Our research is divided into 3 primary areas:
- Microbial
hydrogenotrophy in the human colon
- Host-intestinal
microbiota interactions as they pertain to
inflammatory disorders and colorectal cancer
- Redox
regulatory mechanisms governing cell fate decisions
1. Microbial hydrogenotrophy in
the human colon. The hydrogen gas produced during microbial
fermentation in the human colon is either excreted or used in situ by resident hydrogenotrophic microbes: primarily reductive acetogens (generating acetate), methanogenic
archaea (producers of methane), and sulfate-reducing
bacteria (SRB; producers of hydrogen sulfide). Although colonic metabolism of
hydrogen has a significant impact on intestinal health, little is known about
the diversity and ecology of hydrogenotrophic microbiota in the human colon. We are pursuing studies to
determine the extent of individual variation in the abundance and diversity of
the three groups of hydrogenotrophic microbes and how
diet and genetic background influence interactions between hydrogenotrophic
microbes and fermentative bacteria. A goal is to determine the extent to
which dysbiosis in hydrogenotrophic
microbiota may be linked to colonic disorders.
2. Host-intestinal microbiota
interactions as they pertain to inflammatory disorders and colorectal cancer. This work focuses primarily on defining the role of sulfate-reducing
bacteria (SRB) and intestinal sulfomucins in the
initiation or progression of chronic human intestinal disorders such as
inflammatory bowel disease (IBD). Sulfate-reducing bacteria are members of the
normal microbiota and have a major impact on terminal
fermentative processes that occur in the mammalian colon. The metabolic
pathways used by SRB culminate in the production of the toxic gas hydrogen
sulfide. Using novel reagents and approaches for studying both SRBs and host
epithelial cell responses to sulfide, we have demonstrated that host sulfomucins are a likely key source of sulfate for dissimilatory sulfate respiration by SRBs and that
exogenous sulfide is a potent genotoxin. Accordingly,
we are exploring the working model that multifactorial interactions between
polymorphic genes (alleles) that influence SRB colonization and those that influence
epithelial responses to the environmental agent sulfide may contribute to
IBD-associated or sporadic colorectal cancer.
3. Redox regulatory mechanisms governing cell fate
decisions. In simple terms, cancer can be viewed as a
state in which the balance between cell proliferation and cell death aberrantly
favors the former. We and others have discovered that the intracellular redox
environment exerts a profound influence on the normal cellular processes that
regulate this balance including DNA synthesis, enzyme activation, selective
gene expression, cell cycle progression, proliferation, differentiation, and
apoptosis. In fact, it could be argued that redox homeostasis is more central
to the governance of cell fate than any other biochemical phenomenon. However,
this is a difficult area of study and molecular mechanisms mediating redox
sensitivity and regulation are poorly defined. Motivated by these limitations,
we have created novel genetic constructs that enable real-time and extended
assessment of alterations in intracellular redox without cellular disruption.
We are using these FRET-based redox biosensors to study compartmentalization of
the cellular redox environment and to address the crucial question of whether
tumor cells have lost the ability to mount the apparent changes in
intracellular redox potential that accompany normal cell growth or
alternatively an ability to sense these changes.
