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MIBRC Research

Principal Investigators:

Bobby Cherayil, MD

Alessio Fasano, MD

Verena Göbel, MD

Bryan Hurley, PhD

Hai Ning Shi, DVM, PhD

W. Allan Walker, MD >>

Collaborators:

Beth McCormick, PhD

Hans-Christian Reinecker, MD

Research Lab

W. Allan Walker, MD

Professor of Pediatrics, Chief, Harvard Medical School
Conrad Taff Professor of Nutrition, Harvard Medical School
Professor of Nutrition, Harvard School of Public Health

Phone: 617-726-7988
Fax: 617-724-1731
Email: wwalker@partners.org

Research team:

Kriston Ganguli, MD - Instructor of Pediatrics
Shuba Iyenger, MD, MPH
Di Meng, MD, PhD - Instructor of Pediatrics
Meiqiang Weng, MD, PhD - Instructor of Pediatrics
Weishu Zhu, MD - Instructor of Pediatrics

Developmental Responses to Early Intestinal Invaders

Dr. Walker founded the Mucosal Immunology and Developmental Gastroenterology Laboratories—renamed the Mucosal Immunology  and Biology Research Center—in the 1990s as part of the Gastroenterology and Nutrition Division at MGHfC at Harvard Medical School. His research efforts include defining the passive and active protective properties of human breast milk with regard to protection from disease during the newborn period. Dr. Walker also studies the development of human intestinal host defenses using human fetal organ cultures, cell lines, and xenograft transplant models.

Walker Research

Figure 1: Diagram of cross-section of human fetal small intestine showing an immature, slowly proliferating epithelium and a paucity of lymphoid elements in contrast to the same cross-section of a fully colonized infant with actively proliferating, mature epithelium and an abundance of lymphoid elements.

Specifically, his laboratory has reported that the human fetal epithelium responds inappropriately to both endotoxin and exotoxins, which helps to explain an increased incidence and severity of certain inflammatory and secretory diarrheas in this age group. More recently, they have studied the effect of initial colonizing microbiota on the development of mucosal protective function and the mechanism of probiotics in this process.

Dr. Allan Walker’s laboratory has been one of the leading laboratories in the study of developmental changes of intestinal host defense in response to invading microorganisms and their toxins. Studies in animal models and recent studies in human fetal intestinal models suggest that, under certain circumstances, the immature human enterocyte is not able to protect against bacteria, or it responds inappropriately to microbes and enterotoxins.

Walker Research Walker Research

Figure 2a and 2b: Diagram of mucosal immune defenses expressed in the human neonatal intestine as a function of gestational age. A) All components of mucosal immune function are mature at birth in the term human infant. B) However, the stimulus of initial colonization is needed before defenses become operational. Selected intestinal immune defenses include: (1) a specialized epithelium (M cell) overlying, (2) Peyer’s patches containing aggregates of lymphoid elements, (3) interstitial lymphocytes, and (4) intra-epithelial lymphocytes resulting in efferent immune responses.

This “inappropriate” response may be central to the pathophysiology of age-related infectious gastrointestinal diseases. Recent exciting results indicate that the inability of the immature gut to discriminate between commensal and pathologic may be related, at least in part, to reduced expression of IkB by the immature enterocyte.

Walker Research

Figure 3: Diagram depicting sub-epithelial dendritic cells extending their appendages between enterocytes into the intestinal lumen. These appendices, displaying TLRs, are activated by colonizing bacteria, mature and secrete cytokines which activate naïve T cells (TH0) to mature into a balanced T helper cell response (Th1, Th2 and Treg).

Dr. Walker’s laboratory focuses on identifying the mechanisms of developmental regulation of enterocyte responses to colonizing intestinal bacteria and their products. Researchers in the Walker lab also examine the role of Toll-like receptors in this response. These studies are undertaken in collaboration with Drs. Pothoulakis and McCormick and Dr. Ciarán Kelly, director of gastroenterology training and medical director of the Celiac Center at Beth Israel Deaconess Medical Center in Boston, Mass.