The Role of Probiotics in Colorectal Cancer Management

Table 2

Effect of probiotic supplementation in CRC experimental animals.

Experimental model	Intervention	Duration of treatment	Key results	References
Apc^Min/+ CRC mouse model	L. acidophilus ATCC 314, L. fermentum NCIMB 5221 (each 0.5 × 10^10 CFU; total 1 × 10^10 CFU/day)	12 weeks	↓ multiplicity of tumors; ↓ β-catenin and Ki-67	[29]
Azoxymethane-mediated colonic neoplasm induced Sprague-Dawley rats	B. lactis (1 × 10^11 CFU/g), and/or resistant starch (Hi-maize® 958 or Hi-maize® 260; 100 g/kg diet)	∼22 weeks	↓ incidence and development of colonic neoplasms; The protective effects were observed to be higher in the synbiotic supplemented group	[33]
Trinitrobenzene sulfonic acid-mediated chronic colitis induced Sprague-Dawley rats	VSL#3 (B. breve, B. infantis, B. longum, L. acidophilus, L. bulgaricus, L. casei, L. plantarum, and Streptococcus salivarius subsp. thermophilus), 5 × 10^9 CFU/100 g of body weight	Differs	No carcinoma development; No high-grade dysplasia; ↓ colon damage; ↑ expression of antiangiogenic factor angiostatin, alkaline sphingomyelinase, and vitamin D receptor.	[34]
Azoxymethane/dextran sodium sulfate-mediated colitis-associated CRC induced mouse model	VSL#3 (1.3 × 10^6 CFU/day), and/or Balsalazide (300 mg/kg body weight/day)	2 weeks before azoxymethane exposure and continued for 9 weeks until sacrification	↓ number of tumors; ↓ F4/80-positive macrophages; ↓ p-STAT3 expression; ↓ BCL-2 expression; ↓ MIP-1β, MCP-1, IL-6, IL-10 level; ↑ BAX expression	[35]
Azoxymethane-mediated colitis-associated CRC induced mouse model	VSL#3 (1 × 10^9 CFU/day)	19 weeks (from 6^th week to 24^th week)	↓ Clostridium species; No reduction in tumorigenesis	[36]
1,2-Dimethyl hydrazine (DMH)-mediated CRC induced Sprague Dawley rats	L. rhamnosus GG, or L. casei, L. plantarum, or L. acidophilus, or B. bifidum. (probiotic dose: 1 × 10^9 CFU/day)	Seven weeks (1 week before starting DMH exposure and continued for 6 weeks)	↓ percentage of Aberrant crypt foci (ACF); ↓ nitroreductase activity, β-glucuronidase activity, β-glucosidase activity	[37]
DMH-mediated CRC-induced Sprague Dawley rats	Synbiotic (L. rhamnosus GG, L. acidophilus, and inulin; 1 × 10^9 CFU probiotic +5 mg inulin/day) or probiotic (L. rhamnosus GG, and/or L. acidophilus; 1 × 10^9 CFU probiotic/day) or prebiotic (inulin; 5 mg/day)	19 weeks (1 week before starting DMH exposure and continued for 18 weeks)	↓ MDA level; ↑ GSH, SOD, and GPx; Improved the histopathological score	[38]
DMH-mediated CRC-induced rats	L. acidophilus LaVK2 and B. bifidum BbVK3 or both probiotic + piroxicam; 2 × 10^9 CFU/g of each probiotic	32 weeks	↓ number of ACF, mucin-depleted foci, and proliferating cell nuclear antigen	[39]
DMH-mediated CRC-induced rats	L. plantarum AS1 (1 × 10^9 CFU/day)	5–21 weeks	↑ antioxidant system of the host; ↓ tumor diameter and number of tumors	[40]
DMH-mediated CRC-induced rats	L. salivarius (5 × 10^8 or 1 × 10^10 CFU/kg body weight/day)	15 weeks (2 week before starting DMH exposure and continued until 15 weeks)	Improved the colonic microflora and luminal metabolisms.; ↓ number and multiplicity of ACF, azoreductase activity; ↑ short-chain fatty acid levels	[41]
