Inflammatory Bowel Disease (IBD)
IBD – comprised of Crohn’s disease (CD) and ulcerative colitis (UC) – is a chronic inflammatory disease with growing prevalence in the Western world. It is believed to arise from a combination of genetic susceptibility and environmental factors that trigger an inappropriate mucosal inflammatory response. A role for the microbiome in the pathogenesis of IBD has been suggested by studies demonstrating alterations in the composition and function of the intestinal microbiome in IBD patients compared to healthy controls. This is consistent with the results of genome-wide association studies, which have found that many IBD-associated genes are involved in mucosal host-microbe interactions, and animal studies demonstrating resistance to colitis in many experimental models in the absence of a microbiome.
Current Research Projects
Microbiome studies of IBD patients have largely focused on microbial composition. The Braun laboratory utilizes a multi’omic approach encompassing analysis of the microbiome, metabolome, and proteome to elucidate the functional properties of intestinal microbes in IBD patients. Microbial function is placed in the context of variation in human genetics and disease phenotype / penetrance. Dr. Braun serves as the PI of the CCFA Microbiome Initiative and participates in the NIDDK IBD Genetics Consortium and NIH Human Microbiome Project 2.
- Tong M, McHardy I, Ruegger P, Goudarzi M, Kashyap PC, Haritunians T, Li X, Graeber TG, Schwager E, Huttenhower C, Fornace AJ Jr, Sonnenburg JL, McGovern DP, Borneman J, Braun J. Reprograming of gut microbiome energy metabolism by the FUT2 Crohn’s disease risk polymorphism. ISME J. 2014 Nov;8(11):2193-206. doi: 10.1038/ismej.2014.64. PMID: 24781901
- McHardy IH, Goudarzi M, Tong M, Ruegger PM, Schwager E, Weger JR, Graeber TG, Sonnenburg JL, Horvath S, Huttenhower C, McGovern DP, Fornace AJ Jr, Borneman J, Braun J. Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships. Microbiome. 2013 Jun 5;1(1):17. doi: 10.1186/2049-2618-1-17. PMCID: 3971612
- McHardy IH, Li X, Tong M, Ruegger P, Jacobs J, Borneman J, Anton P, Braun J. HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota.
Microbiome. 2013 Oct 12;1(1):26. doi: 10.1186/2049-2618-1-26. PMID: 24451087
The Jacobs Laboratory is investigating whether dysbiosis – i.e. altered composition and function of the intestinal microbiome – precedes the development of inflammatory bowel disease (IBD). The intestinal microbiome and metabolome were studied in a cohort of high-risk families with pediatric IBD. Dysbiosis was observed in IBD patients in clinical remission and in a subset of their healthy first degree relatives. This microbial state was associated with alterations in bioactive intestinal metabolites that affect immune activity and epithelial function. The significance of dysbiosis in healthy relatives of IBD patients is being further explored using humanized gnotobiotic mice to determine whether dysbiosis confers increased susceptibility to experimental IBD. Dysbiosis in individuals at risk for IBD may arise due to genetic variants that disrupt regulation of the microbiome by the mucosal immune system. This possibility is being studied with a combination of human studies to identify genetic variants associated with microbial composition and knockout/transgenic mice to validate a causal relationship between candidate IBD-associated genes and microbial composition.
- Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS Letters. 588(22):4102-11, 2014.
- Jacobs J, Braun J. Host genes and their effect on the intestinal microbiome garden. Genome Med. 6(12):119, 2014.
- Jacobs et al. Disease-associated enterotypes and metabotypes in families with pediatric inflammatory bowel disease. Gastroenterology. 148:S-190, 2015. [DDW abstract]
Dr. Hon Wai Koon’s research is focused on the synthetic mechanism and roles of the antimicrobial peptide Cathelicidin in inflammatory bowel disease, intestinal infections, colorectal cancer, obesity, and diabetes. Cathelicidin is a natural endogenous anti-microbial peptide that is protective to its host as a part of innate immune system. Our laboratory was the first to show that endogenous cathelicidin ameliorates dextran sulfate (DSS) colitis via bone marrow-derived immune cells. We also found increased expression of cathelicidin in monocytes/macrophages in the colonic mucosa of ulcerative colitis patients. Cathelicidin-deficient mice develop more severe bacterial penetration into intestinal mucosa and associated intestinal inflammation than wild-type mice. Therefore, we understand that endogenous cathelicidin may be a protective response to intestinal infection and inflammation. Moreover, intracolonic administration of the cathelicidin peptide ameliorates C. difficile-mediated colitis in mice. We are now studying the role of cathelicidin in the change of intestinal microflora in the development of obesity and diabetes. Dr. Koon is now investigating the role of a non-peptide cathelicidin-mimic, Ceragenin CSA13, in the protection against intestinal inflammation, C. difficile infection, obesity, and diabetes. This protection may be related to change of intestinal microflora. CSA13 is more chemically stable than natural cathelicidin and may be suitable for clinical use. Our research establishes a new direction of research in digestive diseases using microflora study, clinically relevant human primary cells, fresh intestinal biopsies, biologically induced colitis animal models, and system biology approaches.
