Abstract
Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: a randomized, double-blind clinical trial. Aline Taborda Flesch;Stael T Tonial;Paulo DE Carvalho Contu;Daniel C Damin. 2017. Rev Col Bras Cir. 44. PMID: 29267553

OBJECTIVE: to evaluate the effect of perioperative administration of symbiotics on the incidence of surgical wound infection in patients undergoing surgery for colorectal cancer. METHODS: We conducted a randomized clinical trial with colorectal cancer patients undergoing elective surgery, randomly assigned to receive symbiotics or placebo for five days prior to the surgical procedure and for 14 days after surgery. We studied 91 patients, 49 in the symbiotics group (Lactobacillus acidophilus 108 to 109 CFU, Lactobacillus rhamnosus 108 to 109 CFU, Lactobacillus casei 108 to 109 CFU, Bifi dobacterium 108 to 109 CFU and fructo-oligosaccharide (FOS) 6g) and 42 in the placebo group. RESULTS: surgical site infection occurred in one (2%) patient in the symbiotics group and in nine (21.4%) patients in the control group (p=0.002). There were three cases of intraabdominal abscess and four cases of pneumonia in the control group, whereas we observed no infections in patients receiving symbiotics (p=0.001). CONCLUSION: the perioperative administration of symbiotics significantly reduced postoperative infection rates in patients with colorectal cancer. Additional studies are needed to confirm the role of symbiotics in the surgical treatment of colorectal cancer.
Probiotics (Lactobacillus acidophilus and Lactobacillus rhamnosus GG) in Conjunction with Celecoxib (selective COX-2 inhibitor) Modulated DMH-Induced Early Experimental Colon Carcinogenesis. Leila Kaeid Sharaf;Geeta Shukla. 2018. Nutr Cancer. 70. PMID: 30183370

Epidemiological and experimental observations have shown that nonsteroidal anti-inflammatory drugs especially selective cyclooxygenase-2 (COX-2) inhibitors and probiotics reduce the incidence risk of colon cancer. Therefore, the present study was designed to assess the prophylactic potentials of probiotics (Lactobacillus acidophilus and Lactobacillus rhamnosus GG) in conjunction with celecoxib, a selective cox-2 inhibitor in 1,2 dimethylhydrazine dihydrochloride (DMH)-induced experimental colon carcinogenesis, a well-established, well appreciated and widely used model for colorectal cancer that shares many similarities to human sporadic colorectal cancer with respect to response to some promotional and preventive agents. More specifically, it was observed that L. rhamnosus GG + celecoxib + DMH-treated animals had significantly reduced aberrant crypt foci (ACF) count and the expression of procarcinogenic molecular markers (β-catenin, NF-κB, and COX-2) in early experimental colon carcinogenesis compared with probiotic-DMH, celecoxib-DMH or DMH-treated animals. This is the first ever such study to demonstrate that probiotic in conjunction with celecoxib can be opted as an alternate prophylactic strategy in highly susceptible individuals to reduce both the incidence and severity of the life style diseases as prevention is better than cure.
Characterization of Biosynthesized Silver Nanoparticles Using Lactobacillus rhamnosus GG and its In Vitro Assessment Against Colorectal Cancer Cells. Seyed Mohammad Ali Aziz Mousavi;Seyed Ali Mirhosseini;Mona Rastegar Shariat Panahi;Hamideh Mahmoodzadeh Hosseini. 2019. Probiotics Antimicrob Proteins. 12. PMID: 31020619