CT26 tumor-bearing mice	L. plantarum or L. rhamnosus; 1 × 10^9 CFU/day	Pre-exposure for 14 days	↓ CT26 growth; ↑ lifespan of tumor-bearing mice; ↑ IFN-γ, Th1-type CD4^+ T differentiation; ↑ CD8^+ function; ↑ NK cell infiltration	[42]
DMH-mediated CRC-induced rats	L. salivarius Ren (5 × 10^10 CFU/kg body weight/day)	32 weeks	Reversed the DMH-induced altered microbiota	[43]
DMH-mediated CRC-induced rats	L. rhamnosus GG CGMCC 1.2134 (1 × 10^9 CFU/day)	25 weeks	↓ incidence, multiplicity, and volume of tumor; ↓expression of inflammatory proteins, and antiapoptotic protein; ↑ proapoptotic proteins	[44]
DMH-mediated CRC-induced mice	L. casei BL23 (10 µl; 1 × 10^8 CFU/µl)	3 days (on days 0, 14, 28)	↓ incidence of tumor; ↓ multiple plaque lesions; Regulates the Treg and Th17 T cells; Altered the expression of IL-6, IL-10, IL-17, and TGF-β	[45]
DMH and SW480 cell-mediated CRC-induced rat	B. infantis (1 × 10^9 CFU/day) and/or 5-FU + oxaliplatin	11 days	↑ body weight and intestinal villus height; ↓ IL-6, IL-1β, TNF-α levels, and Th17 and Th1 cell-associated cytokines; ↑ CD4^+, CD25^+, Foxp^3+, Tregs expressions	[46]
Azoxymethane/dextran sodium sulfate-mediated colitis-associated cancer-induced mice model	B. longum, L. acidophilus, and E. faecalis (1.2 × 10^7 CFU/day)	Pretreatment for 2 weeks and continued till the end of the experiment	↓ intestinal inflammation and tumor formation.; ↓ Desulfovibrio, Mucispirillum, and Odoribacter species; ↑ Lactobacillus species; Altered the expression of CXCR2 ligand genes	[47]
Azoxymethane-mediated CRC-induced mice	L. acidophilus (1 × 10^9 CFU/day) and B. bifidum (1 × 10^9 CFU/day)	5 months	↓ miR-135b, miR-155, and KRAS ↑ miR-26b, miR-18a, APC, PU.1, and PTEN	[48]
Azoxymethane/dextran sodium sulfate-mediated CRC-induced rat model	L. acidophilus LA5 and/or B. animalis subsp. Lactis BB-12, and GBR; 5 × 10^7 CFU of single probiotic strain/day or 2.5 × 10^7 CFU each strain/day	10 weeks	↓ mucin-depleted foci formation; ↑ expression of p53, Bax, caspase-3, and Bax/Bcl-2 ratio; ↓ Bcl-2 expression; ↑ SOD activity; ↓ aberrant crypt foci (ACF)-producing sialomucin	[49]
DMH-mediated CRC-induced rats	L. rhamnosus GG MTCC #1408, and/or L. acidophilus NCDC #15 (1 × 10^9 CFU/day), and/or celecoxib (6 mg/kg body weight)	18 weeks	↓ multiplicity and tumor burden; ↓ Bcl-2, K-ras expression; ↑ Bax, p53 expression	[50]
DMH-mediated CRC-induced rats	L. rhamnosus GG MTCC #1408, and/or L. acidophilus NCDC #15 (1 × 10^9 CFU/day), and/or celecoxib (6 mg/kg body weight)	6 weeks	↓ ACF formation; ↓ β-catenin, COX-2, and NF-κB expression	[51]

↑: increased; ↓: decreased; MDA: malondialdehyde; GSH: glutathione; SOD: superoxide dismutase; GPx: glutathione peroxidase; NK: natural killer; IFN-γ: interferon-γ; p-STAT3: phospho-signal transducer and activator of transcription 3; BCL-2: B-cell lymphoma 2; BAX: BCL2-associated X protein; MIP-1β: macrophage inflammatory protein 1 beta; MCP-1: monocyte chemoattractant protein-1; IL-6: interleukin-6; IL-10: interleukin-10; KRAS: Kirsten rat sarcoma 2 viral oncogene homolog; GBR: germinated brown rice; Hi-maize® (high-amylose maize starch was used as a source of resistant starch); From one week before colitis induction to death of the experimental animal.