About

Shehzad Z. Sheikh, MD, PhD, is a Full Professor with Tenure in Medicine and Genetics at the University of North Carolina School of Medicine, specializing in the Division of Gastroenterology and Hepatology within the Center of Gastrointestinal Biology and Disease. His research focuses on deciphering the chromatin code in Inflammatory Bowel Diseases (IBD), aiming to understand the molecular and genetic mechanisms underlying these complex conditions. Dr. Sheikh leads a multidisciplinary lab that integrates genomic, transcriptomic, and epigenomic approaches to investigate the pathophysiology of IBD and related gastrointestinal disorders. His work involves the use of advanced techniques such as ATAC-seq, CUT&RUN, and RNA-seq to study chromatin structure and gene regulation in both human and mouse models. Through this research, Dr. Sheikh contributes to identifying key drivers of gut inflammation and disease heterogeneity, which may inform the development of targeted therapies for IBD patients.

Research topics

• Biology
• Medicine
• Pathology
• Internal medicine
• Genetics
• Cell biology
• Computational biology
• Immunology
• Molecular biology
• Endocrinology
• Materials science
• Gastroenterology
• Cancer research
• Biophysics
• Biochemistry
• Chemistry

Selected publications

• Fatty Acid Oxidation Suppression Reprograms Fibroblasts in Fibrostenotic Crohn’s Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-10

  articleOpen accessSenior authorCorresponding

  Abstract Fibrostenotic complications represent a major cause of morbidity in Crohn’s disease (CD), yet the cellular mechanisms that drive intestinal fibrosis independent of active inflammation remain poorly understood. Here, we identify impaired fatty acid oxidation (FAO) as a defining metabolic feature of fibroblasts in fibrostenotic CD. Untargeted lipidomics of non-inflamed colonic tissue from CD patients demonstrated enrichment of triacylglycerols and long-chain acylcarnitines, suggesting altered lipid utilization. Across three independent RNA-sequencing cohorts, including treatment-naïve pediatric ileal biopsies, FAO genes ( CPT1A, CPT2, SLC25A20 ) were selectively downregulated in patients with or destined to develop fibrostenotic disease. Single-cell RNA-sequencing localized these transcriptional alterations specifically to fibroblasts within strictured ileum. Primary fibroblasts derived from fibrostenotic CD exhibited increased neutral lipid accumulation, impaired mitochondrial fatty acid trafficking, and diminished responsiveness to PPARγ-mediated suppression of TGFβ-induced myofibroblast activation. Together, these findings demonstrate that FAO impairment is a conserved, fibroblast-specific metabolic program associated with intestinal fibrosis in CD and suggest that metabolic modulation of stromal cells represents a potential therapeutic strategy for fibrostenotic disease.

  PublisherOA PDFDOI

• Myeloid Cell Adhesion Molecule 1 (CADM1) Promotes Proinflammatory Signaling in Human Inflammatory Bowel Diseases

  Cellular and Molecular Gastroenterology and Hepatology · 2025-08-27 · 3 citations

  articleOpen accessSenior author

  BACKGROUND & AIMS: Cytotoxic T cells have been postulated to facilitate the destruction of intestinal epithelium in inflammatory bowel diseases (IBDs). CADM1, which encodes a membrane adhesion protein that can bind the T cell receptor CRTAM, was markedly up regulated in colons of IBD patients compared with non-IBD (NIBD) patients. METHODS: We performed comprehensive small RNA and RNA profiling on colon tissue from IBD and NIBD control patients in addition to characterizing the serum cleaved ectodomain of CADM1 (sCADM1) function in lamina propria mononuclear cells isolated from these patients. Last, a conditional loss-of-function mouse was developed to assess Cadm1 function in the myeloid compartment during chemical-induced colitis. RESULTS: T cells within colons of ulcerative colitis patients compared with NIBD patients. Conditional deletion of Cadm1 in myeloid cells resulted in reduced numbers of activated T cell populations and protected mice from chemical-induced colitis. Similarly, administration of a Cadm1 "neutralizing" antibody, which binds its extracellular domain reduced tissue inflammation and breakdown of the intestinal epithelium and crypts after induction of colitis in mice. Last, serum levels of sCADM1 were elevated in IBD patients compared with NIBD control subjects and treatment of lamina propria mononuclear cells with recombinant sCADM1 enhanced inflammatory STAT3 phosphorylation. CONCLUSIONS: CADM1 is a mediator of proinflammatory signaling cascades in the colon and a potential therapeutic target for the IBDs.