Silver nanoparticles are the most desirable nanoparticles broadly used in diverse fields. This study intends to investigate the anticancer properties of synthesized silver/Lactobacillus rhamnosus GG nanoparticles (Ag-LNPs) as a reducing and stabilizing agent in the synthesis process. To prepare silver/Lactobacillus rhamnosus GG nanoparticles, 1 mg/ml cell lysate of Lactobacillus rhamnosus GG and 1 mM silver nitrate solution were mixed and incubated for 72 h. XRD, FTIR, and TEM methods were used for nanoparticle characterization. MTT assay and annexin/PI staining were employed to analyze the toxicity and apoptotic cells levels of Ag-LNPs, respectively. TEM showed that these nanoparticles are spherical shaped about 233 nm in size. FTIR spectroscopy demonstrated that Ag-LNPs were functionalized with biomolecules. XRD pattern showed high purity and face-centered crystal structure of Ag-LNPs. MTT assay revealed that the percentages of HT-29 live cells significantly reduced in the high concentration of Ag-LNPs. Annexin/PI staining showed that these nanoparticles could lead HT-29 cells to apoptosis. This study showed the new Ag-LNP-synthesizing method using Lactobacillus rhamnosus GG as a cost-effective and efficient approach. Also, it showed that these nanoparticles can be considered as a potential active agent for biomedical applications and drug delivery due to their anticancer activities.
Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. P Osterlund;T Ruotsalainen;R Korpela;M Saxelin;A Ollus;P Valta;M Kouri;I Elomaa;H Joensuu. 2007. Br J Cancer. 97. PMID: 17895895

5-Fluorouracil (5-FU)-based chemotherapy is frequently associated with diarrhoea. We compared two 5-FU-based regimens and the effect of Lactobacillus and fibre supplementation on treatment tolerability. Patients diagnosed with colorectal cancer (n=150) were randomly allocated to receive monthly 5-FU and leucovorin bolus injections (the Mayo regimen) or a bimonthly 5-FU bolus plus continuous infusion (the simplified de Gramont regimen) for 24 weeks as postoperative adjuvant therapy. On the basis of random allocation, the study participants did or did not receive Lactobacillus rhamnosus GG supplementation (1-2 x 10(10) per day) and fibre (11 g guar gum per day) during chemotherapy. Patients who received Lactobacillus had less grade 3 or 4 diarrhoea (22 vs 37%, P=0.027), reported less abdominal discomfort, needed less hospital care and had fewer chemotherapy dose reductions due to bowel toxicity. No Lactobacillus-related toxicity was detected. Guar gum supplementation had no influence on chemotherapy tolerability. The simplified de Gramont regimen was associated with fewer grade 3 or 4 adverse effects than the Mayo regimen (45 vs 89%), and with less diarrhoea. We conclude that Lactobacillus GG supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to 5-FU-based chemotherapy.
Antiproliferative and proapoptotic effects of viable or heat-killed Lactobacillus paracasei IMPC2.1 and Lactobacillus rhamnosus GG in HGC-27 gastric and DLD-1 colon cell lines. A Orlando;M G Refolo;C Messa;L Amati;P Lavermicocca;V Guerra;F Russo. 2012. Nutr Cancer. 64. PMID: 23061912

Data from literature suggest the possible use of probiotics as chemopreventive agents against colon cancer, but few investigations are available on their effects on gastric cancer proliferation. In our previous study, a specific Lactobacillus, strain L. paracasei IMPC2.1, was demonstrated to colonize the human gut and positively affect fecal bacteria and biochemical parameters. The aims of the present study were to investigate the effects of L. paracasei IMPC2.1, comparing them with those of Lactobacillus rhamnosus GG (L.GG), either as viable or heat-killed cells, on cell proliferation and apoptosis in a gastric cancer (HGC-27) and a colorectal cancer cell line (DLD-1). Both the gastric and colon cancer cells were sensitive to the growth inhibition and apoptosis induction by both viable or heat-killed cells from L. paracasei IMPC2.1 and L.GG. These findings suggest the possibility for a food supplement, based on dead probiotics, including L. paracasei IMPC2.1 cells, which could represent an effective component of a functional food strategy for cancer growth inhibition, with potential for cancer prevention.
Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice. Jingtao Hu;Chunfeng Wang;Liping Ye;Wentao Yang;Haibin Huang;Fei Meng;Shaohua Shi;Zhuang Ding. 2015. J Biosci. 40. PMID: 25963256

