From intestinal metabolites to the brain: Investigating the mysteries of Long COVID DOI Creative Commons

Shan Liu,

Ashwarya S. Devason, Maayan Levy

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

To date, more than 770 million individuals have been infected with SARS-CoV-2 worldwide.1 Postacute sequelae of COVID-19 (PASC), commonly called 'Long COVID', constitute a primary public health concern. Long COVID involves symptoms that emerge, persist, or relapse over 30 days after acute infection. The PASC span wide range organs and are heterogeneous among patients. A recent study aimed at developing comprehensive definition based on in prospective cohort involving 9764 patients.2 Given the intricacies PASC, underlying etiology remains poorly understood, posing an urgent global challenge necessitates resolution. We recently conducted may shed new light one possible biological causes PASC.3 This began exploring metabolite profiles distinct Among most significantly depleted metabolites observed postacute patients, compared to recovered was serotonin (5-hydroxytryptamine, 5-HT). Mouse models viral infection intestinal organoids model were employed elucidate molecular mechanisms this phenotype. found RNA triggered type I interferon (IFN) signalling, which turn suppressed levels by affecting production, storage degradation. Beyond establishing association between 5-HT elucidating potential connection, our further suggests decrease peripheral can lead impaired hippocampal responses memory impeding activity vagus nerve. findings investigation contribute understanding involved suggest predictive biomarkers therapeutic targets for intervention. reduction plasma identified through metabolomics analysis 58 symptom-free recovery 60 COVID-19. Consistent these human cohorts, SARS-CoV-2-infected K18-ACE2 mouse model, expresses ACE2. By using synthetic double-stranded polyinosinic:polycytidylic acid (poly(I:C)) infection, additionally revealed mediated viral-induced response TLR3- STAT1-dependent manner. next investigated inflammation leads (Figure 1). Notably, tryptophan, precursor is used as substrate synthesis enterochromaffin cells gastrointestinal tract, also diminished Using epithelial cells, we uncovered viral-driven inhibits tryptophan absorption suppressing expression amino uptake genes, such (Slc6a19), encodes neutral transporter B0AT1, its chaperone In addition suppression turnover. Following platelets store transport MAO enzymes rapidly free serotonin. platelet counts decreased following poly(I:C) treatment, suggesting carrying capacity systemic circulation diminished. could not be rescued supplementation, indicating independent reduced uptake. Lastly, transcription Maoa 5-hydroxyindoleacetic (5-HIAA), degradation product, increased virally poly (I:C)-treated mice. characterised spectrum including fatigue, cognitive difficulties, headaches, endurance loss, sleep disturbances, anxiety lapses. crucial role central nervous system function, sought explore physiological consequences depletion neurocognitive 2). Utilising exposed chronic infections, novel object recognition paradigm assess ability. treatment test. selective reuptake inhibitor (SSRI) fluoxetine restored function mice injected poly(I:C). Furthermore, supplementation 5-hydroxytryptophan (5-HTP) only reinstated but demonstrated reversal impairment. None interventions tested altered brain amidst inflammation, pivotal regulating function. How does communicate brain? neuronal brainstem poly(I:C)-treated during novelty exposure, involvement sensory neurons terminate region brain. impairment induced successfully reversed administration capsaicin, Trpv1 ligand potent stimulant neurons. Consistently, when chemogenetics selectively activate Phox2b-expressing vagal restoration neuron Further validation came from experiment pharmacological agonist receptors neurons, emphasised importance signalling nerve cognition. These results important nerve, key mediator sickness behaviour has implicated pathophysiology fatigue syndrome.4, 5 However, unravelling precise circuitry relay explored future research. Understanding complexities holds promise refining approaches address challenges SARS-CoV-2, low documented other conditions high interferons, lupus erythematosus multiple sclerosis, broader implications findings.6-8 Our eliminating trigger chronically elevated levels, restoring activation might clinical utility prevention COVID. efficiency approaches, however, first requires detailed evaluation. Dutch 95 patients showed significant SSRIs; randomised controlled trial.9 preprint detailing multicentre retrospective 17 933 National Cohort Collaborative (N3C) 26% relative risk who received SSRI unexposed controls.10 Extensive, double-blind, studies needed establish whether SSRIs targeting play managing long-term disease burden Serotonin alternative avenue, demanding rigorous formulation testing safety efficacy. Overall, proposes pathway linking persistence, sustained responses, dysfunction potentially postviral syndromes. emphasise necessity extensive investigations into PASC. Directly connection reservoirs inflammatory manifestations gap field, calling initiation large-scale investigate conditions. SL ASD performed literature research wrote manuscript. ML guided edited All authors contributed article approved submitted version. thank members Levy laboratory discussions input. supported NIH Director's New Innovator Award (DP2-AG-067511), American Cancer Society Scholar Award, , Searle Scholars Program, Edward Mallinckrodt, Jr. Foundation, W. Smith Charitable Trust, Burroughs Wellcome Fund, grants Abramson Center (P30-CA- 016420), PennCHOP microbiome program, Penn Nutritional Science Medicine, Coronavirus Center, Institute Immunology, Molecular Studies Digestive Liver Diseases (P30-DK- 050306), Precision Aging, Colton Excellence Environmental Toxicology (P30-ES 013508), Borrelli Family Pilot Grant Lynch Syndrome. Figures created BioRender.com. declare they no conflicts interest. Not applicable