Dr. Sang Hoon Rhee not only focuses on studying the important genetic and microbial factors causing IBD, but also on deciphering an underlying molecular mechanism. We recently found that the amount of Bacteroides acidifaciens was substantially increased in the fecal microbiome of the mice suffering from colonic inflammation. Conversely, targeting the bacteria provided protective effects against the inflammatory condition in an animal model of IBD. These observations indicate some important role of Bacteroides acidifaciens in the development and progress of colonic inflammation. Therefore, our laboratory investigates how Bacteroides acidifaciens would regulate the disease condition and what specific components of the bacteria could be involved in developing the disease.
Irritable Bowel Syndrome and Brain Gut Disorders
While bidirectional communication between the nervous system and the gut have been well established, it has only been during the past few years that preclinical evidence for an important role of the gut microbiota in this dialogue has emerged. In a series of high impact publications, evidence for a role of the gut microbiota in the modulation of nociceptive, affective, social and ingestive behaviors in mice has been demonstrated. Some studies have also identified changes in brain signaling systems associated with observed behavioral alterations. While the majority of these studies has identified such behavioral abnormalities in germfree animals, others have shown that modification of the adult microbiome by antibiotics, probiotics and fecal transplantation can alter behaviors as well. A small number of human studies suggests a possible relationship between gut microbes, brain function and emotion. Basic and translational studies are needed to determine to what degree the observed rodent findings translate to alterations of the human brain gut axis (such as irritable bowel syndrome) and of the human brain (including anxiety, depression, autism, Parkinson’s disease).
Current Research Projects
The Brain Gut Microbiome Program, Oppenheimer Center for Neurobiology of Stress
The Brain Gut Microbiome Program of the Oppenheimer Center for Neurobiology of Stress (CNS) aims to characterize the relationship of the gut microbiota and their metabolites with structural and functional brain signatures in healthy subjects and in patients with irritable bowel syndrome and inflammatory bowel diseases. These aims are based on findings observed in rodent models, and initial studies by center investigators demonstrating cross sectional correlations between brain signatures, gut microbial composition and certain metabolites. In addition, ongoing studies aim to determine the effects of mind based therapies (cognitive behavioral therapy, mindfulness based stress reduction) on gut microbial composition and function. These efforts are supported by several grants from the NIDDK and local pilot funds. Center investigator have published a landmark study in 2013 demonstrating for the first time in humans that regular ingestion of a probiotic mix can alter the brain’s reactivity to an emotional stimulus.
- Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013 Jun;144(7):1394-401, 1401.e1-4. PMCID: PMC3839572.
- Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015 Mar 2;125(3):926-38. Review. PMCID: PMC4362231.
- Mayer EA, Labus JS, Tillisch K, Cole SW, Baldi P. Towards a systems view of IBS. Nat Rev Gastroenterol Hepatol. 2015 Aug 25. [Epub ahead of print] Review.
Lin Chang, MD
Director, Functional GI Disroders Program, UCLA Oppenheimer Family Center for Neurobiology of Stress; Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Lin Chang, MD, is a Professor of Medicine in the Department of Medicine, Division of Digestive Diseases, at the David Geffen School of Medicine at UCLA. She serves as the Co-Director of the Center for Neurobiology of Stress at the David Geffen School of Medicine at UCLA. She is also Director of the Digestive Health and Nutrition Clinic at UCLA. Dr. Chang’s clinical expertise is in functional gastrointestinal disorders which include irritable bowel syndrome (IBS), chronic constipation, and functional dyspepsia. Dr. Chang’s research is focused on the pathophysiology of IBS related to stress, sex differences, and neuroendocrine alterations and the treatment of IBS. She is a funded NIH-investigator studying the central and peripheral mechanisms underlying IBS.
