Reverse metabolomics for the discovery of chemical structures from humans.

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

Screening for Chemotherapy-induced Peripheral Neuropathy and Utilization of Physical Therapy in Pediatric Patients Receiving Treatment for Hematologic Malignancies.

Physical therapy (PT) has been shown to be a helpful intervention in the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Our aim was to screen for CIPN in patients with hematologic malignancies receiving vincristine chemotherapy and obtain a baseline assessment on the percentage of patients utilizing PT in the treatment of CIPN. A retrospective review of surveys administered to parents and patients regarding the severity of peripheral neuropathy symptoms from October 2016 through March 2018 was conducted. Of 116 patients, a total of 102 patients (67 male and 35 female; 4 to 10 y of age, N=63; 11 to 15 y of age, N=19; 16 to 20 y of age, N=20) were eligible for the study, with 67.6% (N=69) reporting symptoms of CIPN. Of these patients, 16.7% scored 4 or greater on the surveys, suggesting clinically severe CIPN. Common parental concerns included decreased strength, difficulty walking up stairs, tripping, and foot drops. Approximately 55.1% of the 69 patients who reported CIPN symptoms were referred to outpatient PT, while 44.9% were not referred. A simple survey consisting of 4 questions that only took several minutes to administer was capable of identifying CIPN in 67.6% of patients receiving vincristine chemotherapy.