Colorectal cancer (CRC) is one of the most prevalent forms of cancer that shows a high mortality and increasing incidence. There are numerous successful treatment options for CRC, including surgery, chemotherapy, radiotherapy and immunotherapy; however, their side effects and limitations are considerable. Probiotics may be an effective strategy for preventing and inhibiting tumour growth through stimulation of host innate and adaptive immunity. We investigated and compared potential anti-tumour immune responses induced by two isolated Lactobacillus strains, Lactobacillus plantarum A and Lactobacillus rhamnosus b, by pre-inoculating mice with lactobacilli for 14 days. Subsequently, subcutaneous and orthotopic intestinal tumours were generated in the pre-inoculated mice using CT26 murine adenocarcinoma cells and were assessed for response against the tumour. Our results indicated that oral administration with L. plantarum inhibited CT26 cell growth in BALB/c mice and prolonged the survival time of tumour-bearing mice compared with mice administered L. rhamnosus. L. plantarum produced protective immunity against the challenge with CT26 cells by increasing the effector functions of CD8+ and natural killer (NK) cell infiltration into tumour tissue, up-regulation of IFN-gamma (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. Consequently, our results suggest that L. plantarum can enhance the anti-tumour immune response and delay tumour formation.
Colorectal Cancer Therapy Using a Pediococcus pentosaceus SL4 Drug Delivery System Secreting Lactic Acid Bacteria-Derived Protein p8. Byung Chull An;Yongku Ryu;Yeo-Sang Yoon;Oksik Choi;Ho Jin Park;Tai Yeub Kim;Song-In Kim;Bong-Kyu Kim;Myung Jun Chung. 2019. Mol Cells. 42. PMID: 31707776

Despite decades of research into colorectal cancer (CRC), there is an ongoing need for treatments that are more effective and safer than those currently available. Lactic acid bacteria (LAB) show beneficial effects in the context of several diseases, including CRC, and are generally regarded as safe. Here, we isolated a Lactobacillus rhamnosus (LR)-derived therapeutic protein, p8, which suppressed CRC proliferation. We found that p8 translocated specifically to the cytosol of DLD-1 cells. Moreover, p8 down-regulated expression of Cyclin B1 and Cdk1, both of which are required for cell cycle progression. We confirmed that p8 exerted strong anti-proliferative activity in a mouse CRC xenograft model. Intraperitoneal injection of recombinant p8 (r-p8) led to a significant reduction (up to 59%) in tumor mass when compared with controls. In recent years, bacterial drug delivery systems (DDSs) have proven to be effective therapeutic agents for acute colitis. Therefore, we aimed to use such systems, particularly LAB, to generate the valuable therapeutic proteins to treat CRC. To this end, we developed a gene expression cassette capable of inducing secretion of large amounts of p8 protein from Pediococcus pentosaceus SL4 (PP). We then confirmed that this protein (PP-p8) exerted anti-proliferative activity in a mouse CRC xenograft model. Oral administration of PP-p8 DDS led to a marked reduction in tumor mass (up to 64%) compared with controls. The PP-p8 DDS using LAB described herein has advantages over other therapeutics; these advantages include improved safety (the protein is a probiotic), cost-free purification, and specific targeting of CRC cells.
The synergistic effect of cell wall extracted from probiotic biomass containing Lactobacillus acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2 on the anticancer activity of cranberry juice-HPLC fractions. Kerlynn Desrouillères;Mathieu Millette;Leila Bagheri;Behnoush Maherani;Majid Jamshidian;Monique Lacroix. 2020. J Food Biochem. 44. PMID: 32185816

Anticancer effects were evaluated on three HPLC fractions obtained from a concentrated cranberry juice and cell wall constituents extracted from a probiotic biomass containing Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2. The samples were tested at increasing concentrations for the antiproliferative assay using HT-29 cells' line and for the quinone reductase (QR) assay using Hepa-1c1c7 murine hepatoma cells. Fraction 1 (F1) which is highly concentrated with phenolic acids inhibited the growth of the HT-29 cells' line with IC50 values of 14.80 µg Gallic acid equivalent (GAE)/ml. The fraction 3 (F3) which is highly concentrated in flavonols had potency as QR inducer. Furthermore, the results showed that all cranberry fractions combined with cell wall constituents extracted from the probiotic biomass were more effective in inhibiting the growth of HT-29 as compared to the cranberry fractions tested alone, indicating a possible synergy effect between these bio-functional compounds. PRACTICAL APPLICATIONS: This study strongly evidenced that cranberry juice fractions combined with cell wall constituents extracted from the probiotic biomass can be used as a potent preventive functional compound against colorectal cancer. Therefore, this research proposes a natural dietary compound to prevent mutagenesis and carcinogenesis of colorectal cancer. Furthermore, the industry can formulae products containing probiotic and phenolic compounds as colon cancer cell growth preventive and anticancer products.
Probiotics Lactobacillus rhamnosus GG, Lactobacillus acidophilus suppresses DMH-induced procarcinogenic fecal enzymes and preneoplastic aberrant crypt foci in early colon carcinogenesis in Sprague Dawley rats. Angela Verma;Geeta Shukla. 2013. Nutr Cancer. 65. PMID: 23368917

Diet makes an important contribution to colorectal cancer (CRC) risk implying risks for CRC are potentially reducible. Therefore, the probiotics have been suggested as the prophylactic measure in colon cancer. In this study, different probiotics were used to compare their protective potential against 1,2 dimethylhydrazine dihydrochloride (DMH)-induced chemical colon carcinogenesis in Sprague Dawley rats. Animals belonging to different probiotic groups were fed orally with 1 × 10(9) lactobacilli daily for 1 week, and then a weekly injection of DMH was given intraperitoneally for 6 wks with daily administration of probiotic. Lactobacillus GG and L.acidophilus + DMH-treated animals had maximum percent reduction in ACF counts. A significant decrease (P < 0.05) in fecal nitroreductase activity was observed in L.casei + DMH and L.plantarum + DMH-treated rats whereas β-glucuronidase activity decreased in L.GG + DMH and L.acidophilus + DMH-treated rats. Animals treated with Bifidobacterium bifidum + DMH had significant decreased β-glucosidase activity. However, not much difference was observed in the colon morphology of animals belonging to various probiotic + DMH-treated rats compared with DMH-treated alone. The results indicated that probiotics, L.GG, and L.acidophilus can be used as the better prophylactic agents for experimental colon carcinogenesis.
Synbiotic (Lactobacillus rhamnosus+Lactobacillus acidophilus+inulin) attenuates oxidative stress and colonic damage in 1,2 dimethylhydrazine dihydrochloride-induced colon carcinogenesis in Sprague-Dawley rats: a long-term study. Angela Verma;Geeta Shukla. 2014. Eur J Cancer Prev. 23. PMID: 25025584

The inexorable increase in the incidence of colorectal cancer has led to growing interest in its prevention by natural interventions. Thus, the present study was designed with the aim of delineating the antioxidative and antitumorigenic effects of synbiotics in experimental colon carcinogenesis. It was observed that administration of a synbiotic, before 1,2 dimethylhydrazine dihydrochloride (DMH)-induced colon carcinogenesis in Sprague-Dawley rats, led to increased body weight and growth rate, and decreased tumor incidence compared with the DMH-only-treated group of animals. Most notably, the level of malondialdehyde, a measure of lipid peroxidation, decreased, and levels of the antioxidants, glutathione reductase, superoxide dismutase, and glutathione peroxidase increased in animals in the Lactobacillus acidophilus+DMH, inulin+DMH, and synbiotic+DMH groups compared with DMH-only-treated animals. Histopathological observations of the colon also documented fewer dysplastic changes and increased the number of goblet cells in the probiotic-treated, prebiotic-treated, and synbiotic-treated animals compared with DMH-only-treated animals. Taken together, the present study shows that the use of synbiotics is a better prophylactic strategy than the use of probiotic and prebiotic alone because of the greater increase in antioxidants associated with the higher degree of attenuation of DMH-induced tumorigenesis.
A review of dose-responses of probiotics in human studies. A C Ouwehand. 2016. Benef Microbes. 8. PMID: 28008787

