by lipophilic bacteria such as Cutibacterium acnes – that tend to cause those unwanted teenager-look-a-like pimples that nobody likes…

Lactic Acid is one of the Natural Moisturizing Factors (NMF) of the skin barrier, that is essential to maintain the hydration and a slightly acidic pH of the skin surface (i.e., “acid mantle”)3. Higher lactic acid concentrations and lower skin surface pH are known to increase our epidermal renewal and promote a healthier skin. 

New in vitro data suggests that Staphylococcus epidermidis, may be one of the major sources of lactic acid in the skin1. 

But only if fed the right way. 

It seems that 1% colloidal oat increases Lactic Acid production by this particular bacteria species, making it rely less on simple sugars such as glucose for its metabolism; and, instead use more complex carbohydrates derived from oat.

Oatmeal-containing skin moisturisers significantly changed the metabolism of the Staphylococcus epidermidis, breaking down starch and promoting good gene expression, with an increased DNA and aminoacid synthesis, and an improved ATP metabolism.

How about that?

Bacteria on a diet makes your skin look healthier!

Next time you think about which moisturiser to buy in the drug store:  don’t forget to feed your skin microbiome it’s oatmeal!

Happy Staphys!

References:

1          Liu-Walsh, F. et al. Prebiotic Colloidal Oat Supports the Growth of Cutaneous Commensal Bacteria Including S. epidermidis and Enhances the Production of Lactic Acid. Clin Cosmet Investig Dermatol 14, 73-82, doi:10.2147/CCID.S253386 (2021).

2          Baviera, G. et al. Microbiota in healthy skin and in atopic eczema. Biomed Res Int 2014, 436921, doi:10.1155/2014/436921 (2014).

3          Thueson, D. O., Chan, E. K., Oechsli, L. M. & Hahn, G. S. The roles of pH and concentration in lactic acid-induced stimulation of epidermal turnover. Dermatol Surg 24, 641-645, doi:10.1111/j.1524-4725.1998.tb04221.x (1998).