  PublisherDOI

• Chromatin profiling to identify biomarkers in inflammatory bowel diseases

  Current Opinion in Gastroenterology · 2025-05-01 · 2 citations

  reviewOpen accessSenior authorCorresponding

  PURPOSE OF REVIEW: Chromatin plays a critical role in gene regulation and disease pathogenesis. In inflammatory bowel disease (IBD), alterations in chromatin structure contribute to disease heterogeneity and impact treatment responses. This review explores chromatin accessibility and chromatin-associated proteins as biomarkers for IBD and highlights recent technological advancements enabling targeted biomarker discovery and novel therapies. RECENT FINDINGS: Advancements in high-throughput sequencing have enabled genome-wide profiling of chromatin interactions in IBD. Studies have identified distinct chromatin landscapes in Crohn's disease (CD) and ulcerative colitis (UC), revealing stable regulatory shifts independent of inflammation. SUMMARY: Chromatin profiling offers a novel approach for identifying biomarkers and therapeutic targets in IBD. Integrating chromatin accessibility data with transcriptomic and epigenomic analyses can refine disease classification and guide personalized treatment strategies. Emerging techniques compatible with formalin-fixed paraffin-embedded (FFPE) samples enhance clinical applicability, bridging the gap between molecular research and precision gastroenterology.

  PublisherDOI

• Mo1918: EXPRESSION QUANTITATIVE TRAIT LOCI IN COLON TISSUE FROM PATIENTS IDENTIFY UNIQUE TARGET GENES ASSOCIATED WITH IBD

  Gastroenterology · 2025-05-01

  article
  PublisherDOI

• A machine learning approach identifies 5-ASA and ulcerative colitis as being linked with higher COVID-19 mortality in patients with IBD

  UNC Libraries · 2025-06-25

  articleOpen access
  PublisherDOI

• Reference-guided Genome Assembly of Long Non-coding RNA Transcripts Reveals Target Genes Associated With Crohn’s Disease

  Scientific Reports · 2025-10-01

  preprintOpen access

  Abstract Crohn’s disease (CD) is highly heterogeneous in presentation and progression with no cure. Molecular phenotyping has been used to elucidate cellular and tissue-based alterations to characterize drivers and effects of disease. One currently understudied class of functional molecules is long non-coding RNAs (lncRNAs). Studying the full lncRNA landscape in IBD is challenging due in part to an incomplete lncRNA annotation and a lack of their functional characterization in tissues of interest. We used a genome-guided alignment strategy to assemble predicted lncRNA transcripts using short RNA-sequencing data from colon tissue of adult patient samples. When combining our predicted lncRNAs with previous lncRNA annotations, we determined 98 that were differentially expressed, recapitulating many from previous IBD studies while also uncovering new ones. We built gene co-expression networks to cluster lncRNAs with functionally characterized protein-coding genes. Clusters containing differential lncRNAs were correlated to disease status and associated with pathways related to the humoral immune response, metabolism, and tissue regeneration. We uncovered multiple differential lncRNAs whose expression significantly correlated with nearby differential protein-coding genes that have also been differentially expressed in other IBD datasets, such as PITX2 . We focused on a predicted lncRNA that is antisense to the PITX2-adjacent lncRNA PANCR , which we called PANCR-AS1 , and provide multiple lines of evidence that support PANCR-AS1 functioning as an enhancer of PITX2 expression. Overall, we determined lncRNAs that are potential contributors to CD pathogenesis. We developed a robust pipeline for identifying lncRNAs in diseased and non-diseased tissue that are absent from reference annotations. We also outlined a framework to pinpoint significant disease-associated lncRNAs with potential functional activity related to their nearby protein-coding genes.

