Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis.

Serge Nataf,Laurent Pays

doi:10.3390/ijms221910440

Abstract

For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.

Highlights

The incidence of neurological manifestations in patients with COVID-19 is raising increasing concerns regarding the acute and long-term impacts of SARS-CoV2 on the central nervous system (CNS)
Only scattered data indicate that enterocytes, a non-endocrine cell type, express a full range of molecules supporting the metabolism of L-DOPA, dopamine and/or trace amines
Protein Atlas confirmed that enterocytes of the small intestine robustly express angiotensin-1 converting enzyme 2 (ACE2), SLC6A19 and the 12 other proteins we identified as molecules of interest due to their involvement in the metabolism of dopamine and/or trace amines (Figure 1)

Summary

Introduction

The incidence of neurological manifestations in patients with COVID-19 is raising increasing concerns regarding the acute and long-term impacts of SARS-CoV2 on the central nervous system (CNS). Irrespective of the considered hypotheses, getting further insights into the pathophysiology of COVID-associated neuropsychiatric symptoms requires a deepening of our knowledge on the potential functions exerted by the human SARS-CoV2 receptor angiotensin-1 converting enzyme 2 (ACE2) on the control of cognition and behavior. In this context, we previously reported that, across a large number of microarray datasets exploring essentially non-neural tissues, dopa-decarboxylase (DDC) is the human gene exhibiting the closest co-expression link with ACE2 [17]. Only scattered data indicate that enterocytes, a non-endocrine cell type, express a full range of molecules supporting the metabolism of L-DOPA, dopamine and/or trace amines

Methods

Results

Discussion

Conclusion