Applied Microbiology and Biotechnology

, Volume 97, Issue 14, pp 6451–6466 | Cite as

A shift in the dominant phenotype governs the pH-induced metabolic switch of Clostridium acetobutylicumin phosphate-limited continuous cultures

  • Thomas Millat
  • Holger Janssen
  • Graeme J. Thorn
  • John R. King
  • Hubert Bahl
  • Ralf-Jörg Fischer
  • Olaf Wolkenhauer
Applied Microbial and Cell Physiology


In response to changing extracellular pH levels, phosphate-limited continuous cultures of Clostridium acetobutylicum reversibly switches its metabolism from the dominant formation of acids to the prevalent production of solvents. Previous experimental and theoretical studies have revealed that this pH-induced metabolic switch involves a rearrangement of the intracellular transcriptomic, proteomic and metabolomic composition of the clostridial cells. However, the influence of the population dynamics on the observations reported has so far been neglected. Here, we present a method for linking the pH shift, clostridial growth and the acetone–butanol–ethanol fermentation metabolic network systematically into a model which combines the dynamics of the external pH and optical density with a metabolic model. Furthermore, the recently found antagonistic expression pattern of the aldehyde/alcohol dehydrogenases AdhE1/2 and pH-dependent enzyme activities have been included into this combined model. Our model predictions reveal that the pH-induced metabolic shift under these experimental conditions is governed by a phenotypic switch of predominantly acidogenic subpopulation towards a predominantly solventogenic subpopulation. This model-driven explanation of the pH-induced shift from acidogenesis to solventogenesis by population dynamics casts an entirely new light on the clostridial response to changing pH levels. Moreover, the results presented here underline that pH-dependent growth and pH-dependent specific enzymatic activity play a crucial role in this adaptation. In particular, the behaviour of AdhE1 and AdhE2 seems to be the key factor for the product formation of the two phenotypes, their pH-dependent growth, and thus, the pH-induced metabolic switch in C. acetobutylicum.


Clostridium acetobutylicum Acetone–butanol–ethanol fermentation Continuous culture pH-induced metabolic shift Phenotypic switch Mathematical modelling 



T.M., H.J., H.B., R.-J.F. and O.W. acknowledge support from the German Federal Ministry for Education and Research (BMBF) as part of the European Transnational Network–Systems Biology of Microorganisms (SysMo) within the COSMIC and BaCell-SysMo consortia (FKZ 0313981D, 0315782D, 0313978F and 0315784E). G.J.T. and J.R.K. acknowledge support from the Biotechnology and Biological Sciences Research Council (UK) (BBSRC grant no. BB/I004513/1) also as part of the European Transnational Network–SysMo within the COSMIC consortium. J.R.K. also acknowledges the funding of the Royal Society and Wolfson Foundation. We thank Ulf W. Liebal and Carola Berger for their critical comments and fruitful discussions. The responsibility for the content of this manuscript lies with the authors.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Thomas Millat
    • 1
  • Holger Janssen
    • 2
    • 5
  • Graeme J. Thorn
    • 3
  • John R. King
    • 3
  • Hubert Bahl
    • 2
  • Ralf-Jörg Fischer
    • 2
  • Olaf Wolkenhauer
    • 1
    • 4
  1. 1.Department of Systems Biology and BioinformaticsUniversity of RostockRostockGermany
  2. 2.Division of MicrobiologyUniversity of RostockRostockGermany
  3. 3.School of Mathematical SciencesUniversity of NottinghamNottinghamUK
  4. 4.Wallenberg Research Centre, Institute for Advanced Study (STIAS)Stellenbosch UniversityStellenboschSouth Africa
  5. 5.Department of Food Science and Human NutritionUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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