She is the recipient of the Janssen Award in Gastroenterology for Basic or Clinical Research and the AGA Distinguished Clinician Award, Dr. Chang has authored more than 70 original research articles, 48 review articles, and 19 book chapters on her specialty interests and is a frequent speaker at national and international meetings. She is a fellow of the American Gastroenterological Association and American College of Gastroenterology, and a member of the Society for Neuroscience. Dr. Chang serves as an Associate Editor of the American Journal of Gastroenterology. She is a member of the Rome Foundation Board of Directors, the Rome IV Editorial Board and the Rome IV Functional Bowel Disorders Committee. She is President of the American Neurogastroenterology and Motility Society (ANMS). She served on the FDA GI Advisory Committee from 2005-2010 which she also chaired.
Omai Garner, PhD
Assistant Professor, Pathology & Laboratory Medicine, UCLA
Dr. Omai Garner is a Health Sciences Assistant Clinical Professor and Associate Director of Clinical Microbiology in the UCLA Health System. He received his PhD from UC San Diego in Biomedical Sciences. He was a Postdoctoral Clinical Microbiology CPEP Fellow in the Department of Pathology at UCLA, and a former McNair Scholar. Dr. Garner is Board Certified by the American Board of Medical Microbiology. Dr. Garner’s research focuses on novel Point of Care Devices for infectious disease diagnosis in the developing world. Dr. Garner was always taught that science, at its best, is a collaborative process. “It is collaboration, and not competition, which produces the most significant advances in biomedical research.” He also serves as the Chairman of the Board for the Social Justice Learning Institute of Inglewood, California.
Relevant Recent Publications
- Cellphone-Based Hand-Held Microplate Reader for Point-of-Care Testing of Enzyme-Linked Immunosorbent Assays.
Berg B, Cortazar B, Tseng D, Ozkan H, Feng S, Wei Q, Chan RY, Burbano J, Farooqui Q, Lewinski M, Di Carlo D, Garner OB, Ozcan A.
ACS Nano. 2015 Aug 25;9(8):7857-66
- Comparison of the Vitek MS and Bruker Microflex LT MALDI-TOF MS platforms for routine identification of commonly isolated bacteria and yeast in the clinical microbiology laboratory.
Deak E, Charlton CL, Bobenchik AM, Miller SA, Pollett S, McHardy IH, Wu MT, Garner OB.
Diagn Microbiol Infect Dis. 2015 Jan;81(1):27-33.
- Detection of human viral pathogens: conventional versus molecular approaches.
Wu MT, Garner OB.
MLO Med Lab Obs. 2014 Jul;46(7):8, 10-2; quiz 14
Elaine Y. Hsiao, PhD
Assistant Professor, Department of Integrative Biology and Physiology, De Logi Chair in Biological Sciences, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA
Dr. Elaine Y. Hsiao is an Assistant Professor in the Department of Integrative Biology & Physiology at UCLA, where she leads a laboratory studying fundamental interactions between the microbiome, brain and behavior, and their applications to neurological disorders. Her studies on the relationships between the microbiota, immune system and nervous system led her to discover that the microbiota can regulate behavioral, metabolic and gastrointestinal abnormalities relevant to autism spectrum disorder (ASD). Her work in this area, and on neuroimmune interactions in autism, has led to several honors, including the National Institutes of Health Director’s Early Independence Award, distinction as Forbes’ 30 Under 30 in Science and Healthcare, National Geographic’s Emerging Explorer Award and fellowships from the National Institute of Mental Health and Autism Speaks. Inspired by this interplay between the microbiota and nervous system, the Hsiao laboratory is mining the human microbiota for microbial modulators of host neuroactive molecules, investigating the impact of microbiota-immune system interactions on neurodevelopment and examining the microbiome as an interface between gene-environment interactions in neurological diseases.
Relevant Recent Publications
- Yano JM, Yu K, Donaldson G, Shastri G, Ma L, Ann P, Nagler C, Ismagilov RF, Mazmanian SK, Hsiao EY (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161:264-76.
- Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH*, Mazmanian SK* (2013) The microbiota modulates behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155:1451-1463.
- Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS 109:12776-81
Jonathan Jacobs, MD, PhD
Assistant Professor-in-Residence, Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Dr. Jonathan Jacobs is an Assistant Professor-in-Residence in the Division of Digestive Diseases within the UCLA Department of Medicine. His research background is in immunology and the intestinal microbiome. He originally trained under Diane Mathis and Christophe Benoist at Harvard, where he published three first author papers on the immunopathological mechanisms of arthritis in an autoantibody-mediated model. He later joined Jonathan Braun’s lab at UCLA to investigate the interactions of the mucosal immune system and the intestinal microbiome in inflammatory bowel disease (IBD). He utilized human cohorts and transgenic mice to demonstrate that the IBD-associated genes RORC and TL1A, both involved in mucosal immunity, garden the intestinal microbiome. This raises the possibility that genetic risk factors promote IBD through their effects on the microbiome. An ongoing human cohort study with Dr. Braun aims to define the microbial and metabolomics features of IBD in the colonic mucosa and to characterize their relationship to IBD-associated genetic polymorphisms. In a separate translational study, he found that healthy relatives of pediatric IBD patients could be classified by their intestinal microbial and metabolomics profiles into “enterotypes” and “metabotypes” that may predict their future risk for IBD. He has authored a review article, a commentary, and two textbook chapters on intestinal host-microbiome interactions. His current research employs in vivo models and multi’omics analysis of IBD cohorts to define the role of IBD-associated genes in shaping the intestinal microbiome and to identify microbial products that promote IBD.
Relevant Recent Publications
- Jacobs JP, Lin L, Goudarzi M, Ruegger P, McGovern DPB, Fornace AJ, Borneman J, Xia L, Braun J. Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency. Gut Microbes. 2017 Jan; 8(1):1-16.
- Jacobs JP, Goudarzi M, Singh N, Tong M, McHardy IH, Ruegger P, Asadourian M, Moon B, Ayson A, Borneman J, McGovern DPB, Fornace AJ, Braun J, Dubinsky M. A Disease-associated Enterotype and Metabotype in Healthy Relatives of Pediatric Inflammatory Bowel Disease Patients. Cellular and Molecular Gastroenterology and Hepatology. 2016 Nov; 2(6):750-66.
- Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS Letters. 2014 Nov; 588(22):4102-11.
Complete Publications List
Swapna Joshi, PhD
Assistant Project Scientist, Center for Systems Biomedicine; Oppenheimer Center for Neurobiology of Stress; David Geffen School of Medicine at UCLA
Dr. Swapna (Mahurkar) Joshi received her undergraduate and Master’s degree in Genetics at Osmania University, Hyderabad, India. She received her Ph.D. from Center for Cellular and Molecular Biology, Hyderabad, India. Her research interests as postdoctoral scholar at University of Southern California, Los Angeles, as well as University of California Los Angeles (UCLA) have been geared towards understanding mechanisms of various diseases including obesity, cancer and functional gastrointestinal (GI) disorders using various molecular biology and bioinformatics tools. As an assistant project scientist at UCLA, her research includes using various bioinformatics approached for integrating different data types such as, gene expression, genetic, epigenetic and microbial data to gain meaningful insights into the etiopathology of functional GI diseases including irritable bowel syndrome (IBS). Dr. Joshi has published over 23 papers in peer reviewed high impact journals.
Hon Wai Koon, PhD
Assistant Professor, Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Dr. Koon’s research is focused on the synthetic mechanism and roles of the antimicrobial peptide Cathelicidin in inflammatory bowel disease, intestinal infections, colorectal cancer, obesity, and diabetes. Cathelicidin is a natural endogenous anti-microbial peptide that is protective to its host as a part of innate immune system. Our laboratory was the first to show that endogenous cathelicidin ameliorates dextran sulfate (DSS) colitis via bone marrow-derived immune cells. We also found increased expression of cathelicidin in monocytes/macrophages in the colonic mucosa of ulcerative colitis patients. Cathelicidin-deficient mice develop more severe bacterial penetration into intestinal mucosa and associated intestinal inflammation than wild-type mice. Therefore, we understand that endogenous cathelicidin may be a protective response to intestinal infection and inflammation. Moreover, intracolonic administration of the cathelicidin peptide ameliorates C. difficile-mediated colitis in mice. We are now studying the role of cathelicidin in the change of intestinal microflora in the development of obesity and diabetes. Dr. Koon is now investigating the role of a non-peptide cathelicidin-mimic, Ceragenin CSA13, in the protection against intestinal inflammation, C. difficile infection, obesity, and diabetes. This protection may be related to change of intestinal microflora. CSA13 is more chemically stable than natural cathelicidin and may be suitable for clinical use. Our research establishes a new direction of research in digestive diseases using microflora study, clinically relevant human primary cells, fresh intestinal biopsies, biologically induced colitis animal models, and system biology approaches.
