ABSTRACT The human body hosts tens of trillions of microbes, which number is 10 times greater than the number of human body cells. The collection of these human-associated microbes and their genomes is called the “human microbiome”. More than 90% of these microbes live in the gastrointestinal (GI) tract, representing 500 species on average. With the development of high-throughput sequencing technology and bioinformatics tools (e.g., 16S ribosomal RNA or 16S rRNA sequencing and shotgun metagenomics analysis), recent progress has been made to elaborate the critical role that the gut microbiome is playing in human health and disease. A significant disruption (dysbiosis) of the composition and function of the gut microbiome is associated with carcinogenesis, chemotherapeutic metabolism, and treatment-related symptom toxicities. The current state of the science on the gut microbiome in cancer has been only recently starting in animal models and adults and has not been well investigated in children diagnosed and treated for cancer, nor with associations with cancer treatment-related toxicities. This proposed study will explore the hypothesis that dysbiosis of the gut microbiome is associated with cancer treatment-related GI and psychoneurological symptoms. In order to test our hypothesis, this K99/R00 proposal will execute three specific aims: Aim 1 will characterize the longitudinal changes of the gut microbiome in children aged 7-18 years with solid tumors as compared with their healthy siblings using 16S rRNA sequencing during the K99 Phase; the R00 Phase will focus on two specific aims: Aim 2 will screen specific microbial species and pathogens in children with cancer and healthy siblings following 16S rRNA gene sequencing using whole- genome shotgun metagenomics analysis; and Aim 3 will examine associations between the gut microbiome and GI and psychoneurological symptoms in children with solid tumors throughout chemotherapy based on a conceptual model of the microbiome-gut-brain axis, using 16S rRNA sequencing and shotgun metagenomics analysis. With respect to my expertise and productive research projects in children with cancer, current and future trainings, research mentoring and motivations, and the very supportive research environment, I will be prepared to lead this proposed project. Our findings will help identify potential biological mechanisms underlying symptoms of cancer treatment, and will lead to potentially precise targets for interventions (e.g., prebiotic and probiotic supplementations). This proposal includes cutting-edge approaches such as 16s rRNA sequencing, big data QIIME 2 analytics and whole-genome shotgun metagenomics with the innovative use in cancer treatment-related GI and psychoneurological symptoms and a testable conceptual microbiome-gut-brain axis framework. In summary, the K99/R00 grant represents a unique opportunity for me to learn new approaches and develop my professional skills to successfully transition into an independent nurse scientist focusing on the biopsychosocial mechanisms (i.e., gut microbiome) of symptom science in pediatric oncology.

PUBLIC HEALTH RELEVANCE STATEMENT Gastrointestinal and psychoneurological symptoms are frequently reported among children with solid tumors throughout the trajectory of cancer treatments, which may result in treatment delays, declines in drug dosage and tumor response, as well as significant decrease in a child's quality of life over the active treatment period and into survivorship. Based on hypothesis of the microbiome-gut-brain axis, the gut microbiome provides an avenue to communicate between the gut and brain, as well as between the brain and gut, and may play a critical role in the gastrointestinal and psychoneurological symptoms in children receiving chemotherapy. The proposed study may identify alterations of gut microbiome profiles as an underlying biological mechanism associated with gastrointestinal and psychoneurological symptoms in children with solid tumors that can be used to develop precision health interventions to reduce symptom burden, enhance quality of life, and possibly prevent or reverse the symptom toxicities and adverse heath outcomes associated with cancer diagnosis and its treatment.