Clostridium difficile has become the most frequent cause of antibiotic-associated diarrhea. Moreover, the need to prevent/treat C. difficile infection (CDI) effectively has become more urgent as the severity of CDI has increased. Whereas in the past CDI was rarely a fatal disease, it now kills a significant number of patients, especially among the elderly or immunologically suppressed. Currently employed antibiotics (chiefly vancomycin and metronidazole) fail to eliminate CDI symptoms in 10-20% of patients. In addition, among those apparently cured, a significant fraction suffers multiple recurrences of CDI. In principle, it is better to prevent the occurrence of infection than to rely on post-infectin treatments. The infectious form of C. difficile is the spore;once spores enter the GI tract, they must germinate in order to return to vegetative growth, colonize and produce the toxin proteins that cause the symptoms of the disease. Previous work has shown that C. difficile spore germination is dependent on certain bile acids. The most effective germinant identified so far is the primary bile salt, sodium taurocholate. A metabolic product of taurocholate, deoxycholate, is produced by the normal microflora and is known to kill C. difficile. Interestingly, bile acids of te chenodeoxycholate family, which differ from the cholate family by a single hydroxyl group, are anti-germinant that competitively inhibit taurocholate-dependent germination. These findings have raised the possibility that certain bile acids or their derivatives could be used prophylactically to reduce the likelihood of CDI in patients who are at risk. Before doing so, however, it is critical to establish that patients who have CDI or who are at risk of becoming infected have an intestinal bile acid profile that favors C. difficile spore germination. If so, on could imagine delivering appropriate anti-germinant or growth-inhibiting bile acids to patients at risk to prevent the onset on CDI. In this proposal, we seek to reveal the relationship between bile acid profiles and likelihood of CDI by analyzing the bile acid profiles and presence of certai key members of the microflora in patients with CDI, in patients undergoing antibiotic therapy (which is a major risk factor for CDI) and in patients with recurrent CDI.

Public Health Relevance

Spores of Clostridium difficile, a primary cause of hospital-acquired infection and increasingly responsible for community-acquired infection, are the infectious form of the bacterium but must germinate in the intestinal tract in order to produce the toxins and other virulence factors that cause the inflammation and diarrhea that are characteristic of C. difficile disease. Since the relative concentrations of various bile acids determine the ability of spores to germinate in laboratory experiments, manipulating the bile acid ratios is a potential mechanism for combatting infection. Before embarking on a search for such novel anti-infective, we propose to determine if there is a bona fide correlation between human bile acid profiles and susceptibility to C. difficile infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI107640-02
Application #
8682883
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Ranallo, Ryan
Project Start
2013-06-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$195,710
Indirect Cost
$23,400
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Paredes-Sabja, Daniel; Shen, Aimee; Sorg, Joseph A (2014) Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. Trends Microbiol 22:406-16