Recent Relevant Publications
- Koon HW, Shih DQ, Chen J, Bakirtzi K, Hing TC, Law I, Ho S, Ichikawa R, Zhao D, Xu H, Gallo R, Dempsey P, Cheng G, Targan SR, Pothoulakis C. Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology. 2011 Nov;141(5):1852-63.e1-3. PubMed PMID: 21762664; PubMed Central PMCID: PMC3199285.
- Hing TC, Ho S, Shih DQ, Ichikawa R, Cheng M, Chen J, Chen X, Law I, Najarian R, Kelly CP, Gallo RL, Targan SR, Pothoulakis C, Koon HW. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut. 2013 Sep;62(9):1295-305. PubMed PMID: 22760006; PubMed Central PMCID: PMC3737259.
Active Funding in Microbiome-Related Research
|Funding Agency/Grant Number:||NIH 1R03DK103964-01A1|
|Title:||“Role of cathelicidin in obesity and diabetes”| Jennifer Labus, PhD
Director, Neuroimaging and Biostatistics Core, Oppenheimer Center for Neurobiology of Stress; Associate Professor, Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Dr. Jennifer S. Labus is an Associate Professor in the David GeffenSchool of Medicine at University of California, Los Angeles. She is an investigator and Director for the Neuroimaging and Bioinformatics Core in the Oppenheimer Family Center for Neurobiology of Stress at UCLA. Her research is focused on the interface of stress, pain and emotions and its influence on the role of dysregulation in the pathophysiology of common chronic pain disorders. She has unique expertise in applying advanced statistical and computational technologies to analyze multimodal brain imaging data. She has made seminal contributions to mapping neural networks underlying visceral pain. Dr. Labus’ current research focus lies in applying a biological system based approach using bioinformatics, network analyses, supervised and unsupervised machine learning tools to integrate multimodal brain imaging data with other large scale biological data sets including genetics and metabolomics. This research provides the means to integrate and decipher large amounts of multivariate neuroimaging data to subgroup patients based on objective biological markers, and characterize central nervous system alterations for further pathophysiological investigations targeting treatment of chronic pain and obesity. She has been the recipient of a K08 Career Development award, Effective connectivity of central response in irritable bowel disorder, from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as well as a RO3 award examining the role of altered attention and emotional arousal networks in IBS. Recently, acting as lead Co-Primary investigator she was awarded R01 funding by the National Institute of Childhood Health and Human Development (NICHD) to use brain imaging data, along with genetic, physiological and biological data, to extensively phenotype women with vulvodynia. Dr. Labus is a co-investigator on several NIH funded grants, international research collaborations, and is actively involved in mentoring graduate students and postdoctoral fellows. As a result of her work she was awarded the Master’s Award in Gastroenterology in 2010 for her outstanding achievements in Basic and Clinical Digestive Sciences. Dr. Labus was also the recipient of the American College of Neuropsychopharmacolgy Travel Award in 2013.
Relevant Recent Publications
Emeran Mayer, MD, PhD
Director, Oppenheimer Center for Neurobiology of Stress; Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Dr. Emeran Mayer is a Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA, Executive Director of the Oppenheimer Center for Neurobiology of Stress, and Co-director of the CURE: Digestive Diseases Research Center at UCLA. He is a world renowned gastroenterologist and neuroscientist with 30 years of experience in the study of clinical and neurobiological aspects of how the digestive system and the nervous system interact in health and disease, and his work has been continuously supported by the National Institutes of Health (NIH). He is currently principal investigator on 4 NIH grants including a center grant from ORWH/NIDDK on sex differences in brain gut interactions, a consortium grant by NIDDK on pelvic pain syndromes, a RO1 grant on the effects of cognitive behavioral therapy on brain signatures in IBS and a ROI grant on brain gut microbiome interactions in inflammatory and functional GI disorders (both from NIDDK). He has published over 320 peer-reviewed articles (average H index 90), including 100 chapters and reviews, co-edited four books, and organized several interdisciplinary symposia in the area of visceral pain and mind body interactions. His current research focus is on the role of the gut microbiota in modulating brain gut interactions, and their role in emotion regulation, chronic visceral pain and obesity.
