Probiotic Modulation of Intestinal Cell Apoptosis in Inflammatory
Immunotherapy: Open Access

Immunotherapy: Open Access
Open Access

ISSN: 2471-9552

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Commentary - (2015) Volume 1, Issue 1

Probiotic Modulation of Intestinal Cell Apoptosis in Inflammatory Bowel Disease and Colon Cancer

Estefanía Muñoz-Atienza*
Department of Nutrition, Bromatology and Food Technology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040-Madrid, Spain
*Corresponding Author: Estefanía Muñoz-Atienza, Department of Nutrition, Bromatology and Food Technology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040-Madrid, Spain, Tel: +34-913943750, Fax: +34-913943743 Email:


Probiotic bacteria have been proposed as a therapeutic strategy for chronic intestinal inflammation and colon cancer. One of the mechanisms of action by which probiotics exert their effects is the modulation of apoptosis in intestinal immune and/or epithelial cells. Therefore, the knowledge of how probiotics modulate cell apoptosis provide additional information in the therapeutic strategy of these intestinal disorders. The objective of this commentary is to highlight the most relevant studies focused on pro- and anti-apoptotic effects of probiotics in intestinal cells in order to gain insight into their mechanisms of action.

Keywords: Probiotic; Apoptosis; Inflammatory bowel disease; Colon cancer


Nowadays, the use of probiotics has been proposed as a potential therapeutic strategy of inflammatory diseases and cancer in human medicine, including the treatment of intestinal pathologies, such as inflammatory bowel disease (IBD) and colon cancer. The interest in understanding the mechanisms of action by which probiotics exert their effects has increased during the last years. One of the mechanisms of action reported is the modulation of apoptosis in intestinal immune and/or epithelial cells, but the number of studies focused on this mechanism is limited. The knowledge of how probiotics modulate cell apoptosis provide additional information and could help in the therapeutic strategy of these intestinal disorders, reducing the mucosal inflammation or tumor growth. Therefore, this commentary aims to highlight the most relevant studies focused on pro- and anti-apoptotic effects of probiotics in intestinal cells in order to gain insight into their mechanisms of action.

Apoptosis signaling can be induced through the extrinsic and intrinsic pathways. The extrinsic pathway is mediated by several receptors, including first apoptosis signal (FAS; also called CD95 or APO-1), tumor necrosis factor receptor 1 (TNFR1), TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAIL-R1 or DR4) and TRAIL receptor 2 (TRAIL-R2 or DR5), which are activated by extracellular ligands initiating a protein-protein interaction at cell membranes that active an intracellular caspase cascade [1,2]. On the other hand, the intrinsic pathway is initiated by several stimuli (e.g., DNA damage, starvation, oxidative stress and chemotherapeutic drugs) which involve mitochondrial outer membrane permeabilization and mitochondria-to-cytosol translocation of (i) cytochrome c that forms the apoptosome complex with the apoptotic protease-activating factor-1 (Apaf-1) and activates caspase-9, which subsequently triggers caspase-3; (ii) inhibitors of apoptosis proteins (IAPs), such as Smac/Diablo and Omi/HtrA2, which enhance caspase activation, or (iii) apoptosis-inducing factor (AIF), which causes nuclear chromatin condensation and facilitates DNA fragmentation by the nuclease Endo G (caspase-independent pathway) [1-3]. Pro- and anti-apoptotic effects have been described as beneficial features of probiotics in intestinal pathologies. In this sense, the activation of the cell programmed death could suppress the number of active monocytes and lymphocytes in chronic inflammatory diseases [4] and could limit the number of carcinogenic cells in tumors [5]. However, the anti-apoptotic effect of probiotics in epithelial intestinal cells could reduce the colonic barrier disruption in chemical-induced colitis [6].

