Serum Phenylalanine, Myo-inositol, and 1,5-Anhydrohexitol biosignature differentiate neonatal sepsis cases from controls

Sepsis, a life-threatening multi-organ dysfunction by a dysregulated host response, is one of the leading causes of mortality in neonates. Current microbiology-based sepsis diagnosis is time-consuming, and identifying serum metabolite markers may help develop early screening tools and host-directed therapeutics. A set of 131 neonates (age 41.2% female) were classified as culture-positive or negative sepsis cases (CP, CN) and controls (no sepsis: NS and healthy) based on microbial culture and mass spectrometry results. Most of the sepsis cases were due to Acinetobacter baumannii, and serum samples were collected at the time of presentation and at follow-up time points responding to the treatment. Serum samples were grouped as discovery (n=71) and validation (n=60) sets and analyzed using gas chromatography and mass spectrometry (GC-MS). A set of 882 metabolic features was identified, and molecules with a fold change>1.5, VIP score> 1.0, and t-test p-value<0.05 were identified as important molecules. Signatures of myo-inositol with phenylalanine and myo-inositol with 1,5-anhydrohexitol showed a predictive accuracy of 0.84 and 0.79, respectively, to differentiate CP and CN from HC. Interestingly, the longitudinally followed-up CP and CN sepsis patients completing therapeutic intervention showed a comparable abundance of myo-inositol and phenylalanine to the healthy control levels. These deregulated metabolites contributed by the perturbed metabolic pathways in the immune cells or affected multiple organs of sepsis patients. They could be further explored for their potential as diagnostic and therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Department of Biotechnology (DBT), Government of India. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Ethics Committee of International Centre for Genetic Engineering and Biotechnology, New Delhi, gave ethical approval for this work (ICGEB/IEC/2021/28, version 2). The Institutional Ethics Committee of All India Institute of Medical Sciences, New Delhi, gave ethical approval for this work (IEC-1074/06.11.20, RP-28/2020). The Institutional Ethics Committee of Vardhman Mahavir Medical College (VMMC) and Safdarjung Hospital, New Delhi, gave ethical approval for this work (IEC/VMMC/SJH/Project/2021-05/CC-157, dated 24.07.2021). The Institutional Ethics Committee of Dr. Baba Saheb Ambedkar Medical College and Hospital, New Delhi, gave ethical approval for this work (5(32)/2020/BSAH/DNB/PF, dated 31.08.2020). The Institutional Ethics Committee of Lady Hardinge Medical College, New Delhi, gave ethical approval for this work (LHMC/IEC/2022/03/30). The Institutional Ethics Committee of the University College of Medical Sciences & Guru Teg Bahadur Hospital, New Delhi, gave ethical approval for this work (IECHC-2022-51-R1, dated 07.12.2022). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.