Relevant Recent Publications
- Labus JS, Naliboff B, Kilpatrick L, Liu C, Ashe-McNalley C, dos Santos IR, Alaverdyan M, Woodworth D, Gupta A, Ellingson BM, Tillisch K, Mayer EA. Pain and Interoception Imaging Network (PAIN): A multimodal, multisite, brain-imaging repository for chronic somatic and visceral pain disorders. Neuroimage, 2015 Apr 19. pii: S1053-8119(15)00308-0. doi10.1016/j.neuroimage.2015.04.018. [Epub ahead of print] PMID: 25902408
- Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut Microbes and the Brain: Paradigm Shift in Neuroscience. J Neurosci Nov 12;34(46):15490-6, 2014. PMCID: PMC4228144
- Mayer EA, Labus JS, Tillisch K, Cole DE, Baldi P. Towards a Systems View of Irritable Bowel Syndrome, Nat Rev Gastroenterol Hepatol. 2015, in press
Victoria Niklas, MD, MA
Professor, Department of Pediatrics, David Geffen School of Medicine at UCLA; Director, Neonatal Intensive Care Unit and Newborn Services, Olive View-UCLA Medical Center
Dr. Victoria Niklas is a Professor in the Department of Pediatrics at the David Geffen School of Medicine at UCLA and the Director of the Neonatal Intensive Care Unit and Newborn Services at Olive View-UCLA Medical Center. Dr. Niklas earned her medical degree from Harvard Medical School and a master’s degree in Biochemistry and Molecular Biology from Harvard University. She completed her residency in pediatrics at Children’s Hospital Los Angeles and a fellowship in perinatal and neonatal medicine at UCLA.
Dr. Niklas has over 25 years of experience as a clinician investigator and neonatologist integrating basic and translational science in diseases afflicting the newborn. Her career has focused on understanding the immune system in the susceptibility of the newborn to infection and inflammation in the body’s largest mucosal surface, the intestine. She is a recognized expert in mouse models of intestinal immune T cell development and the pathogenesis of intestinal inflammation, in diseases such as necrotizing enterocolitis, a life-threatening intestinal disease of primarily premature infants. More recently, she was the site PI for a phase I/II RCT of enteral human recombinant lactoferrin evaluating its role in reducing hospital-acquired infections (HAI) in very low birth weight infants. Lactoferrin was safe and reduced HAI in premature infants. Also, the normally pathogenic flora was reduced in the feces of lactoferrin treated infants when compared to controls, suggesting one possible mechanism whereby lactoferrin reduced HAI in these infants.
Dr. Niklas wishes to extend these studies by exploring metagenomic signatures of maternal disease (such as obesity) in the taxonomic composition of the gut microbiota acquired by the newborn at birth. Well-described microbial signatures of obesity in adults may result in disease-associated microbial signatures in the newborn intestine. Hence, maternal flora may have a long-lasting impact on the infant’s later risk of diseases, such as obesity, in later life. The reduction in childhood obesity among breastfed infants suggests that components in breast milk (lactoferrin, milk’s microbiome, or milk oligosaccharides) may lower this risk. Possibly by influencing heritability or stability of an obesity-associated intestinal microbiome. Advanced genomic tools and sequencing will be used to explore the composition and diversity of this microbiome between mother and baby. It is, however, envisioned, that a “Mother Baby Cohort” will serve as a springboard for extended “life studies” enabling interdisciplinary, interventional and observational studies of health and disease. These endeavors will advance knowledge and ultimately improve care practices in the management in the perinatal interface with a far-reaching impact on our understanding of health and the origins of disease throughout life.
Relevant Recent Publications
- Sherman MP, Miller MM, Sherman J, Niklas V. Lactoferrin and necrotizing enterocolitis. Curr Opin Pediatr. 2014 Apr; 26(2): 146-50. PubMed PMID: 24503532.
