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Serotonin is elevated in COVID-19-associated diarrhoea
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  1. Seeun Ha1,
  2. Byungchang Jin1,
  3. Brooke Clemmensen1,
  4. Paul Park1,
  5. Sumaiya Mahboob2,
  6. Vadim Gladwill2,
  7. Farah Madhani Lovely3,
  8. Andres Gottfried-Blackmore4,
  9. Aida Habtezion4,
  10. Subhash Verma5,
  11. Seungil Ro1
  1. 1Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, USA
  2. 2Internal Medicine, University of Nevada School of Medicine, Reno, Nevada, USA
  3. 3Pulmonary and Critical Care Medicine, Renown Health, Reno, Nevada, USA
  4. 4Gastroenterology and Hepatology, Stanford University Department of Medicine, Stanford, California, USA
  5. 5Microbiology and Immunology, University of Nevada School of Medicine, Reno, Nevada, USA
  1. Correspondence to Dr Seungil Ro, Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557-0046, USA; sro{at}unr.edu

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We read with great interest the recent publication by Lin et al,1 which reported diarrhoea as the most common GI symptom in patients with COVID-19. Diarrhoea as a symptom of COVID-19 has been commonly observed,2 3 but the cause remains unknown.

Diarrhoea occurs from excessive production of serotonin (5-hydroxytryptamine, 5-HT) in the GI tract.4 Ninety-five per cent of 5-HT is produced and released from the enterochromaffin cells within the epithelium of the GI tract. 5-HT localised to the GI tract is a key modulator of GI peristalsis.5 We hypothesised that plasma 5-HT levels are increased in patients with COVID-19 with diarrhoea.

Table 1 summarises the COVID-19 severity, interleukin 6 (IL-6), IgM/IgG antibodies, fever, GI symptoms, plasma 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), underlying diabetes, body mass index, gender and age measured in 80 patients with COVID-19 (10 patients with diarrhoea) and 18 healthy donors (see online supplemental material). Correlation analysis identified 5-HT, 5-HIAA and IL-6 as the most noticeable features in the COVID-19 cohort with diarrhoea. Patients with COVID-19 had significantly increased plasma 5-HT and 5-HIAA levels compared with healthy donors (figure 1A,D). When patients were categorised by disease severity, 5-HT and 5-HIAA levels increased with higher severity of symptoms (figure 1B,E). Patients with COVID-19 with diarrhoea had substantially higher 5-HT and 5-HIAA levels compared with patients without diarrhoea and the healthy group (table 1 and figure 1C,F). Diarrhoea was present in 10 of 80 cases with COVID-19, and all 10 cases with diarrhoea had elevated 5-HT and 5-HIAA levels (figure 1C,F). The ratio of 5-HIAA to 5-HT was significantly lower in those with critical symptoms (figure 1G) and was substantially lower in those with diarrhoea compared with healthy donors or patients without diarrhoea (figure 1H and table 1). A Spearman’s rank correlation matrix showed that 5-HT and 5-HIAA levels were correlated with diarrhoea (0.81 and 0.80; p=0.0017 and p=0.0021), but the 5-HIAA to 5-HT ratio was negatively correlated (−0.43; p=0.0094) (figure 1I). Additionally, 5-HT, 5-HIAA, 5-HIAA to 5-HT ratio and diarrhoea were also highly correlated with IL-6 (0.51, 0.47, –0.48, 0.47; p=0.0078, p=0.0092, p=0.0087, p=0.0089, respectively) and symptom severity (0.58; p=0.0065) (figure 1I).

Supplemental material

Table 1

Clinical characteristics of patients with COVID-19 with GI symptoms

Figure 1

Profiles of plasma 5-HT and 5-HIAA in patients with COVID-19 with different severity and diarrhoea. (A–C) Plasma levels of 5-HT in a group of healthy individuals (n=18) and patients with COVID-19 (n=80) (A), in a group of healthy individuals and patients with COVID-19 with asymptomatic, mild, severe and critical conditions (B), and in a group of healthy individuals and patients with COVID-19 with and without diarrhoea (with diarrhoea n=10, without diarrhoea n=70) (C). (D–F) Plasma levels of 5-HIAA in a group of healthy individuals (n=18) and patients with COVID-19 (n=80) (D), in a group of healthy individuals and patients with COVID-19 with asymptomatic, mild, severe and critical conditions (E), and in a group of healthy individuals and patients with COVID-19 with and without diarrhoea (F). (G and H) Comparison of plasma 5-HIAA to 5-HT ratio in patients with COVID-19 with different severity and in a group of healthy individuals (G) and patients with COVID-19 with and without diarrhoea (H). (I) Correlation matrix of severity, fever, IL-6, 5-HT, 5-HIAA and GI symptoms in patients with COVID-19. Correlation matrix shows the Spearman’s rank correlation among severity (asymptomatic, 1; mild, 2; severe, 3; critical, 4), fever, IL-6, 5-HT and GI symptoms (diarrhoea, abdominal pain, nausea, vomiting and GI bleeding) in patients with COVID-19 (n=80). A correlation number of 1.0 or −1.0 indicates 100% of patients with a positive (blue) or negative (red) correlation. Statistical analysis was performed with two-way analysis of variance. P<0.05 was considered significant (*p<0.05, **p<0.01). 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; IL-6, interleukin 6.

5-HT synthesised and released from the enterochromaffin cells is an important GI signalling molecule that regulates GI motility and inflammation.5 Released 5-HT is taken up by enterocytes in the gut and platelets in the blood via the serotonin reuptake transporter and metabolised by the liver and kidney to its metabolite 5-HIAA, which is eventually excreted to urine.6 5-HT and 5-HIAA levels are stable in plasma, serving as useful markers to study patients with IBS.7 Increased 5-HT in the gut leads to diarrhoea in patients with IBS-D.8 GI symptom studies in patients with COVID-19 have shown diarrhoea is common.9 In the present study, we found elevated 5-HT and 5-HIAA levels in patients with COVID-19 are correlated with diarrhoea. Interestingly, the diarrhoea group (0.73; p=0.0409) had a significantly lower ratio of 5-HIAA to 5-HT than the non-diarrhoea (1.2) and healthy donor (1.3; p=0.1105) groups (table 1). This finding suggests 5-HT in the diarrhoea group remains elevated due to delayed or insufficient breakdown to 5-HIAA. In addition, our data indicate 5-HT and 5-HIAA levels are positively correlated with a proinflammatory cytokine IL-6, which is an essential pathogenic cytokine for COVID-19 severity.10 IL-6 levels were substantially higher in patients with diarrhoea (102.7; p=0.0384) compared with patients without diarrhoea (67.4) or healthy donors (4.9; p=0.0003) (table 1).

In summary, we found 5-HT levels are markedly elevated in COVID-19-associated diarrhoea. Elevated 5-HT levels in diarrhoea are also correlated with increased IL-6. These data suggest increased 5-HT may contribute to diarrhoea and the severity of COVID-19.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • SH and BJ contributed equally.

  • Contributors SH, BJ and SR designed the research. SH, BJ and SR analysed and generated the data. PP, SM, VG, FML, AG-B and AH obtained and analysed COVID-19 and healthy donor blood samples and clinical data. SH, BJ, BC and SR wrote the paper. SR revised the paper. All authors have approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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