Dr. Kugathasan’s research goal is to further extend novel genetic discoveries in inflammatory bowel disease (IBD), in particular common and rare susceptibility variants that are the cause of very early onset IBD. In addition, he has been investigating the immunogenetic mechanisms that underlie this chronic intestinal inflammation in children and adults with IBD. He is the principal investigator of a large 40 sites, multicenter research network where thousands of incident cases of early onset IBD are being enrolled. DNA, serum and intestinal biopsy materials are being banked to identify modifier genes, environmental and microbial factors that can be used to stratify the risk of complicated disease and surgery in IBD. As a clinician and an inflammatory bowel disease specialist, he also serves as scientific director of the inflammatory bowel disease program at Children’s Health Care of Atlanta and sees pediatric patients with inflammatory bowel disease, (both Crohn’s disease and ulcerative colitis) at Emory Children’s Center and Egleston Children’s hospital.

Dr. Kugathasan received his medical degree from Sri Lanka. After pediatric residency in Sinai Hospital of Baltimore, he completed his pediatric gastroenterology fellowship at Case Western Reserve University. His research training was in mucosal immunology under the mentorship of Dr. Claudio Fiocchi. In 2002, he received the Physician of the year award from Crohn’s and Colitis Foundation of America.  He was the recipient of the prestigious young clinical investigator award from the society of North American Pediatric Gastrenterology & Nutrition (NASPGHAN) and junior physician investigator award from American Federation for Medical Research (AFMR). He has served as a co-chair for pediatric affairs of Crohn’s and Colitis foundation of America. He moved to Emory University in 2008, and has been appointed as a Marcus Professor of Pediatric Gastroenterology / Inflammatory bowel disease.

​The Kugathasan research team (IBD Dream Team) focuses on early onset Inflammatory Bowel Disease (IBD). Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is estimated to affect approximately 1.2 million Americans. IBD is a destructive, life-long, chronic inflammatory disorder which results in gastrointestinal bleeding, weight loss and poor quality of life. IBD affects all races and onset of the disease is usually in children and young adults. Familial, twin and linkage studies suggest that CD is highly heritable.  The research interest of the laboratory is:

To determine and identify genetic associations in very young onset IBD in comparison to those found in older patients with adult onset disease. In particular, to identify high effect, highly penetrant but rare variants that cannot be identified by genome wide association studies.

To identify susceptibility and modifying factors and perform Genotype – serotype – bacteriotype - gene expression studies in carefully and prospectively identified incident cases of early onset IBD.  

Genome wide association studies to determine common SNPs / loci and copy number variants in African Americans with IBD. Replication studies in African Americans show that the major genetic variants that were found in Caucasians with IBD are not associated with African Americans. 

Use of the latest generation sequencing technologies to comprehensively identify IBD - predisposing causal variants in order to fully characterize the physical scale of various genetic associations in IBD. Performing targeted sequencing in susceptibility loci found in African Americans and Caucasians in parallel is another area on interest. 

The Kugathasan Research Team has many projects that are currently being worked on.  Funding from multiple sources including government and private foundations ensure we are able to keep doing group breaking research.  The current research projects are below:

RISK Stratification:

Pediatric onset CD is the fastest growing incident age group as is considered to be a more aggressive phenotype than adult onset disease. At presentation, the most of the children present with an inflammatory or so called non-complicated disease behavior. Over time a sub-group of CD patients progress to more a complicated disease behavior, which involve hospitalization and sometimes surgery. The factors or pathogenic mechanisms underlying the development of complications are poorly understood. Therefore, discovery of predictive factors contributing to the progression of a CD patient from an uncomplicated to complicated phenotype necessitates engaging a patient population naïve to all therapies and devoid of any confounding factors. In 2008 the RISK (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) study was commenced at 28 investigative centers in North America with the goal of prospectively characterizing and predicting the natural history of newly diagnosed CD in children presenting with uncomplicated disease.