  PublisherDOI

• TNF Promoter Hypomethylation Is Associated With Mucosal Inflammation in IBD and Anti-TNF Response

  Gastro Hep Advances · 2024-01-01 · 2 citations

  articleOpen access

  Background and Aims: Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the tumor necrosis factor (TNF) promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and nonresponders. Methods: We obtained mucosal biopsies from 200 participants (133 IBDs and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 nonresponders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated intestinal epithelial cells from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF nonresponders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed 2 missense variants in DNA methyltransferase 1, 1 of which had reduced function in vivo. Conclusion: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

  PublisherOA PDFDOI

• eQTL in diseased colon tissue identifies novel target genes associated with IBD

  Research Square · 2024-10-03

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Colonic epithelial miR-31 associates with the development of Crohn's phenotypes

  UNC Libraries · 2024-08-14 · 2 citations

  articleOpen access

  BACKGROUND: Crohn's disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. METHODS: We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes. RESULTS: Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgeryCONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies. FUNDING: This work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS).

  PublisherDOI

• Linking gene expression to clinical outcomes in pediatric Crohn’s disease using machine learning

  Scientific Reports · 2024-02-01 · 7 citations

  articleOpen accessSenior author

  Pediatric Crohn's disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene expression. Gene expression data was generated from 101 formalin-fixed, paraffin-embedded (FFPE) ileal and colonic biopsies obtained from treatment-naïve CD patients and controls. Clinical outcomes including development of strictures or fistulas and progression to surgery were analyzed using differential expression and modeled using machine learning. Differential expression analysis revealed downregulation of pathways related to inflammation and extra-cellular matrix production in patients with strictures. Machine learning-based models were able to incorporate colonic gene expression and clinical characteristics to predict outcomes with high accuracy. Models showed an area under the receiver operating characteristic curve (AUROC) of 0.84 for strictures, 0.83 for remission, and 0.75 for surgery. Genes with potential prognostic importance for strictures (REG1A, MMP3, and DUOX2) were not identified in single gene differential analysis but were found to have strong contributions to predictive models. Our findings in FFPE tissue support the importance of colonic gene expression and the potential for machine learning-based models in predicting outcomes for pediatric CD.

  PublisherOA PDFDOI

Recent grants

• Interpreting molecular role of DNA variants associated with Crohn's Disease through integrative analysis of open chromatin, epigenome and transcriptome data in diverse and relevant tissues and cells

  NIH · $588k · 2014–2017

• Integrative Genetic and Genomic Analyses in the Inflammatory Bowel Disease

  NIH · $901k · 2016–2020

• Microbial and inflammatory regulation of intestinal epithelial gene transcription

  NIH · $35.6M · 2013–2025

• Gastroenterology Research Training

  NIH · $7.5M · 1996–2026

• NIH Grant F32DK083186

  NIH · $111k · 2010

Frequent coauthors

• Terrence S. Furey

  University of North Carolina at Chapel Hill

  57 shared

• Scott E. Plevy

  Protagonist Therapeutics (United States)

  37 shared

• Matthew R. Schaner

  University of North Carolina at Chapel Hill

  27 shared

• Caroline Beasley

  University of North Carolina at Chapel Hill

  26 shared

• Hans Herfarth

  University of North Carolina at Chapel Hill

  22 shared

• Erin C. Steinbach

  Sorbonne Université

  21 shared

• Katsuyoshi Matsuoka

  Toho University

  21 shared

• Praveen Sethupathy

  Cornell University

  19 shared

Labs

• Sheikh LabPI

Education

• Ph.D., Toxicology

  University of North Carolina at Chapel Hill

  2000

• M.D., Medicine

  University of North Carolina at Chapel Hill

  1995

• B.S., Biology

  University of North Carolina at Chapel Hill

  1991