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Infection and Immunity, October 2000, p. 5881-5888, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Toxins, Butyric Acid, and Other Short-Chain Fatty Acids Are Coordinately Expressed and Down-Regulated by Cysteine in Clostridium difficile

Sture Karlsson,1,2 Anette Lindberg,3 Elisabeth Norin,4 Lars G. Burman,1 and Thomas Åkerlund1,*

Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82, Solna,1 Microbiology and Tumor Biology Center2 and Laboratory of Medical Microbial Ecology,4 Karolinska Institute, S-171 77, Stockholm, and Department of Medical Biochemistry and Microbiology, Uppsala University, S-751 23, Uppsala,3 Sweden

Received 17 April 2000/Returned for modification 31 May 2000/Accepted 27 July 2000

It was recently found that a mixture of nine amino acids down-regulate Clostridium difficile toxin production when added to peptone yeast extract (PY) cultures of strain VPI 10463 (S. Karlsson, L. G. Burman, and T. Åkerlund, Microbiology 145:1683-1693, 1999). In the present study, seven of these amino acids were found to exhibit a moderate suppression of toxin production, whereas proline and particularly cysteine had the greatest impact, on both reference strains (n = 6) and clinical isolates (n = 28) of C. difficile (>99% suppression by cysteine in the highest toxin-producing strain). Also, cysteine derivatives such as acetylcysteine, glutathione, and cystine effectively down-regulated toxin expression. An impact of both cysteine and cystine but not of thioglycolate on toxin yield indicated that toxin expression was not regulated by the oxidation-reduction potential. Several metabolic pathways, including butyric acid and butanol production, were coinduced with the toxins in PY and down-regulated by cysteine. The enzyme 3-hydroxybutyryl coenzyme A dehydrogenase, a key enzyme in solventogenesis in Clostridium acetobutylicum, was among the most up-regulated proteins during high toxin production. The addition of butyric acid to various growth media induced toxin production, whereas the addition of butanol had the opposite effect. The results indicate a coupling between specific metabolic processes and toxin expression in C. difficile and that certain amino acids can alter these pathways coordinately. We speculate that down-regulation of toxin production by the administration of such amino acids to the colon may become a novel approach to prophylaxis and therapy for C. difficile-associated diarrhea.

* Corresponding author. Mailing address: Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82, Solna, Sweden. Phone: 46 8 4572467. Fax: 46 8 301797. E-mail: Thomas.Akerlund{at}smi.ki.se.

Infection and Immunity, October 2000, p. 5881-5888, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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