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Intestinal Microbiota Increases Cell Proliferation of Colonic Mucosa in Human-Flora-Associated (HFA) Mice - PubMed

  • ️Mon Jan 01 2024

Intestinal Microbiota Increases Cell Proliferation of Colonic Mucosa in Human-Flora-Associated (HFA) Mice

Giovanni Brandi et al. Int J Mol Sci. 2024.

Abstract

Intestinal epithelium renewal strictly depends on fine regulation between cell proliferation, differentiation, and apoptosis. While murine intestinal microbiota has been shown to modify some epithelial cell kinetics parameters, less is known about the role of the human intestinal microbiota. Here, we investigated the rate of intestinal cell proliferation in C3H/HeN germ-free mice associated with human flora (HFA, n = 8), and in germ-free (n = 15) and holoxenic mice (n = 16). One hour before sacrifice, all mice were intraperitoneally inoculated with 5-bromodeoxyuridine (BrdU), and the number of BrdU-positive cells/total cells (labelling index, LI), both in the jejunum and the colon, was evaluated by immunohistochemistry. Samples were also observed by scanning electron microscopy (SEM). Moreover, the microbiota composition in the large bowel of the HFA mice was compared to that of of human donor's fecal sample. No differences in LI were found in the small bowels of the HFA, holoxenic, and germ-free mice. Conversely, the LI in the large bowel of the HFA mice was significantly higher than that in the germ-free and holoxenic counterparts (p = 0.017 and p = 0.048, respectively). In the holoxenic and HFA mice, the SEM analysis disclosed different types of bacteria in close contact with the intestinal epithelium. Finally, the colonic microbiota composition of the HFA mice widely overlapped with that of the human donor in terms of dominant populations, although Bifidobacteria and Lactobacilli disappeared. Despite the small sample size analyzed in this study, these preliminary findings suggest that human intestinal microbiota may promote a high proliferation rate of colonic mucosa. In light of the well-known role of uncontrolled proliferation in colorectal carcinogenesis, these results may deserve further investigation in a larger population study.

Keywords: HFA mice; cell proliferation; germ-free mice; holoxenic mice; intestinal microbiota.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1

(A) Immunohistochemical analysis of BrdU+ cells in the jejunum (a–c) and colon (d–f) tissue from germ-free, holoxenic, and HFA mice. BrdU labels the nuclei of proliferating cells in the S phase of the cell cycle, and labelled cell nuclei appear brown. Black arrows (d,e) show some BrdU+ cells in the colon of germ-free and holoxenic mice. Magnification 10×. (B) Box plots of BrdU LI values, LI median (bold line in the box), and interquartile range (upper and lower lines of the box) in jejunum and colon of germ-free, holoxenic, and HFA mice. * p < 0.05.

Figure 2
Figure 2

SEM analysis of jejunum and colon in germ-free, holoxenic, and HFA mice. No bacteria are detected on the intestinal mucosa of germ-free mice (a,d), whereas different types of bacteria are present in the jejunum and colon of holoxenic and HFA mice (b,c,e,f). In holoxenic mice, many segmented filamentous bacteria (SFB) are observed in the jejunum ((b), red arrows), while a different typology of bacteria in close contact with the epithelium is found in the colon (e). Several bacilli-like bacteria are found in HFA mice: in the colon, the bacteria are facing at the apex of a crypt (f). Bar = 10 μm.

Figure 3
Figure 3

Bacteriological analysis of the fecal colon content from human donor and HFA mice. No significant differences are found in terms of total bacterial count or numbers of Bacteroides, Ruminococcus, Eubacterium Clostridium, Enterobacteria, and Enterococci. Conversely, Bifidobacteria and Lactobacilli significantly decreased in HFA mice in comparison to human donor. * p < 0.05.

Figure 4
Figure 4

CRC development in canonical, traditional serrated, hereditary, and IBD-associated pathways. Hyperproliferation of normal colonic mucosa represents an early and constant event in CRC carcinogenesis in all these pathways.

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