To this end, over 1000 CD patients have been prospectively enrolled at this study. Each patient was followed for over 5 years. All patients were required to undergo a baseline colonoscopy before treatment with findings recorded in a standardized fashion. At enrollment and during ongoing prospective follow-up evaluation, medication exposure, clinical, radiological, endoscopic and laboratory data were obtained for each enrolled patient and submitted to a centralized data management center. All patients were managed according to the dictates of their physicians, not by standardized protocols. The institutional review board of each site reviewed and approved the protocol and each participant provided written informed consent. Blood for genomic DNA, serology, stool and biopsy samples were collected at the time of diagnosis in all subjects. Patients were followed up at minimum of every 6 months. During the follow up visits for up to 3 years, blood samples and (on occasion) ileal biopsy were collected. Currently our team is working towards the primary aim of the project, which is to develop a composite risk score using phenotypes, genetics, serology, microbiome and gene expression markers.

Funding provided by Crohn’s and Colitis Foundation of America (CCFA)

Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT Study):

The PROTECT study is a multi-center prospective cohort study of standardized medical therapy (mesalamine or corticosteroids) in newly diagnosed ulcerative colitis in children and adolescents. It is funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases.

Funding provided by National Institutes of Health (NIH/NIDDK) U01DK095745

Gene Discoveries in Subjects with Crohn’s Disease of African Descent (Genesis AA Study):

Nearly all genetic studies of IBD are focused on Caucasians; however, there is emerging data suggesting that the disease burden is similar in African Americans (AA). Variation data from HapMap, 1000 Genomics and other disease studies suggests that the allelic architecture of AA populations could be significantly different from Caucasians.  A large sample size is needed for an adequately powered genetic study.  Additionally, the AA population has much more genetic variation.  We are currently in alliance with the NIDDK IBD Genetic Consortium’s (IBDGC) mission to dramatically increase the recruitment of AA patients (pediatric and adult) IBD subjects for gene discovery purposes.

Funding provided by National Institutes of Health (NIH/NIDDK) R01DK087694

 

Longitudinal Characterization of Gut Microbiota and its Correlation with Host Genetics, Metabolomics and Protein Function in Children and Adults With and Without Inflammatory Bowel Disease (STINKI):

The human microbiome is comprised of more than 100 trillion cells, or roughly 10X the number of human cells.  The intestinal microbiome plays an essential role in health and disease through its role in immune system maturation and host defense. Numerous cross sectional studies have demonstrated the individuals diagnosed with IBD have intestinal microbiomes that are significantly altered (both quantitatively and qualitatively) from their healthy counterparts: decreased proportion of Firmicutes and Bacteroidetes and increased proportion of proteobacteria.

Very little is known about how the intestinal microbiota, proteomics and metabololmics of an individual change over the course of an illness in response to intestinal inflammation and disease activity. Longitudinal analyses are critical in our ability to characterize the relationship between environment, microbial profile and clinical outcomes.

This study aims to characterize the fecal microbial community and its correlation with host genetic, metabolomics and protein function by obtaining repeated samples in participants both with and without IBD.  The potential impact of this analysis is far-reaching, as it will not only provide more awareness into the pathogenesis of IBD, but also provide future avenues to explore new therapeutic opportunities.

 

Causes and Consequences of neutrophil dysfunction in early onset Crohn’s disease (Neutrophil):

Anti-microbial sero-reactivity (AMS) and chronic intestinal inflammation similar to Crohn's Disease (CD) during the first decade of life in children with inherited disorders of phagocyte function suggests that loss-of-function in neutrophil antimicrobial pathways is likely to be a fundamental mechanism of pediatric CD pathogenesis. GWAS in CD have accounted for only a portion of the heritability and have rarely identified few loci of large effect. Rare variants, which GWAS are underpowered to detect, have been hypothesized to explain a substantial fraction of complex disorders like CD, so gene discovery efforts have now shifted to characterization of deleterious / loss of function mutations. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is required for priming of neutrophil antimicrobial function, and bioinformatic analysis of genomic studies has suggested a central role in CD pathogenesis. We discovered that older pediatric (early onset, EO, age 10-17) and adult patients exhibit an acquired basis for neutrophil dysfunction, GM-CSF auto-antibodies (GM-CSF Ab), which increase in titer with increasing age. GM-CSF Ab carriage is associated with reduced neutrophil STAT5 activation, phagocytic capacity, and bacterial killing, and high rates of AMS and stricturing behavior. To test the significance of these exciting developments, we have established a prospective clinical database and biobank for 1130 pediatric CD patients enrolled at diagnosis (the RISK study). We found that neutrophil phagocytosis and bacterial killing is reduced in a subset of patients. VEO patients have exhibited rare coding region mutations in genes predicted to affect GM-CSF priming of bacterial killing (CSF2RB & ITGAM/CD11b) and neutrophil oxidative burst (CYBA/p22phox), while EO patients have exhibited increasing titers of GM-CSF Ab. We hypothesize that genetic variants and GM-CSF Ab cause neutrophil dysfunction and thereby contribute to disease pathogenesis in an age-dependent manner in pediatric CD. Aim 1: Identify all coding genetic mutations in 127 genes likely to disrupt GM-CSF signaling and/or neutrophil function in 500 very early onset pediatric CD patients. Aim 2: Test the functional consequences of genetic mutations upon neutrophil GM-CSF signaling and bacterial killing. Peripheral blood samples will be collected from RISK patients carrying genetic mutations predicted to affect GM-CSF priming and neutrophil function including neutrophil candidate protein expression/localization, GM- CSF signaling, CD64 activation, adhesion, chemotaxis, oxidative burst, phagocytosis, and bacterial killing. We will use state-of-the-art genomic and immune approaches to define for the first time the causes and consequences of neutrophil dysfunction in the largest pediatric CD inception cohort in North America. Collectively, this studies will have direct implications for novel therapeutic approaches designed to modulate this critical host defense pathway in patients who experience the worst outcomes with current approaches.

