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. 2020 Jun 2:10:746.
doi: 10.3389/fonc.2020.00746. eCollection 2020.

Administration of Metabiotics Extracted From Probiotic Lactobacillus rhamnosus MD 14 Inhibit Experimental Colorectal Carcinogenesis by Targeting Wnt/β-Catenin Pathway

Mridul Sharma  1 , Geeta Shukla  1
Affiliations

Administration of Metabiotics Extracted From Probiotic Lactobacillus rhamnosus MD 14 Inhibit Experimental Colorectal Carcinogenesis by Targeting Wnt/β-Catenin Pathway

Mridul Sharma et al. Front Oncol. .

Abstract

Background and Objective: The cellular microenvironment, diet, and lifestyle play a key role in the occurrence of colorectal cancer. Due to its rising trend, attempts are being made to devise novel biointerventions as adjunct to conventional therapies to prevent this deadly disease. "Metabiotics," the beneficial metabolic signatures of probiotics are emerging as potential anticancer agent due to their ability to alter metabolic processes in the gut lumen and reduce the severity of colon carcinogenesis. Although beneficial attributes of metabiotics have been elucidated in vitro, yet their anticancer mechanism in vivo needs to be explored. Thus, the present study was performed to envisage anticancer potential of metabiotic extract obtained from indigenous probiotic, Lactobacillus rhamnosus MD 14, in early experimental colon carcinogenesis. Materials and Methods: Sprague-Dawley rats were daily administered with low, medium, and high dose of metabiotic extract orally along with a single dose of weekly intraperitoneal injection of 1,2-dimethylhydrazine up to 6 weeks and monitored for the markers of early colon carcinogenesis. Results: It was observed that the medium dose of metabiotic extract attenuated early colon carcinogenesis by reducing fecal procarcinogenic enzymes, oxidants, aberrant crypt foci, vis-à-vis downregulating oncogenes [K-ras, β-catenin, Cox-2, nuclear factor kappa B (NF-κB)] and upregulating tumor suppressor p53 gene leading to almost normal colon histology. Conclusions: It can be suggested that metabiotics modulate experimental colorectal cancer and could be used as a promising alternative of probiotics, particularly in immunocompromised individuals.

Keywords: aberrant crypt foci; bioactive substances; colon cancer; metabiotics; probiotics.

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Figures

Figure 1
Figure 1
Schematic representation of experimental design for the induction of colon carcinogenesis in Sprague–Dawley (SD) rats by 1,2-dimethylhydrazine (DMH).
Figure 2
Figure 2
Liquid chromatography mass spectrometry chromatogram of metabiotic extract depicting the presence of various chemical compounds as indicated by arrows: acetate (mol. wt, 59), butyrate (mol. wt, 87), propionate (mol. wt, 73), acetamide (mol. wt, 127), thiocyanic acid (mol. wt, 97), and oxalic acid (mol. wt, 90).
Figure 3
Figure 3
Fecal enzymes activity in different groups of animals: (A) nitroreductase, (B) β-glucosidase, and (C) β-glucuronidase. Experiment was performed in triplicates. Values are expressed as mean ± SD. *p < 0.05 vs. 1,2-dimethylhydrazine (DMH)-treated.
Figure 4
Figure 4
(A) Macroscopic observation of inflammation (yellow arrows) and lesions (white arrows). (B) Topographic view of the colon stained with methylene blue showing: (a) normal crypts, (b) flat mucin depleted aberrant crypt foci (arrow), (c) almost normal crypts, (d) numerous aberrant crypts (arrows), and (e, f) fewer aberrant crypts. (C) Ethidium bromide/acridine orange stained colonocytes of animals belonging to different groups: (a) control, (b) 1,2-dimethylhydrazine (DMH)-treated, (c) metabiotic extract (ME), (d) LDME + DMH, (e) MDME + DMH, (f) HDME + DMH (400 × ). Quantification of (D) number of colonic lesions. (E) Aberrant crypt foci (ACF) count. (F) Percent apoptotic cells in various groups of animals.
Figure 5
Figure 5
Oxidant and antioxidant levels in animals belonging to different groups: (A) malondialdehyde (MDA), (B) superoxide dismutase (SOD), (C) reduced glutathione (GSH), and (D) glutathione peroxidase (Gpx) levels. Experiment was performed in triplicates. Values are expressed as mean ± SD, *p < 0.05 vs. 1,2-dimethylhydrazine (DMH)-treated.
Figure 6
Figure 6
Fold change in expression of molecular markers by real-time PCR in various groups of animals: (A) Cox-2, (B) β-catenin, (C) nuclear factor kappa B (NF-κB), (D) K-ras, and (E) p53. Experiment was performed in triplicates. Values are expressed as mean ± SD, *p < 0.05 vs. 1,2-dimethylhydrazine (DMH)-treated.
Figure 7
Figure 7
Photomicrograph of the colon of animals belonging to different groups showing (a) normal histoarchitecture in control; (b,c) severely damaged mucosa and aberrant crypt foci (ACF) (arrow) in 1,2-dimethylhydrazine (DMH)-treated; (d) normal colon cells in metabiotic extract (ME); (e) colitis in LDME + DMH-treated; (f,g) mild inflammation in MDME + DMH and HDME + DMH-treated (H&E staining, 100 × ).
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