(May 2017) The GI and Liver Innate Immune Program (GALIIP) plans to build on
strengths already on the CU Anschutz Medical Campus to expand
understanding of some of the fastest-growing diseases facing society.
the U.S. health system nearly $500 billion annually, gastrointestinal
and liver-related diseases are significant burden, yet there is an unmet
need in diagnosis, treatment and understanding of conditions such as
fatty liver disease, eosinophilic esophagitis and inflammatory bowel
A common element of these diseases is dysfunction of the
immune system, particularly the innate immune system. The innate immune
system is a first line of defense against infection by microorganisms
and it plays a critical role in resolving inflammation after injury or
infection. The innate immune system presents physical and chemical
barriers to infectious agents, recruits immune cells to sites of
infection, and identifies and removes foreign substances present in
organs, tissues, blood and lymph.
“The concept of innate immune response
is that it happens much sooner than adaptive response,” said Hugo
Rosen, MD, professor of medicine and immunology, head of the Division of
Gastroenterology and Hepatology and one of the leaders of GALIIP.
“They’re kind of the first line of defense against a pathogen infection.
“Where an adaptive or T cell response takes four to eight weeks, this happens
in hours to days,” he said. “And organs like the gut and the liver are
characterized by a very high frequency, or what we call an enrichment,
of these innate lymphocytes and nowhere else in the body do you find
In recent years, scientists have focused
their attention on gaining a better understanding the concentrated
microbe population living in the human intestines.
PhD, professor and vice chair for research in the Department of
Medicine and one of the leaders of GALIIP, said, “The GI tract and the
liver are termed mucosal tissues and a mucosal tissue is one that
interacts with the environment, the outside world.”
particular, think about the gut,” he said. “The gut interacts with more
bacteria, more microbes than any other organ in the body. And in fact
one of the great strengths we have here on this campus is the microbiota
work that’s going on.”
One of the leaders in that effort, Colgan
said, is Catherine Lozupone, PhD, in the Department of Medicine’s
Division of Biomedical Informatics and Personalized Medicine. Using
state-of-the art, high-throughput gene sequencing and a groundbreaking
algorithm she designed, Lozupone has published more than 50 papers,
laying a foundation for a field believed to hold great promise for
yielding more personalized treatments and prevention strategies.
also draws on a rich legacy. Work by Norman Pace, PhD, who now is a
Distinguished Professor of the University in CU Boulder’s Department of
Molecular, Cellular and Developmental Biology and who previously held
faculty positions at National Jewish and the University of Colorado
Health Sciences Center, informs the program. Pace’s laboratory led the
development and use of molecular methods to study microbial ecosystems.
“We have a very large footprint in microbiota analysis,” Colgan said.
The next step is to expand into new areas of discovery, outlined by GALIIP as:
Mucosal innate immunity. Accumulating evidence indicates that the
unique anatomy and complex architecture of the GI tract and liver
provide cues that contribute significantly to both disease progression
and resolution of mucosal disease. Compartmentalized tissue and microbe
populations within the intestine, for example, result in significant
metabolic shifts within these tissue microenvironments. During active
inflammatory disease, metabolic demands often exceed supply, resulting
in localized areas of metabolic stress.
• Microbiota. Advances in DNA sequence-based technologies now permit genetic analysis of complex microbial populations without the
need for prior cultivation. These molecular methods of
culture-independent microbiology and their recent application to studies
of the human GI tract in health and disease have served as a paradigm
shift in understanding of host-microbe interactions. Upwards of 40,000
bacterial species are estimated to comprise the collective
gastrointestinal microbiome, most of which have not been charac-terized.
Hepatic diseases and innate immunity. Innate immunity is critical to
the health of the normal liver and central to the pathogenesis of common
hepatic disorders, such as non-alcoholic fatty liver disease (NAFLD).
Given the epidemic of obesity in our society, NAFLD and subsequent liver
fibrosis have emerged as a major morbidity risk. Innate immunity is
central to the development of NAFLD. Among the advantages for
researchers at the CU Anschutz Medical Campus are existing repositories
of specimens for research and the proximity of clinical centers for
adults and children.
“We have been building repositories of human
specimens. So in addition to murine models of disease, we have human
models of disease,” said Rosen. “In my lab, we started a repository in
1999 and we now have over 60,000 specimens.
“Using those samples, researchers can look at the populations of cells residing
over the liver and ask how many of these cells are autoimmune liver
conditions, viral conditions, fibrotic-scar-forming conditions, and
interestingly in the liver the predominant population is actually innate
lymphocyte population,” he said.
With such knowledge, GALIIP
researchers building a better understanding of the vast landscape of
the microbiome and why it manifests differently in particular
“One of our big pushes is to understand the
differences between liver disease and gut disease in kids and in
adults,” Colgan said. “So being on this campus and having Children’s
Hospital and University Hospital here and the basic science is a big
With the combined insights, GALIIP researchers hope to improve the understanding of the vast landscape of the microbiome.
get this genetic foundation in terms of what’s known about certain
receptors, or certain pathways, that are regulated genetically, but
there is so much more going on within the microenvironment,” Rosen said.