Effects of mesalamine (5-aminosalicylic acid) on bacterial gene expression.
BACKGROUND
5-Aminosalicylic acid (5-ASA) is a well-established treatment for inflammatory bowel disease (IBD) and may reduce the risk of colon cancer in patients with chronic colitis, but the mechanisms underlying these effects have not been fully elucidated. Although 5-ASA delivery is targeted to the distal gut, little is known about its effects on the luminal bacteria that reside there. Intestinal bacteria are believed play a role in causing or perpetuating IBD, and bioremediation has been studied as a therapeutic strategy. In an effort to better understand the bacteriological effects of 5-ASA, we examined the role of this compound at the level of bacterial gene expression.


METHODS
5-ASA was screened for its effects on a random promoter library representing the genome of Salmonella enterica serovar Typhimurium as a model enteric bacterium. Forty-five constructs representing 38 unique promoters were found to be responsive to 5-ASA, and included genes involved in bacterial invasion, cellular metabolism, and stress resistance. Several genes of unknown function were also identified. These effects occurred at 5-ASA concentrations that are relevant to those achieved in the distal intestinal tract in patients with IBD but did not inhibit bacterial growth.


RESULTS
Bacterial invasiveness was decreased by 5-ASA. Some of the identified genes had homologs among commensal Gram-negative enteric bacteria.


CONCLUSIONS
This study demonstrates that 5-ASA has potent effects on bacterial gene expression. These novel findings implicate intestinal bacteria as pharmacological targets of 5-ASA, perhaps contributing to the therapeutic action of this important class of IBD drugs.
Kaufman
Jaime
J
Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
Griffiths
Tanya A
TA
Surette
Michael G
MG
Ness
Susan
S
Rioux
Kevin P
KP
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D052978:Disk Diffusion Antimicrobial Tests; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000382:microbiology*; D019804:Mesalamine / Q000494:pharmacology*; D009876:Operon / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012480:Salmonella Infections / Q000188:drug therapy / Q000382:microbiology; D012485:Salmonella typhi / Q000187:drug effects / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine