Genome Gut microbiome mediated epigenetic regulation of brain disorder and application of machine learning for multi- omics data analysis Journal: Genome Manuscript ID gen-2020-0136.R1 Manuscript Type: Mini Review Date Submitted by the 25-Sep-2020 Author: Complete List of Authors: Kaur, Harpreet; University of North Dakota School of Medicine and Health Sciences, Department of Biomedical Science Singh, Yuvraj; University of Calgary Faculty of Science, Department of Biological SciencesDraft Singh, Surjeet; University of Lethbridge, Department of Neuroscience, Canadian Centre for Behavioural Neuroscience (CCBN) Singh, Raja; University of Alberta, Faculty of Medicine and Dentistry; University of Calgary Cumming School of Medicine Gut-brain axis, epigenetics, neurodegenerative diseases, Machine Keyword: learning, Microbiota Is the invited manuscript for consideration in a Special Genome Biology Issue? : © The Author(s) or their Institution(s) Page 1 of 46 Genome 1 Gut microbiome mediated epigenetic regulation of brain disorder and application of 2 machine learning for multi-omics data analysis 3 4 Harpreet Kaur1*#, Yuvraj Singh2#, Surjeet Singh3, Raja B Singh4,5 5 1Department of Biomedical Sciences, School of Medicine and Health Sciences, University of 6 North Dakota, Grand Forks, ND, USA 7 2Department of Biological Sciences, Faculty of Science, University of Calgary, Alberta, Canada 8 3Department of Neuroscience, Canadian Centre for Behavioural Neuroscience (CCBN), 9 University of Lethbridge, Lethbridge, AB, Canada 10 4Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada 11 5Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada 12 13 # equal contribution 14 15 Draft 16 17 18 19 20 21 *Corresponding author: 22 Harpreet Kaur, PhD 23 Department of Biomedical Sciences 24 School of Medicine and Health Sciences 25 University of North Dakota 26 Grand Forks, ND, 58202, USA. 27 E-mail address: [email protected] 28 1 © The Author(s) or their Institution(s) Genome Page 2 of 46 29 Abstract 30 The gut-brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) 31 and enteric nervous system (ENS). Clinical and experimental evidence suggests gut microbiota as 32 a key regulator of GBA. Microbes living in the gut, not only interact locally, with the intestinal 33 cells and ENS, but have also been found to modulate CNS through neuroendocrine and metabolic 34 pathways. Studies have also explored the involvement of gut microbiota dysbiosis in depression, 35 anxiety, autism, stroke, and pathophysiology of other neurodegenerative diseases. Recent reports 36 suggest that microbe-derived metabolites can influence host metabolism by acting as epigenetic 37 regulators. Butyrate, an intestinal bacterial metabolite is a known histone deacetylase inhibitor that 38 has shown to improve learning and memoryDraft in animal models. Due to high disease variability 39 amongst the population, a multi-omics approach that utilizes artificial intelligence and machine 40 learning to analyze and integrate omics data is necessary to better understand the role of GBA in 41 pathogenesis of neurological disorders, generate predictive models and develop precise and 42 personalized therapeutics. This review examines our current understanding of epigenetic 43 regulation of GBA and proposes a framework to integrate multi-omics data for prediction, 44 prevention and development of precision health approaches to treat brain disorders. 45 46 47 48 49 Key words: Gut-brain axis, epigenetics, neurodegenerative diseases, Alzheimer’s disease, 50 Machine learning 2 © The Author(s) or their Institution(s) Page 3 of 46 Genome 51 Introduction 52 A biochemical link exists between the central nervous system (CNS) and the enteric nervous 53 system (ENS) of the body, which is known as the gut-brain axis (GBA) (Sharon et al. 2016). In 54 fact, ENS is often referred to as the “second brain” based on its size, complexity, and similarity in 55 producing neurotransmitters and signaling molecules alike brain (Mayer 2011). ENS produces 56 more than 30 neurotransmitters most of which are identical to the ones found in CNS, such as 57 acetylcholine, dopamine, and serotonin. This complex network of communication consists of CNS, 58 ENS and the autonomic nervous system (ANS), where ANS with the sympathetic and 59 parasympathetic limbs, drives both afferent signals, arising from the lumen and transmitted though 60 enteric, spinal and vagal pathways to CNS,Draft and efferent signals from CNS to the intestinal wall 61 (Carabotti et al. 2015). The ENS also consists of a complex peripheral neural circuit embedded 62 within its wall comprising sensory neurons, motor neurons, and interneurons (Foster et al. 2017). 