Intestinal Microecology in Chronic Constipation

Chronic constipation is a common condition with a heterogeneous pathophysiology and
resulting clinical manifestations. Recent evidence in the literature and collected in our
laboratory confirm that there are differences in the gut microbiota between healthy
individuals and those with a variety of disorders (e.g., inflammatory bowel disease,
irritable bowel syndrome and obesity) suggesting that the development of certain disorders
may be determined by the composition of the gut microbiota. Existing evidence warrants
further investigation of the role of the microbial ecology of the human gut in constipation
and an exploration of modification of the gut microbiota as a means to treat constipation by
its actions on the colonic metabolism of nutrient substrates to alter colonic transit and
fluid fluxes.

The proposed research will exploit our proven capability to use high-throughput molecular
genomic techniques to define the intestinal microbiome in order to help define the role of
the gut microbiota in chronic constipation and will explore the potential value of altering
the microbiota as a management strategy in constipation. The linkage of high-throughput
genomic analyses with cause-and-effect understanding of how the gut microbiota affects bowel
function may lead to a reliable means to manage the gut microbiota with the intent to
prevent and/or treat constipation. The immediate goals of this project are to expand on
existing information about the microbial ecology in the human intestines focusing on its
relationship with constipation using molecular microbiological techniques and to assess the
effects on the gut microorganisms resulting from the use of the FDA-approved medication,
lubiprostone. Lubiprostone is a member of a novel therapeutic class called prostones and is
an orally active, bicyclic fatty acid that selectively acts on type 2 chloride channels to
stimulate chloride secretion which induces a net increase in luminal fluid secretion.
Unlike antibiotic, probiotic and prebiotic agents, it has no known direct effects on the gut
microbiota. It is FDA-approved for the treatment of chronic constipation in men and women
and for women with constipation-predominant IBS (C-IBS). The rationale for using
lubiprostone to modify the gut microbiota stems from the use of similar strategies for
controlling recalcitrant small intestinal bacterial overgrowth (i.e., altering fluid fluxes
in the gut lumen).

We believe that this research will greatly improve our understanding of the role that the
gut microbiota play in the development of constipation and potentially lead to new
strategies with which to combat this common problem.