The probiotic definition requires the administration of an 'adequate amount' in order to obtain a health benefit. What that amount should be is not indicated. Here, an overview is given of studies that investigated the dose-response relation of probiotics in human interventions. Studies were divided in; meta-analyses, meta-analyses on specific probiotic strains, and studies testing two or more doses of a probiotic (combination) in the same study. Meta-analyses on the effect of probiotics on antibiotic associated diarrhoea (AAD) suggest a dose-response effect; for Clostridium difficile-associated diarrhoea on the other hand no dose-response was observed. For other end-points; such as necrotising enterocolitis, prevention of atopic dermatitis and slow intestinal transit, no dose-response relation was identified in meta-analyses. For prophylaxis in colorectal cancer and relief of irritable bowel syndrome, no dose-response relation was determined. However, for blood pressure, a meta-analysis observed that higher doses (greater than 1011 cfu) were more effective than lower doses. Meta-analyses of specific strains suggest a break-point for effectiveness of Lactobacillus rhamnosus GG in the treatment of acute gastroenteritis in children; no dose-response was observed for two other probiotics assessed. Studies comparing two or more doses indicate that faecal recovery and risk reduction of AAD follow a positive dose-response relationship. Other end-points such as immune markers, general health, and bowel function did not exhibit clear dose-response relations. For AAD, the findings are very compelling; both meta-analyses and dedicated dose-response studies observe a positive correlation between dose and AAD risk. These findings do not allow for extrapolation, but suggest that studying higher doses for this end-point would be worthwhile. The lack of a clear dose-response for other end-points, does not mean it does not exist; present data does just not allow drawing any conclusions.
Prophylactic intervention of probiotics (L.acidophilus, L.rhamnosus GG) and celecoxib modulate Bax-mediated apoptosis in 1,2-dimethylhydrazine-induced experimental colon carcinogenesis. Leila Kaeid Sharaf;Mridul Sharma;Deepika Chandel;Geeta Shukla. 2018. BMC Cancer. 18. PMID: 30424722

BACKGROUND: Colorectal cancer has been found to be attenuated either with prophylactic manipulation of gut microbiome with probiotics or celecoxib, a non-steroidal anti-inflammatory drug mainly by suppressing early pro-carcinogenic markers in various experimental studies. Therefore, the present study was designed to assess the prophylactic potential of combinatorial administration of probiotics (Lactobacillus rhamnosus GG, Lactobacillus acidophilus) and celecoxib in experimental colon carcinogenesis. METHODS: Six groups of Spraugue Dawely rats received probiotics L.rhamnosus GG or/and L.acidophilus in combination with celecoxib one week prior to the inducement of tumor by 1,2-dimethylhydrazine (DMH) and the treatment continued for 18 weeks. Prophylactic potentials of probiotics and celecoxib were determined by employing various methods such as tumor incidence, tumor burden, tumor multiplicity, apoptosis, caspase activity, expression of proto-oncogene K-ras and tumor suppressor p53 gene in colonic tumors. RESULTS: Interestingly, it was found that one week prior supplementation of both probiotics and celecoxib reduced tumor burden, tumor multiplicity, down-regulated the expression of anti-apoptotic Bcl-2, proto-oncogene K-ras and up-regulated pro-apoptotic Bax as well as tumor suppressor p53 in L.rhamnosus GG + celecoxib+DMH animals compared with counter controls and DMH-treated. CONCLUSIONS: It can be concluded that such combinatorial approach may be useful in reducing the burden and severity of disease in highly susceptible individuals but needs to be validated clinically.
Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Joseph Rafter;Michael Bennett;Giovanna Caderni;Yvonne Clune;Roisin Hughes;Pernilla C Karlsson;Annett Klinder;Micheal O'Riordan;Gerald C O'Sullivan;Beatrice Pool-Zobel;Gerhard Rechkemmer;Monika Roller;Ian Rowland;Maddalena Salvadori;Herbert Thijs;Jan Van Loo;Bernhard Watzl;John K Collins. 2007. Am J Clin Nutr. 85. PMID: 17284748