Regarding intestinal inflammatory diseases, previous studies have reported probiotic strains with different mechanisms to modulate cell apoptosis. Angulo et al. (2011) [7] showed that Lactobacillus brevis and Streptococcus thermophilus sonicates induced more apoptosis in lamina propria mononuclear cells (LPMC) isolated from patients with Crohn’s disease and ulcerative colitis than control LPMC. They also demonstrated that the pro-apoptotic effect of these probiotics was mediated by the neutral sphingomyelinase/ceramide pathway. Therefore, promoting apoptosis by these sonicates could stabilize the deficient cell death and decrease the inflammation response in IBD [7]. Moreover, Chiu et al. (2010) [4] described that heat-stable factor(s) (5–30 kDa fraction) produced by Lactobacillus rhamnosus promoted apoptosis in lymphocytes and monocytes isolated from healthy blood donors and human monocytic leukemia-derived cell lines (THP-1) by a mitochondrial pathway without affecting human colonic epithelial carcinoma cells (HT-29), suggesting its administration to prevent IBD. However, the effect on apoptosis in lamina propia mononuclear cells obtained from patients with intestinal pathologies was not determined. Interestingly, Yan et al. (2011) [6] reported an anti-apoptotic effect of a derived soluble protein (p40) produced by L. rhamnosus GG, which prevented cytokine-induced apoptosis in intestinal epithelial cells mediated through activation of the epidermal growth factor receptor (EGFR) phosphorylation in young adult mouse colon epithelial cells and HT-29 cells. In addition, p40 reduced intestinal epithelial apoptosis in dextran sulfate sodium-induced acute colitis and oxazolone-induced chronic colitis. This anti-apoptotic effect of L. rhamnosus GG was also observed previously [8]. This probiotic strain reduced staurosporine-induced apoptosis in rat intestinal epithelial cells (IEC-6) and using ex vivo models in mice, inhibiting caspase-3 activation and stimulating the up-regulation of anti-apoptotic genes.

With respect to models with tumoral cells, most studies reported the induction of apoptosis as an anti-carcinogenic effect. Altonsy et al. (2010) [1] reported that L. rhamnosus GG and Bifidobacterium lactis Bb12 could provide protection against colon cancer by inducing apoptosis, via the mitochondrial route, as indicated by the re-localization of Bax from the cytoplasm to the mitochondria, the cytochrome c release from the mitochondria into the cytoplasm, and the caspase-9 and -3 activation in colon cancer cell line Caco-2. Chen et al. (2012) [5] described that the oral administration of Lactobacillus acidophilus NCFM in mice increased apoptosis of CT-26 murine colon adenocarcinoma cells in the segmental orthotopic colon cancer, and the expression of the caspase-3 and -9, attenuating the tumor growth during CT-26 cell carcinogenesis. Wang et al. (2014) [9] demonstrated that the cell extract from three lactobacilli possessed the ability to induce HT-29 cells apoptosis through the breakdown of mitochondrial membrane potential. Recently, Song et al. (2015) [10] indicated that the membrane proteins (12 and 15 kDa fractions) from heat-inactivated Lactobacillus plantarum L67 had a pro-apoptotic effect in HT-29 cells by the induction of the mitochondrial (intrinsic) cell death pathway confirmed by caspase-8-mediated cleavage of Bid to the t-Bid protein, induction of the translocation of cytochrome c from mitochondria to cytosol, and stimulation of the caspase-8 and caspase-3 activities. Similar results were observed in colon cancer SW620 cells treated with the supernatant obtained from Lactobacillus delbrueckii, which efficiently induced apoptosis through the intrinsic caspase 3-depedent pathway, with a corresponding decreased expression of Bcl-2 [11]. Furthermore, Baldwin et al. (2010) [12] demonstrated a synergistic pro-apoptotic effect of the combination of a chemotherapeutic agent, 5-fluorouracil, and a mixture of viable L. acidophilus CL1285 and Lactobacillus casei LBC80R probiotic strains in a colorectal carcinoma cell line LS513, correlated with the activation of the caspase-3 and a faster reduction of p21 expression.

In veterinary medicine, there are few studies concerning the mechanisms of action of probiotics in chronic enteropathies, being these studies focused specifically on dogs [13-16]. However, none of them related to the apoptotic effect of probiotics on intestinal cells.

In conclusion, Lactobacillus spp. is the most reported genus with ability to modulate apoptosis in intestinal immune and/or epithelial cells. Moreover, the most common mechanism by which probiotics exert their pro-apoptotic effect in colon cancer seems to be through the mitochondrial (intrinsic) pathway. However, further studies on pro- and anti- apoptotic effects of probiotics in chronic intestinal diseases should be carried out in an attempt to explain the specific mechanisms by which probiotics reduce the bowel inflammation promoting immune cell apoptosis and also protect intestinal integrity reducing intestinal epithelial cell apoptosis.