63 It is estimated that the human ENS consists of some 500 million neurons which are about five 64 times the neurons present in human spinal cord. It can independently regulate the basic 65 gastrointestinal (GI) functions (i.e., motility, mucous secretion, and blood flow), but the central 66 control of gut functions is provided by vagal and, to a lesser extent, spinal motor inputs that serve 67 to coordinate gut functions with the general homeostatic state of the organism (Mertz 2003). It is 68 believed that brain can influence enteric system indirectly, via changes in gastrointestinal motility 69 and secretion, and intestinal permeability, or directly, via the signaling molecules which are 70 released from intestinal cells (enterochromaffin cells, neurons, immune cells) into the gut lumen 71 (Rhee et al. 2009). Likewise, there are multiple ways by which gut can influence brain, most 72 commonly through neural, endocrine, immune and humoral pathways (Sherman, Zaghouani, & 73 Niklas, 2a015) (Figure 1). Multiple studies have suggested the role of GBA in health and disease 3 © The Author(s) or their Institution(s) Genome Page 4 of 46 74 ranging from psychiatric disorders (e.g. anxiety, depression) to neurological and 75 neurodevelopmental disorders including autism, Alzheimer’s (AD), Parkinson’s disease etc. Gut 76 microbiota also plays a significant role in epigenetic modifications such as DNA methylation, 77 histone modifications which have known to influence brain and behavior. Recent advancements 78 in multi-omics data integration and analysis provides an opportunity for comprehensive 79 investigation of gut microbiota and its contribution to host health (Tilocca et al. 2020). 80 Gut microbiome 81 Research in the past decade has shown that gut microbiota is a key regulator of gut-brain axis (de 82 la Fuente-Nunez et al. 2018; Mittal et al. 2017). Gut microbiota refers to the total of all 83 microorganisms that live in the gastrointestinalDraft tract and includes not just bacteria, but also other 84 microbes such as fungi, archaea, viruses and protozoans (Sekirov et al. 2010). It is considered as 85 the largest reservoir of microbes in the human body, containing about 1014 microbes (Sender et al. 86 2016). These microbes maintain a symbiotic relationship with gut mucosa and impart metabolic, 87 immunological and gut protective function in host. The collective genomes of the microorganisms 88 in any given environment i.e. microorganism plus their set of genes is known as the microbiome 89 (Ursell et al. 2013). But the term “microbiome” is often used interchangeably with microbiota 90 (Ursell et al. 2012). Among the four most dominant phyla in the gut microbiota, Firmicutes and 91 Bacteroidetes accounts for 90% of the total population and Actinobacteria and Proteobacteria 92 accounting for less than 1–5%, the alteration in the balance of these phyla is known as dysbiosis, 93 which has been suggested to link with several disease including intestinal and extra-intestinal 94 diseases (Rogers et al. 2016; Tamboli et al. 2004). In recent times, interest within the scientific 95 community has focused on the role of gut microbiota in human disease ranging from 96 inflammatory bowel diseases (IBD) and irritable bowel syndrome, metabolic diseases such obesity 4 © The Author(s) or their Institution(s) Page 5 of 46 Genome 97 and diabetes, allergic disease to neurodevelopmental illnesses (Jandhyala et al. 2015). In 98 recognition of fundamental involvement of commensal microbes in important functions such as 99 human development, immunity and nutrition, NIH launched the human microbiome project (HMP) 100 in 2007. The primary goal of HMP was to study the functional contributions of microbial 101 communities to human health and disease. This 10 year project was divided into two phases where 102 the phase I (HMP 1) was designed to conduct a survey of microbial communities from five major 103 habitats of the human body (oral, skin, nares, gastrointestinal tract, and urogenital tract) and to 104 evaluate whether a characteristic microbial community was associated with a specific host health 105 status (Team 2019). The second phase of HMP (HMP 2), was designed to create an integrated 106 dataset of the biological properties of both the microbiome and host over time, in a series of disease 107 cohorts, as a resource for the broader researchDraft community. The analysis of HMP data has revealed 108 a high degree of microbial community specialization as well as considerable variation in overall 109 microbiome composition between individuals. The study provided a vast knowledge in the field, 110 including development of reference sequences, multi-omic data sets, computational and statistical 111 tools, and analytical and clinical protocols