BACKGROUND: Animal studies suggest that prebiotics and probiotics exert protective effects against tumor development in the colon, but human data supporting this suggestion are weak. OBJECTIVE: The objective was to verify whether the prebiotic concept (selective interaction with colonic flora of nondigested carbohydrates) as induced by a synbiotic preparation-oligofructose-enriched inulin (SYN1) + Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (BB12)-is able to reduce the risk of colon cancer in humans. DESIGN: The 12-wk randomized, double-blind, placebo-controlled trial of a synbiotic food composed of the prebiotic SYN1 and probiotics LGG and BB12 was conducted in 37 colon cancer patients and 43 polypectomized patients. Fecal and blood samples were obtained before, during, and after the intervention, and colorectal biopsy samples were obtained before and after the intervention. The effect of synbiotic consumption on a battery of intermediate bio-markers for colon cancer was examined. RESULTS: Synbiotic intervention resulted in significant changes in fecal flora: Bifidobacterium and Lactobacillus increased and Clostridium perfringens decreased. The intervention significantly reduced colorectal proliferation and the capacity of fecal water to induce necrosis in colonic cells and improve epithelial barrier function in polypectomized patients. Genotoxicity assays of colonic biopsy samples indicated a decreased exposure to genotoxins in polypectomized patients at the end of the intervention period. Synbiotic consumption prevented an increased secretion of interleukin 2 by peripheral blood mononuclear cells in the polypectomized patients and increased the production of interferon gamma in the cancer patients. CONCLUSIONS: Several colorectal cancer biomarkers can be altered favorably by synbiotic intervention.
Cell-free supernatants from probiotic Lactobacillus casei and Lactobacillus rhamnosus GG decrease colon cancer cell invasion in vitro. Juanita Escamilla;Michelle A Lane;Vatsala Maitin. 2012. Nutr Cancer. 64. PMID: 22830611

Probiotics have been shown to have a preventative role in colorectal carcinogenesis but research concerning their prophylactic potential in the later stages of colorectal cancer, specifically metastasis is limited. This study explored the potential of cell-free supernatants (CFS) from 2 probiotic Lactobacillus sp., Lactobacillus casei and Lactobacillus rhamnosus GG, to inhibit colon cancer cell invasion by influencing matrix metalloproteinase-9 (MMP-9) activity and levels of the tight junction protein zona occludens-1 (ZO-1) in cultured metastatic human colorectal carcinoma cells. HCT-116 cells were treated with CFS from L. casei, L. rhamnosus, or Bacteroides thetaiotaomicron (a gut commensal); or with uninoculated bacterial growth media. Treatment with CFS from both Lactobacillus sp. decreased colorectal cell invasion but treatment with CFS from B. thetaiotaomicron did not. CFS from both Lactobacillus sp. decreased MMP-9 and increased ZO-1 protein levels. L. rhamnosus CFS also lowered MMP-9 activity. To begin elucidating the secreted bacterial factor conveying these responses, Lactobacillus sp. CFS were fractionated into defined molecular weight ranges and cell invasion assessed. Fractionation revealed that the inhibitory activity was contained primarily in the >100 kDa and 50-100 kDa fractions, suggesting the inhibitory compound may be a macromolecule such as a protein, nucleic acid, or a polysaccharide.