, Volume 12, Issue 3, pp 573–591 | Cite as

Acidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteria

  • Annaïg Lan
  • Dominique Lagadic-Gossmann
  • Christophe Lemaire
  • Catherine Brenner
  • Gwénaël JanEmail author


The human probiotic Propionibacterium freudenreichii kills colorectal adenocarcinoma cells through apoptosis in vitro via its metabolites, the short chain fatty acids (SCFA), acetate and propionate. However, the precise mechanisms, the kinetics of cellular events and the impact of environmental factors such as pH remained to be specified. For the first time, this study demonstrates a major impact of a shift in extracellular pH on the mode of propionibacterial SCFA-induced cell death of HT-29 cells, in the pH range 5.5 to 7.5 prevailing within the colon. Propionibacterial SCFA triggered apoptosis in the pH range 6.0 to 7.5, a lethal process lasting more than 96 h. Indeed at pH 7.5, SCFA induced cell cycle arrest in the G2/M phase, followed by a sequence of cellular events characteristic of apoptosis. By contrast, at pH 5.5, the same SCFA triggered a more rapid and drastic lethal process in less than 24 h. This was characterised by sudden mitochondrial depolarisation, inner membrane permeabilisation, drastic depletion in ATP levels and ROS accumulation, suggesting death by necrosis. Thus, in digestive cancer prophylaxis, the observed pH-mediated switch between apoptosis and necrosis has to be taken into account in strategies involving SCFA production by propionibacteria to kill colon cancer cells.


Cell death Colorectal cancer Short-chain fatty acids 





mitochondrial transmembrane potential




dihexyloxacarbocyanine iodide






fluorescein diacetate


inner membrane




superoxide anion




poly-ADP-ribose polymerase


programmed cell death


propidium iodide


permeability transition pore complex


receptor-interacting protein


reactive oxygen species


short-chain fatty acid


tumor necrosis factor


TNF α related apoptosis inducing ligand



The authors wish thank Dr. O. Meurette and Dr. L. Huc for their helpful advice on cytometric analysis, and C. Longin for technical assistance in TEM assay.


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Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Annaïg Lan
    • 1
    • 2
  • Dominique Lagadic-Gossmann
    • 3
  • Christophe Lemaire
    • 4
  • Catherine Brenner
    • 4
  • Gwénaël Jan
    • 1
    Email author
  1. 1.UMR 1253 INRA AgrocampusScience & Technologie du Lait et de l’Oeuf, 65, rue de St BrieucRennes cedexFrance
  2. 2.Laboratoires Standa68 rue R. KaskoreffCaen cedex 4France
  3. 3.INSERM U620, Université Rennes1Faculté de Pharmacie, 2 av Prof Léon Bernard35043 Rennes cedexFrance
  4. 4.CNRS UMR 8159, LGBCUniversité de VersaillesVersaillesFrance

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