Funding provided by National Institutes of Health (NIH/NIDDK) R01DK098231

 

DNA Methylation / Epigenetics

 

Epigenetic modifications induce changes in gene expression through structural alterations of DNA that are maintained through each round of cell division; they respond to changes in the environment, are potentially reversible and can be targeted for disease therapies. DNA methylation at cytosine-guanine dinucleotides (CpG sites) is the epigenetic modification that is most commonly studied in humans. It regulates gene expression by influencing the recruitment and binding of regulatory proteins to DNA. Typically, an increase in methylation at gene promoter regions correlates with a decrease in expression of that gene Intragenic DNA methylation is also important to regulate alternative promoters and enhancers that define a variety of alternative transcripts.

  •  Aim 1: Characterize DNA methylation differences over the course of treatment in pediatric Crohn’s cases over 3 years of treatment.
  •  Aim 2: Characterize epigenetic markers in intestinal tissue to assess the utility of both whole blood and intestinal methylation patterns as biomarkers to predict side effects following treatment.

Funding provided by Crohn’s and Colitis Foundation of America (CCFA)

The Kugathasan Research Team has many clinical trails that patients are actively being recruited for.  These studies are used to better understand how IBD effects patients, and provides a mechanism for patients to actively participate in research.  The current clinical trials are below:

Develop - A Multi-center, Prospective, Long-term, Observational Registry of Pediatric Patients with Inflammatory Bowel Disease. The purpose of this study is to collect long-term safety information on the disease and medications that you received or are receiving for your inflammatory bowel disease.

Adapt - A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and
Efficacy and Safety of Dose Escalation in Pediatric Patients with Inflammatory Bowel Disease. The purpose of this study is to determine if pediatric patients with inflammatory bowel disease who do not respond to the approved dose of infliximab will respond to a higher than approved dose of infliximab.  The study will explore whether patients will respond to a higher than approved dose of infliximab, as well as any associated side effects.  (A dose is a measured amount of a drug taken at one time.)

Abbvie Humira Trial (M11-290) - M11-290 A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Pediatric Subjects with Moderate to Severe Ulcerative Colitis. The purpose of this study is to evaluate the effectiveness and safety of adalimumab and to assess the pharmacokinetics (PK) (how drug is distributed in the body over time) of adalimumab following subcutaneous (under the skin injection) administration in pediatric subjects with moderate to severe ulcerative colitis.

Cape Registry - A long term (10 years) post marketing observational study to assess safety and effectiveness of Humira (Adalimumab) in pediatrics with moderately to severely active Crohn’s Disease. 

MSC Infusion (No more recruitment) – In this Phase I trial the investigators intend to show safety and tolerability of autologous MSC, expanded using a non-xenogeneic, human component platelet lysate expansion media. Fresh, non-cryopreserved, autologous MSCs will delivered intravenously as a single bolus dose in a dose escalation phase I study. The investigators intend to test whether the product is clinically safe in adults (18-65 years old) with CD and to determine maximal deliverable dose. Secondary endpoint will monitor effectiveness using CDAI as an endpoint.