- Sherman MP, Zaghouani H, Niklas V. Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis. Pediatr Res. 2015 Jan; 77(1-2): 127-35. PubMed PMID: 25303278.
- Sherman MPS, Adamkin DH, Radmacher PG, Sherman J and Niklas V. Protective Proteins in Human Milk: Lactoferrin Steps Forward. NeoReveiws 13(5): 293-301, 2012.
- Sherman MP, Sherman J, Arcinue R and Niklas V. Lactoferrin meets the NICU Habitat: Effects on the fecal microbiome of VLBW infants. Submitted, 2015.
- Sherman MP, Adamkin DH, Niklas V, Radmacher P Sherman J, Wertheimer F and Petrak K. Randomized Trial of Human Recombinant Lactoferrin (Talactoferrin) Oral Solution in Preterm Infants, In preparation 2015
Charalobos Pothoulakis, MD
Director of Research, UCLA Center for Inflammatory Bowel Diseases; Professor, Pathology and Laboratory Medicine Digestive Diseases/Gastroenterology, David Geffen School of Medicine at UCLA
Dr. Pothoulakis is the Eli and Edythe Broad Professor of Medicine at the Department of Medicine at UCLA. He is the Director of the IBD Research Center, and the Chair of Research at the Division of Digestive Diseases at UCLA.. He is currently an Associate Editor for the American Journal of Physiology, Gastrointestinal and Liver Physiology and a member of the founding Editorial Board of the new AGA Journal Cellular and Molecular Gastroenterology and Hepatology. He is also the Chair of the Regulatory Peptides, Cell Signaling and Molecular Biology Section of the AGA. He is an author of over 185 original articles and numerous reviews and book chapters. His research program is primarily focused on the role of neuropeptides and hormones in several disease states, including Inflammatory Bowel Disease, Irritable Bowel Syndrome. Dr. Pothoulakis has been contributing to the Clostridium difficile field since its inception and published over 100 manuscripts in mechanisms of action of this pathogen and its toxins. He also works on mechanisms of probiotics in intestinal inflammation and he is one of the pioneers in this field. Dr. Pothoulakis’ research projects have been supported by multiple grants from the National Institutes of Health with no interruption over the past 25 years, as well as by grants from the Broad Foundation, the Crohn’s and Colitis Foundation and several pharmaceutical companies.
Relevant Recent Publications
- Kokkotou E, Moss AC, Torres D, Karagiannides I, Cheifetz A, Liu S, O’Brien M, Maratos-Flier E, Pothoulakis C. Melanin-Concentrating Hormone as a mediator of intestinal inflammation. Proc Natl Acad Sci (USA) 2008; 105:10613-8 PMCID: PMC2492477
- Savidge TC, Urvil P, Oezguen N, Kausar A, Choudhury A, Acharya V, Pinchuk I, Torres AG, English RD, Wiktorowicz JE, Leoffelholz M, Kumar R, Shi L, Nie W, Feng H, Braun W, Herman B, Stamler JS, Pothoulakis C. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nature Medicine; 2011; 17(9):1136-41. PMCID: PMC3277400
- Koon HW, Ho S, Hing TC, Cheng M, Chen X, Ichikawa Y, Kelly CP, Pothoulakis C. Fidaxomicin inhibits Clostridium difficile toxin A–mediated enteritis in the mouse ileum. Antimicr Agents Chemother 2014; 58(8):4642-50.
- Chen X, Fruehauf J, Katchar KK, Mustafa N, Koon HW, Xu H, Zhao D, Kokkotou E, Goldsmith JD, Pothoulakis C, Kelly CP. Saccharomyces boulardii inhibits EGF receptor signaling and intestinal tumor growth in Apc(min) mice. Gastroenterology 2009; 137:914-23
- Pothoulakis C. Review Article: anti-inflammatory mechanisms of action of Saccharomyces boulardii. Alim Pharmacol Ther, 2009 ; 30(8):826-33.
