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Antibiotic-mediated bacteriome depletion in ApcMin/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression.

ABSTRACT: Recent epidemiological evidence suggests that exposure to antibiotics in early-to-middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long-term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long-term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.

SUBMITTER: Kaur K

PROVIDER: S-EPMC5943478 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Antibiotic-mediated bacteriome depletion in Apc<sup>Min/+</sup> mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression.

Kaur Kamaljeet K Saxena Arpit A Debnath Irina I O'Brien Jacqueline L JL Ajami Nadim J NJ Auchtung Thomas A TA Petrosino Joseph F JF Sougiannis Alexander-Jacques AJ Depaep Sarah S Chumanevich Alexander A Gummadidala Phani M PM Omebeyinje Mayomi H MH Banerjee Sourav S Chatzistamou Ioulia I Chakraborty Paramita P Fayad Raja R Berger Franklin G FG Carson James A JA Chanda Anindya A

Cancer medicine 20180406 5

Recent epidemiological evidence suggests that exposure to antibiotics in early-to-middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long-term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the Apc<sup>Min/+</sup> mouse, an established genetic ...[more]

PMID: 29624892

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Project description:Mucinous colorectal adenocarcinoma (MCA) is characterized by a great mount of extracellular mucus fundamentally composed of Mucin2 (MUC2) which is significantly correlated with the high malignancy and strong invasive ability of MCA. However, rare is known about the underlying mechanism of the mucus accumulation in MCA. Our latest study demonstrated that SCF/c-KIT signaling was highly activated in MCA patients and mouse model, which up-regulated MUC2 transcription. In the present study, we paid a special interest in whether and how SCF/c-KIT signaling promoted mucus secretion by using wild-type (WT) C57BL mice and their littermates who harbor mutational c-kit gene (Wadsm/m), clinical colorectal cancer (CRC) samples, as well as human CRC cell lines. Our results clearly showed that the inner mucus layer of colon was thinner and the intracellular mucin residual was more in Wadsm/m mice than those in WT mice by Alcian blue and PAS staining, suggesting that the mucus secretion process was crippled when SCF/c-KIT signaling was hypo-activated. Inhibiting SCF/c-KIT signaling by Imatinib also resulted in weakened mucus secretion in WT mice. Intraperitoneal administration of MANS which competitively inhibits the activity of the vesicular transport protein MARCKS efficiently reduced mucus secretion in colonic goblet cells of WT mice. Significantly, phosphorylated MARCKS (p-MARCKS) was overtly decreased in colonic mucosa of Wadsm/m mice compared with WT mice, indicating that SCF/c-KIT signaling-regulated mucus secretion was probably mediated by MARCKS activation. Similar results were obtained in MCA patients and mouse model. Moreover, SCF/c-KIT signaling was activated or inhibited in HT-29 and LS174T CRC cells, which potently increased or decreased MARCKS activity, respectively. Finally, we found that PKCδ, a known kinase for MARCKS, was activated in WT and MCA mice along with MARCKS. Inhibition or activation of SCF/c-KIT signaling resulted in decreased or increased PKCδ activity respectively in vitro. In conclusion, we demonstrated that SCF/c-KIT signaling can promote the mucus secretion by activating PKCδ-MARCKS, which provided a new insight into understanding the mechanism of mucus secretion of goblet cells and MCA development.

Dataset Information

Antibiotic-mediated bacteriome depletion in ApcMin/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression.

Publications

Antibiotic-mediated bacteriome depletion in Apc<sup>Min/+</sup> mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression.

Similar Datasets

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