Language: Английский

From intestinal metabolites to the brain: Investigating the mysteries of Long COVID DOI Creative Commons

Shan Liu,

Ashwarya S. Devason, Maayan Levy

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

To date, more than 770 million individuals have been infected with SARS-CoV-2 worldwide.1 Postacute sequelae of COVID-19 (PASC), commonly called 'Long COVID', constitute a primary public health concern. Long COVID involves symptoms that emerge, persist, or relapse over 30 days after acute infection. The PASC span wide range organs and are heterogeneous among patients. A recent study aimed at developing comprehensive definition based on in prospective cohort involving 9764 patients.2 Given the intricacies PASC, underlying etiology remains poorly understood, posing an urgent global challenge necessitates resolution. We recently conducted may shed new light one possible biological causes PASC.3 This began exploring metabolite profiles distinct Among most significantly depleted metabolites observed postacute patients, compared to recovered was serotonin (5-hydroxytryptamine, 5-HT). Mouse models viral infection intestinal organoids model were employed elucidate molecular mechanisms this phenotype. found RNA triggered type I interferon (IFN) signalling, which turn suppressed levels by affecting production, storage degradation. Beyond establishing association between 5-HT elucidating potential connection, our further suggests decrease peripheral can lead impaired hippocampal responses memory impeding activity vagus nerve. findings investigation contribute understanding involved suggest predictive biomarkers therapeutic targets for intervention. reduction plasma identified through metabolomics analysis 58 symptom-free recovery 60 COVID-19. Consistent these human cohorts, SARS-CoV-2-infected K18-ACE2 mouse model, expresses ACE2. By using synthetic double-stranded polyinosinic:polycytidylic acid (poly(I:C)) infection, additionally revealed mediated viral-induced response TLR3- STAT1-dependent manner. next investigated inflammation leads (Figure 1). Notably, tryptophan, precursor is used as substrate synthesis enterochromaffin cells gastrointestinal tract, also diminished Using epithelial cells, we uncovered viral-driven inhibits tryptophan absorption suppressing expression amino uptake genes, such (Slc6a19), encodes neutral transporter B0AT1, its chaperone In addition suppression turnover. Following platelets store transport MAO enzymes rapidly free serotonin. platelet counts decreased following poly(I:C) treatment, suggesting carrying capacity systemic circulation diminished. could not be rescued supplementation, indicating independent reduced uptake. Lastly, transcription Maoa 5-hydroxyindoleacetic (5-HIAA), degradation product, increased virally poly (I:C)-treated mice. characterised spectrum including fatigue, cognitive difficulties, headaches, endurance loss, sleep disturbances, anxiety lapses. crucial role central nervous system function, sought explore physiological consequences depletion neurocognitive 2). Utilising exposed chronic infections, novel object recognition paradigm assess ability. treatment test. selective reuptake inhibitor (SSRI) fluoxetine restored function mice injected poly(I:C). Furthermore, supplementation 5-hydroxytryptophan (5-HTP) only reinstated but demonstrated reversal impairment. None interventions tested altered brain amidst inflammation, pivotal regulating function. How does communicate brain? neuronal brainstem poly(I:C)-treated during novelty exposure, involvement sensory neurons terminate region brain. impairment induced successfully reversed administration capsaicin, Trpv1 ligand potent stimulant neurons. Consistently, when chemogenetics selectively activate Phox2b-expressing vagal restoration neuron Further validation came from experiment pharmacological agonist receptors neurons, emphasised importance signalling nerve cognition. These results important nerve, key mediator sickness behaviour has implicated pathophysiology fatigue syndrome.4, 5 However, unravelling precise circuitry relay explored future research. Understanding complexities holds promise refining approaches address challenges SARS-CoV-2, low documented other conditions high interferons, lupus erythematosus multiple sclerosis, broader implications findings.6-8 Our eliminating trigger chronically elevated levels, restoring activation might clinical utility prevention COVID. efficiency approaches, however, first requires detailed evaluation. Dutch 95 patients showed significant SSRIs; randomised controlled trial.9 preprint detailing multicentre retrospective 17 933 National Cohort Collaborative (N3C) 26% relative risk who received SSRI unexposed controls.10 Extensive, double-blind, studies needed establish whether SSRIs targeting play managing long-term disease burden Serotonin alternative avenue, demanding rigorous formulation testing safety efficacy. Overall, proposes pathway linking persistence, sustained responses, dysfunction potentially postviral syndromes. emphasise necessity extensive investigations into PASC. Directly connection reservoirs inflammatory manifestations gap field, calling initiation large-scale investigate conditions. SL ASD performed literature research wrote manuscript. ML guided edited All authors contributed article approved submitted version. thank members Levy laboratory discussions input. supported NIH Director's New Innovator Award (DP2-AG-067511), American Cancer Society Scholar Award, , Searle Scholars Program, Edward Mallinckrodt, Jr. Foundation, W. Smith Charitable Trust, Burroughs Wellcome Fund, grants Abramson Center (P30-CA- 016420), PennCHOP microbiome program, Penn Nutritional Science Medicine, Coronavirus Center, Institute Immunology, Molecular Studies Digestive Liver Diseases (P30-DK- 050306), Precision Aging, Colton Excellence Environmental Toxicology (P30-ES 013508), Borrelli Family Pilot Grant Lynch Syndrome. Figures created BioRender.com. declare they no conflicts interest. Not applicable

Language: Английский

Citations

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