  1. Altonsy MO, Andrews SC, Tuohy KM (2010) Differential induction of apoptosis in human colonic carcinoma cells (Caco-2) by Atopobium, and commensal, probiotic and enteropathogenic bacteria: mediation by the mitochondrial pathway. Int J Food Microbiol 137: 190-203.
  2. Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free RadicBiol Med 48: 749-762.
  3. Zhong L, Zhang X, Covasa M (2014) Emerging roles of lactic acid bacteria in protection against colorectal cancer.World J Gastroenterol 20: 7878-7886.
  4. Chiu YH, Hsieh YJ, Liao KW, Peng KC (2010) Preferential promotion of apoptosis of monocytes by Lactobacillus caseirhamnosus soluble factors.ClinNutr 29: 131-140.
  5. Chen CC, Lin WC, Kong MS, Shi HN, Walker WA, et al. (2012) Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue.Br J Nutr 107: 1623-1634.
  6. Yan F, Cao H, Cover TL, Washington MK, Shi Y, et al. (2011) Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism.J Clin Invest 121: 2242-2253.
  7. Angulo S, Morales A, Danese S, Llacuna L, Masamunt MC, et al. (2011) Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase.PLoS One 6: e16953
  8. Lin PW, Nasr TR, Berardinelli AJ, Kumar A, Neish AS (2008) The probiotic Lactobacillus GG may augment intestinal host defense by regulating apoptosis and promoting cytoprotective responses in the developing murine gut.Pediatr Res 64: 511-516.
  9. Wang SM, Zhang LW, Fan RB, Han X, Yi HX, et al. (2014) Induction of HT-29 cells apoptosis by lactobacilli isolated from fermented products.Res Microbiol 165: 202-214.
  10. Song S, Oh S, Lim KT (2015) The proteins (12 and 15 kDa) isolated from heat-killed Lactobacillus plantarum L67 induces apoptosis in HT-29 cells.Cell BiochemFunct 33: 89-96.
  11. Wan Y, Xin Y, Zhang C, Wu D, Ding D, et al. (2014) Fermentation supernatants of inhibit growth of human colon cancer cells and induce apoptosis through a caspase 3-dependent pathway. OncolLett 7: 1738-1742.
  12. Baldwin C, Millette M, Oth D, Ruiz MT, Luquet FM, et al. (2010) Probiotic Lactobacillus acidophilus and L. casei mix sensitize colorectal tumoral cells to 5-fluorouracil-induced apoptosis.Nutr Cancer 62: 371-378.
  13. Rossi G, Pengo G, Caldin M, Palumbo Piccionello A, Steiner JM, et al. (2014) Comparison of microbiological, histological, and immunomodulatory parameters in response to treatment with either combination therapy with prednisone and metronidazole or probiotic VSL#3 strains in dogs with idiopathic inflammatory bowel disease.PLoS One 9: e94699.
  14. Sauter SN, Allenspach K, Gaschen F, Gröne A, Ontsouka E, et al. (2005) Cytokine expression in an ex vivo culture system of duodenal samples from dogs with chronic enteropathies: modulation by probiotic bacteria.DomestAnimEndocrinol 29: 605-622.
  15. Schmitz S, Henrich M, Neiger R, Werling D, Allenspach K (2014) Stimulation of duodenal biopsies and whole blood from dogs with food-responsive chronic enteropathy and healthy dogs with Toll-like receptor ligands and probiotic Enterococcus faecium.Scand J Immunol 80: 85-94.
  16. Schmitz S, Werling D, Allenspach K (2015) Effects of ex-vivo and in-vivo treatment with probiotics on the inflammasome in dogs with chronic enteropathy.PLoS One 10: e0120779.
Citation: Atienza EM (2015) Probiotic Modulation of Intestinal Cell Apoptosis in Inflammatory Bowel Disease and Colon Cancer. Immunother open acccess 1: 101.

Copyright: © 2015 Atienza EM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.