Abstract：Objective To investigate the effect of ceftriaxone on the intestinal epithelium and microbiota in mice in the early-life stage, as well as the recovery of the intestinal epithelium and reconstruction of intestinal microbiota in adult mice. Methods A total of 36 BALB/C neonatal mice were randomly divided into control group and experimental group, with 18 mice in each group. The mice in the experimental group were given ceftriaxone 100 mg/kg every day by gavage within 21 days after birth. Those in the control group were given an equal volume of normal saline by gavage. Immunohistochemistry was used to measure the expression of Ki67, Muc2, and ZO-1 in the intestinal epithelium. qPCR and next-generation sequencing were used to analyze the overall concentration and composition of fecal bacteria. Results After 21 days of ceftriaxone intervention, the experimental group had a significant reduction in body weight, a significant reduction in the expression of Ki67 and ZO-1 and a significant increase in the expression of Muc2 in intestinal epithelial cells, a significant reduction in the overall concentration of fecal bacteria, and a significant increase in the diversity of fecal bacteria compared with the control group (P < 0.05). Firmicutes was the most common type of fecal bacteria in the experimental group, and there were large amounts of Staphylococcus and Enterococcus. The experimental group had a certain degree of recovery of the intestinal epithelium, but there were still significant differences in body weight and the structure of intestinal microbiota between the two groups at 56 days after birth (P < 0.05). Conclusions Early ceftriaxone intervention significantly affects the development of the intestinal epithelium and the construction of intestinal microbiota in the early-life stage. The injury of the intestinal microbiota in the early-life stage may continue to the adult stage and affect growth and development and physiological metabolism.
WAN Qun,CHENG Ru-Yue,GUO Jia-Wen et al. Effect of ceftriaxone on the intestinal epithelium and microbiota in neonatal mice[J]. CJCP, 2018, 20(4): 318-325.
Organization WH. WHO model list of essential medicines-19th List[DB/OL]. (2015-04).
[2]
Vehapoğlu A, Göknar N, Tuna R, et al. Ceftriaxone-induced hemolytic anemia in a child successfully managed with intravenous immunoglobulin[J]. Turk J Pediatr, 2016, 58(2):216-219.
[3]
Li N, Zhou X, Yuan J, et al. Ceftriaxone and acute renal failure in children[J]. Pediatrics, 2014, 133(4):e917-e922.
[4]
Hebert M, Licursi M, Jensen B, et al. Single rapamycin administration induces prolonged downward shift in defended body weight in rats[J]. PLoS One, 2014, 9(5):e93691.
[5]
Saleem B, Okogbule-Wonodi AC, Fasano A, et al. Intestinal barrier maturation in very low birth weight infants:relationship to feeding and antibiotic exposure[J]. J Pediatr, 2017, 183:31-36.
[6]
Li F, Wang H, Liu J, et al. Immunotoxicity of β-diketone antibiotic mixtures to zebrafish (danio rerio) by transcriptome analysis[J]. PLoS One, 2016, 11(4):e0152530.
[7]
Cheng RY, Li M, Li SS, et al. Vancomycin and ceftriaxone can damage intestinal microbiota and affect the development of the intestinal tract and immune system to different degrees in neonatal mice[J]. Pathog Dis, 2017, 75(8):1-9.
[8]
Buffie CG, Jarchum I, Equinda M, et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis[J]. Infect Immun, 2012, 80(1):62-73.
[9]
Kozyrskyj AL, Ernst P, Becker AB. Increased risk of childhood asthma from antibiotic use in early life[J]. Chest, 2007, 131(6):1753-1759.
[10]
Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences[J]. Cell, 2014,158(4):705-721.
[11]
Luo X, Zheng Y, Wen R, et al. Effects of ceftriaxone induced intestinal dysbacteriosis on lymphocytes in different tissues in mice[J]. Immunobiology, 2016, 221(9):994-1000.
[12]
Li M, Li W, Wen S, et al. Effects of ceftriaxone-induced intestinal dysbacteriosis on dendritic cells of small intestine in mice[J]. Microbiol Immunol, 2013, 57(8):561-568.
[13]
Gao F, Li M, Liu Y, et al. Intestinal dysbacteriosis induces changes of T lymphocyte subpopulations in Peyer's patches of mice and orients the immune response towards humoral immunity[J]. Gut Pathog, 2012, 4(1):19.
[14]
Morgun A, Dzutsev A, Dong X, et al. Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks[J]. Gut, 2015, 64(11):1732-1743.
[15]
Biasucci G, Benenati B, Morelli L, et al. Cesarean delivery may affect the early biodiversity of intestinal bacteria[J]. J Nutr, 2008, 138(9):1796S-1800S.
[16]
Ren D, Gong S, Shu J, et al. Mixed lactobacillus plantarum strains inhibit staphylococcus aureus induced inflammation and ameliorate intestinal microflora in mice[J]. Biomed Res Int, 2017, 2017:7476467.
[17]
Puhl NJ, Uwiera RR, Yanke LJ, et al. Antibiotics conspicuously affect community profiles and richness, but not the density of bacterial cells associated with mucosa in the large and small intestines of mice[J]. Anaerobe, 2012, 18(1):67-75.
[18]
Trasande L, Blustein J, Liu M, et al. Infant antibiotic exposures and early-life body mass[J]. Int J Obes (Lond), 2013, 37(1):16-23.
[19]
Murphy EF, Cotter PD, Hogan A, et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity[J]. Gut, 2013, 62(2):220-226.
[20]
Morel FB, Oosting A, Piloquet H, et al. Can antibiotic treatment in preweaning rats alter body composition in adulthood?[J]. Neonatology, 2013, 103(3):182-189.
[21]
Rigby RJ, Carr J, Orgel K, et al. Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis[J]. Gut Microbes, 2016, 7(5):414-423.
[22]
Tan L, Wen S, Sun MZ, et al. Changes in protein profile in cecum of mouse with intestinal dysbacteriosis induced by ceftriaxone sodium[J]. J Hard Tissue Biol, 2011, 20(2):93-98.
[23]
Wang S, Li Q, Zang Y, et al. Apple polysaccharide inhibits microbial dysbiosis and chronic inflammation and modulates gut permeability in HFD-fed rats[J]. Int J Biol Macromol, 2017, 99:282-292.
[24]
Strickertsson JA, Desler C, Martin-Bertelsen T, et al. Enterococcus faecalis infection causes inflammation, intracellular oxphos-independent ROS production, and DNA damage in human gastric cancer cells[J]. PLoS One, 2013, 8(4):e63147.
[25]
Hong SW, Kim MR, Lee EY, et al. Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation[J]. Allergy, 2011, 66(3):351-359.