Anti-TNF Therapy for Refractory Colitis in Hospitalized Children (ARCH) - A multicenter pilot and feasibility prospective cohort study to test the hypothesis that children hospitalized with severe steroid-refractory colitis exhibit rapid IFX clearance that influences clinical outcomes, and is predicted by baseline albumin and inflammatory markers. The ultimate goal is to develop strategies for optimizing therapy in children with severe colitis, thus minimizing the need for chronic steroid exposure and colectomy.

If interested please email ibdresearch@emory.edu for more information

Clinical Research Coordinators


Laboratory Research Team

 

 


Current Clinical Fellows

 


Research Scholar / Graduate Student


Past Clinical Fellows

 

Please see a few of the recent publications that have originated directly from our research group

2017

Kugathasan, S., L. A. Denson, T. D. Walters, M. O. Kim, U. M. Marigorta, M. Schirmer, K. Mondal, C. Liu, A. Griffiths, J. D. Noe, W. V. Crandall, S. Snapper, S. Rabizadeh, J. R. Rosh, J. M. Shapiro, S. Guthery, D. R. Mack, R. Kellermayer, M. D. Kappelman, S. Steiner, D. E. Moulton, D. Keljo, S. Cohen, M. Oliva-Hemker, M. B. Heyman, A. R. Otley, S. S. Baker, J. S. Evans, B. S. Kirschner, A. S. Patel, D. Ziring, B. C. Trapnell, F. A. Sylvester, M. C. Stephens, R. N. Baldassano, J. F. Markowitz, J. Cho, R. J. Xavier, C. Huttenhower, B. J. Aronow, G. Gibson, J. S. Hyams and M. C. Dubinsky (2017). "Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study." Lancet.

Brant, S. R., D. T. Okou, C. L. Simpson, D. J. Cutler, T. Haritunians, J. P. Bradfield, P. Chopra, J. Prince, F. Begum, A. Kumar, C. Huang, S. Venkateswaran, L. W. Datta, Z. Wei, K. Thomas, L. J. Herrinton, J. A. Klapproth, A. J. Quiros, J. Seminerio, Z. Liu, J. S. Alexander, R. N. Baldassano, S. Dudley-Brown, R. K. Cross, T. Dassopoulos, L. A. Denson, T. A. Dhere, G. W. Dryden, J. S. Hanson, J. K. Hou, S. Z. Hussain, J. S. Hyams, K. L. Isaacs, H. Kader, M. D. Kappelman, J. Katz, R. Kellermayer, B. S. Kirschner, J. F. Kuemmerle, J. H. Kwon, M. Lazarev, E. Li, D. Mack, P. Mannon, D. E. Moulton, R. D. Newberry, B. O. Osuntokun, A. S. Patel, S. A. Saeed, S. R. Targan, J. F. Valentine, M. H. Wang, M. Zonca, J. D. Rioux, R. H. Duerr, M. S. Silverberg, J. H. Cho, H. Hakonarson, M. E. Zwick, D. P. McGovern and S. Kugathasan (2017). "Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease." Gastroenterology 152(1): 206-217 e202.

Chandrakasan, S., S. Venkateswaran and S. Kugathasan (2017). "Nonclassic Inflammatory Bowel Disease in Young Infants: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome, and Other Disorders." Pediatr Clin North Am 64(1): 139-160.


2016

Shaw, K. A., M. Bertha, T. Hofmekler, P. Chopra, T. Vatanen, A. Srivatsa, J. Prince, A. Kumar, C. Sauer, M. E. Zwick, G. A. Satten, A. D. Kostic, J. G. Mulle, R. J. Xavier, and S. Kugathasan. 2016. 'Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease', Genome Med, 8: 75.

Dhere, T., I. Copland, M. Garcia, K. Y. Chiang, R. Chinnadurai, M. Prasad, J. Galipeau, and S. Kugathasan. 2016. 'The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease - a phase 1 trial with three doses', Aliment Pharmacol Ther, 44: 471-81.

Palle, S. K., M. Prasad and S. Kugathasan (2016). "Approach to a Child with Colitis." Indian J Pediatr. 

Manyapu, M., G. J. Warraich, S. Kugathasan and S. Syed (2016). "2-Year-Old with a Limp and Suspected Non-Accidental Injury." J Pediatr Gastroenterol Nutr.


