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