The value of prospective metabolomic susceptibility endotypes: broad applicability for infectious diseases

Yulu Chen; Kevin Mendez; Sofina Begum; Emily Dean; Haley Chatelaine; John Braisted; Vrushali D Fangal; Margaret Cote; Mengna Huang; Su H Chu; Meryl Stav; Qingwen Chen; Nicole Prince; Rachel Kelly; Kenneth B Christopher; Joann Diray-Arce; Ewy A Mathé; Jessica Lasky-Su

doi:10.1016/j.ebiom.2023.104791

The value of prospective metabolomic susceptibility endotypes: broad applicability for infectious diseases

EBioMedicine. 2023 Oct:96:104791. doi: 10.1016/j.ebiom.2023.104791. Epub 2023 Sep 19.

Authors

Yulu Chen¹, Kevin Mendez¹, Sofina Begum¹, Emily Dean¹, Haley Chatelaine², John Braisted², Vrushali D Fangal¹, Margaret Cote¹, Mengna Huang¹, Su H Chu¹, Meryl Stav¹, Qingwen Chen¹, Nicole Prince¹, Rachel Kelly¹, Kenneth B Christopher³, Joann Diray-Arce⁴, Ewy A Mathé⁵, Jessica Lasky-Su⁶

Affiliations

¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Division of Preclinical Innovation, National Center for Advancing Translational Science, National Institutes of Health, Rockville, MD, USA.
³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Division of Preclinical Innovation, National Center for Advancing Translational Science, National Institutes of Health, Rockville, MD, USA. Electronic address: ewy.mathe@nih.gov.
⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: rejas@channing.harvard.edu.

Abstract

Background: As new infectious diseases (ID) emerge and others continue to mutate, there remains an imminent threat, especially for vulnerable individuals. Yet no generalizable framework exists to identify the at-risk group prior to infection. Metabolomics has the advantage of capturing the existing physiologic state, unobserved via current clinical measures. Furthermore, metabolomics profiling during acute disease can be influenced by confounding factors such as indications, medical treatments, and lifestyles.

Methods: We employed metabolomic profiling to cluster infection-free individuals and assessed their relationship with COVID severity and influenza incidence/recurrence.

Findings: We identified a metabolomic susceptibility endotype that was strongly associated with both severe COVID (OR_ICUadmission = 6.7, p-value = 1.2 × 10^-08, OR_mortality = 4.7, p-value = 1.6 × 10^-04) and influenza (OR_incidence = 2.9; p-values = 2.2 × 10^-4, β_recurrence = 1.03; p-value = 5.1 × 10^-3). We observed similar severity associations when recapitulating this susceptibility endotype using metabolomics from individuals during and after acute COVID infection. We demonstrate the value of using metabolomic endotyping to identify a metabolically susceptible group for two-and potentially more-IDs that are driven by increases in specific amino acids, including microbial-related metabolites such as tryptophan, bile acids, histidine, polyamine, phenylalanine, and tyrosine metabolism, as well as carbohydrates involved in glycolysis.

Interpretations: These metabolites may be identified prior to infection to enable protective measures for these individuals.

Funding: The Longitudinal EMR and Omics COVID-19 Cohort (LEOCC) and metabolomic profiling were supported by the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.

Keywords: COVID-19 severity; Electronic medical records; Endotypes; Mass general brigham biobank; Metabolomics; Similarity network fusion.

MeSH terms

COVID-19*
Communicable Diseases* / etiology
Humans
Influenza, Human* / epidemiology
Metabolome
Metabolomics
Prospective Studies

Grants and funding

K01 HL153941/HL/NHLBI NIH HHS/United States