2015

Huang, C., T. Haritunians, D. T. Okou, D. J. Cutler, M. E. Zwick, K. D. Taylor, L. W. Datta, J. C. Maranville, Z. Liu, S. Ellis, P. Chopra, J. S. Alexander, R. N. Baldassano, R. K. Cross, T. Dassopoulos, T. A. Dhere, R. H. Duerr, J. S. Hanson, J. K. Hou, S. Z. Hussain, K. L. Isaacs, K. E. Kachelries, H. Kader, M. D. Kappelman, J. Katz, R. Kellermayer, B. S. Kirschner, J. F. Kuemmerle, A. Kumar, J. H. Kwon, M. Lazarev, P. Mannon, D. E. Moulton, B. O. Osuntokun, A. Patel, J. D. Rioux, J. I. Rotter, S. Saeed, E. J. Scherl, M. S. Silverberg, A. Silverman, S. R. Targan, J. F. Valentine, M. H. Wang, C. L. Simpson, S. L. Bridges, R. P. Kimberly, S. S. Rich, J. H. Cho, A. Di Rienzo, L. W. Kao, D. P. McGovern, S. R. Brant and S. Kugathasan (2015). "Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans." Gastroenterology 149(6): 1575-1586.

Cutler, D. J., M. E. Zwick, D. T. Okou, S. Prahalad, T. Walters, S. L. Guthery, M. Dubinsky, R. Baldassano, W. V. Crandall, J. Rosh, J. Markowitz, M. Stephens, R. Kellermayer, M. Pfefferkorn, M. B. Heyman, N. LeLeiko, D. Mack, D. Moulton, M. D. Kappelman, A. Kumar, J. Prince, P. Bose, K. Mondal, D. Ramachandran, J. F. Bohnsack, A. M. Griffiths, Y. Haberman, J. Essers, S. D. Thompson, B. Aronow, D. J. Keljo, J. S. Hyams, L. A. Denson, P.-K. R. Group and S. Kugathasan (2015). "Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping." PLoS One 10(6): e0128074.

Natarajan, B., C. Sauer, B. Shehata and S. Kugathasan (2015). "Hidradenitis suppurativa and pediatric Crohn disease." J Pediatr Gastroenterol Nutr 60(4): e29-30.


2014

Gevers, D., S. Kugathasan, L. A. Denson, Y. Vazquez-Baeza, W. Van Treuren, B. Ren, E. Schwager, D. Knights, S. J. Song, M. Yassour, X. C. Morgan, A. D. Kostic, C. Luo, A. Gonzalez, D. McDonald, Y. Haberman, T. Walters, S. Baker, J. Rosh, M. Stephens, M. Heyman, J. Markowitz, R. Baldassano, A. Griffiths, F. Sylvester, D. Mack, S. Kim, W. Crandall, J. Hyams, C. Huttenhower, R. Knight and R. J. Xavier (2014). "The treatment-naive microbiome in new-onset Crohn's disease." Cell Host Microbe 15(3): 382-392.

Okou, D. T., K. Mondal, W. A. Faubion, L. J. Kobrynski, L. A. Denson, J. G. Mulle, D. Ramachandran, Y. Xiong, P. Svingen, V. Patel, P. Bose, J. P. Waters, S. Prahalad, D. J. Cutler, M. E. Zwick and S. Kugathasan (2014). "Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease." J Pediatr Gastroenterol Nutr 58(5): 561-568.

Okou, D. T., and S. Kugathasan. 2014. 'Role of genetics in pediatric inflammatory bowel disease', Inflamm Bowel Dis, 20: 1878-84.


2013

Middleton, J. P., A. P. Bhagavathula, B. Gaye, J. A. Alvarez, C. S. Huang, C. G. Sauer, G. Tenjarla, B. T. Schoen, A. Kumar, M. Prasad, D. T. Okou, W. C. Ifeadike, T. A. Dhere, K. N. Conneely, T. R. Ziegler, V. Tangpricha and S. Kugathasan (2013). "Vitamin D status and bone mineral density in African American children with Crohn disease." J Pediatr Gastroenterol Nutr 57(5): 587-593.

Waters, J., V. Dhere, A. Benjamin, A. Sekar, A. Kumar, S. Prahalad, D. T. Okou and S. Kugathasan (2013). "A practical and novel method to extract genomic DNA from blood collection kits for plasma protein preservation." J Vis Exp(75): e4241.