Sang Hoon Rhee, PhD
Adjunct Associate Professor, Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Dr. Rhee’s research focuses on studying roles of host-microbial interaction in the gastrointestinal tract. Specifically, the lab has been investigating the function of Toll-like receptors (TLRs) which is a family of pattern recognition receptor recognizing microbial products to elicit inflammatory and innate immune responses. Recently, Dr. Rhee demonstrated that TLR5 is associated with the development and progress of inflammatory bowel diseases. Moreover, Dr. Rhee’s studies also showed that TLR5 plays an important role to elicit innate immunity to regulate anti-tumor activity. Studies to be presented will include a role of TLR5 in regulating colon cancer and a potential mechanism to modulate anti-tumor activity against colonic tumor. This research program has a record of continuous support from the NIH/NIDDK, Crohn’s and Colitis Foundation of America, Flight Attendant Medical Research Institute at both UCLA and Harvard Medical School.
Relevant Recent Publications
- Choi YJ., Im E., Pothoulakis C., and Rhee SH. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5. (2010) The Journal of Biological Chemistry 285: 21382-21390. PMCID: PMC2898416.
- Choi YJ., Im E., Chung HK., Pothoulakis C., and Rhee SH. TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells (2010) The Journal of Biological Chemistry 285:37570-37578. PMCID: PMC2988362.
- Im E., Riegler FM., Pothoulakis C., and Rhee SH. Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice. (2012) The American Journal of Physiology – Gastrointestinal and Liver Physiology 303(4):G490-7. PMCID: PMC3423140. (Selected as an “Editor’s Pick” from the journal).
- Im E., Jung J., and Rhee SH.., Toll-like receptor 5 engagement induces IL-17C expression in intestinal epithelial cells. (2012) Journal of Interferon & Cytokine Research 32:583-591. PMCID: PMC3514012.
- Choi YJ., Jung J., Chung HK., Im E., and Rhee SH., PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. (2013) The FASEB Journal 27:243-254. PMCID: PMC3528317
- Im E., Jung J, Pothoulakis C., and Rhee SH. Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10–/– mice. (2014) Gastroenterology 147:667-679. PMCID: PMC4143453.
Kirsten Tillisch, MD
Director, Mind Body Research Program, Oppenheimer Center for Neurobiology of Stress; Associate Professor, Department of Medicine, David Geffen School of Medicine at UCLA
Dr. Kirsten Tillisch completed her undergraduate work at the Otis Institute of Parsons School of Design, earning a Bachelor of Fine Arts with Honors. She obtained her medical degree from the David Geffen School of Medicine at UCLA and was elected to the medical honor society Alpha Omega Alpha. She continued on at UCLA to complete her training in internal medicine and gastroenterology, graduating in 2003. Her clinical interests are functional bowel disorders such as irritable bowel syndrome, functional dyspepsia, and cyclic vomiting syndrome. Her research interests include brain-gut interactions , the effects of nonpharmacological therapies on functional gastrointestinal disorders, and pharmacological treatment of irritable bowel syndrome. Her recent research projects include defining resting state brain dysfunction in irritable bowel syndrome patients, evaluating the role of gut microbiota modulation on emotional processing in the brain, and assessment of neurokinin-1 receptor antagonists effects on the gut and brain in irritable bowel syndrome. She is a member of the Neuroimaging Program of the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress.
Relevant Recent Publications
- Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015 Mar 2;125(3):926-38. doi: 10.1172/JCI76304. Epub 2015 Feb 17. Review. PubMed PMID: 25689247; PubMed Central PMCID: PMC4362231.
- Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014 Nov 12;34(46):15490-6. doi: 10.1523/JNEUROSCI.3299-14.2014. Review. PubMed PMID: 25392516; PubMed Central PMCID: PMC4228144.
- Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays. 2014 Oct;36(10):933-9. doi: 10.1002/bies.201400075. Epub 2014 Aug 22. Review. PubMed PMID: 25145752.
- Tillisch K, Labus JS. Neuroimaging the microbiome-gut-brain axis. Adv Exp Med Biol. 2014;817:405-16. doi: 10.1007/978-1-4939-0897-4_18. Review. PubMed PMID: 24997044.
- Tillisch K. The effects of gut microbiota on CNS function in humans. Gut Microbes. 2014 May-Jun;5(3):404-10. doi: 10.4161/gmic.29232. Epub 2014 May 16. Review. PubMed PMID: 24838095; PubMed Central PMCID: PMC4153780.
- Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013 Jun;144(7):1394-401, 1401.e1-4. doi: 10.1053/j.gastro.2013.02.043. Epub 2013 Mar 6. PubMed PMID: 23474283; PubMed Central PMCID: PMC3839572.