Systemic antibiotics increase microbiota pathogenicity and oral bone loss

Abstract

Periodontitis is the most widespread oral disease and is closely related to the oral microbiota. The oral microbiota is adversely affected by some pharmacologic treatments. Systemic antibiotics are widely used for infectious diseases but can lead to gut dysbiosis, causing negative effects on the human body. Whether systemic antibiotic-induced gut dysbiosis can affect the oral microbiota or even periodontitis has not yet been addressed. In this research, mice were exposed to drinking water containing a cocktail of four antibiotics to explore how systemic antibiotics affect microbiota pathogenicity and oral bone loss. The results demonstrated, for the first time, that gut dysbiosis caused by long-term use of antibiotics can disturb the oral microbiota and aggravate periodontitis. Moreover, the expression of cytokines related to Th17 was increased while transcription factors and cytokines related to Treg were decreased in the periodontal tissue. Fecal microbiota transplantation with normal mice feces restored the gut microbiota and barrier, decreased the pathogenicity of the oral microbiota, reversed the Th17/Treg imbalance in periodontal tissue, and alleviated alveolar bone loss. This study highlights the potential adverse effects of long-term systemic antibiotics-induced gut dysbiosis on the oral microbiota and periodontitis. A Th17/Treg imbalance might be related to this relationship. Importantly, these results reveal that the periodontal condition of patients should be assessed regularly when using systemic antibiotics in clinical practice.

References

[1.] Seymour RA, Thomason JM, Ellis JS. The pathogenesis of drug-induced gingival overgrowth. J. Clin. Periodontol., 1996, 23: 165-175.

[2.] Montero-Melendez T, . Association between periodontal disease and inflammatory arthritis reveals modulatory functions by melanocortin receptor type 3. Am. J. Pathol., 2014, 184: 2333-2341.

[3.] Epstein JB, . Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J. Clin., 2012, 62: 400-422.

[4.] Choo, J. M. et al. Divergent relationships between fecal microbiota and metabolome following distinct antibiotic-induced disruptions. mSphere 2, e00005-17 (2017).

[5.] Klein EY, . Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl. Acad. Sci. USA, 2018, 115: e3463-e3470.

[6.] Gilbert, J. A. et al. Current understanding of the human microbiome. 24, 392–400 (2018).

[7.] Gasbarrini, A. et al. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut 69, 1555–1563 (2020).

[8.] Jia X, . Gut-bone axis: a non-negligible contributor to periodontitis. Front. Cell. Infect. Microbiol., 2021, 11: 752708.

[9.] Mor A, . Prenatal exposure to systemic antibacterials and overweight and obesity in Danish schoolchildren: a prevalence study. Int. J. Obes., 2015, 39: 1450-1455.

[10.] Mueller NT, . Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Int. J. Obes., 2015, 39: 665-670.

[11.] Parker A, . Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 2022, 10

[12.] Mossad O, . Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat. Neurosci., 2022, 25: 295-305.

[13.] Jepsen K, Jepsen S. Antibiotics/antimicrobials: systemic and local administration in the therapy of mild to moderately advanced periodontitis. Periodontology 2000, 2016, 71: 82-112.

[14.] Graziani F, Karapetsa D, Alonso B, Herrera D. Nonsurgical and surgical treatment of periodontitis: how many options for one disease?. Periodontology 2000, 2017, 75: 152-188.

[15.] Kitamoto S, . The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell, 2020, 182: 447-462.e414.

[16.] Brito F, . Subgingival microflora in inflammatory bowel disease patients with untreated periodontitis. Eur. J. Gastroenterol. Hepatol., 2013, 25: 239-245.

[17.] Curtis MA, Diaz PI, Van Dyke TE. The role of the microbiota in periodontal disease. Periodontology 2000, 2020, 83: 14-25.

[18.] Tsukasaki M, . Host defense against oral microbiota by bone-damaging T cells. Nat. Commun., 2018, 9

[19.] Wang L, Wang J, Jin Y, Gao H, Lin X. Oral administration of all-trans retinoic acid suppresses experimental periodontitis by modulating the Th17/Treg imbalance. J. Periodontol., 2014, 85: 740-750.

[20.] Alvarez C, . Osteoimmunology of oral and maxillofacial diseases: translational applications based on biological mechanisms. Front. Immunol., 2019, 10: 1664.

[21.] Alvarez C, . Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci. Rep., 2020, 10

[22.] Han YK, Jin Y, Miao YB, Shi T, Lin XP. CD8(+) Foxp3(+) T cells affect alveolar bone homeostasis via modulating Tregs/Th17 during induced periodontitis: an adoptive transfer experiment. Inflammation, 2018, 41: 1791-1803.

[23.] Jia L, . Probiotics ameliorate alveolar bone loss by regulating gut microbiota. Cell Prolif., 2021, 54: e13075.

[24.] Kim S, Covington A, Pamer EG. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens. Immunol. Rev., 2017, 279: 90-105.

[25.] Fernández J, . A diet based on cured acorn-fed ham with oleic acid content promotes anti-inflammatory gut microbiota and prevents ulcerative colitis in an animal model. Lipids Health Dis., 2020, 19

[26.] Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J. Dent. Res., 2019, 98: 148-156.

[27.] Xiao E, . Diabetes enhances IL-17 expression and alters the oral microbiome to increase its pathogenicity. Cell Host Microbe, 2017, 22: 120-128.e124.

[28.] Binda C, . Actinobacteria: a relevant minority for the maintenance of gut homeostasis. Digestive Liver Dis., 2018, 50: 421-428.

[29.] Lippert K, . Gut microbiota dysbiosis associated with glucose metabolism disorders and the metabolic syndrome in older adults. Benef. Microbes, 2017, 8: 545-556.

[30.] Zou J, . Lizhong decoction ameliorates ulcerative colitis in mice via modulating gut microbiota and its metabolites. Appl. Microbiol. Biotechnol., 2020, 104: 5999-6012.

[31.] Li B, . Integrated metagenomic and transcriptomic analyses reveal the dietary dependent recovery of host metabolism from antibiotic exposure. Front. Cell Dev. Biol., 2021, 9: 680174.

[32.] Radaic A, . Modulation of pathogenic oral biofilms towards health with nisin probiotic. J. Oral Microbiol., 2020, 12: 1809302.

[33.] Liu H, Zhu J, Hu Q, Rao X. Morganella morganii, a non-negligent opportunistic pathogen. Int. Soc. Infect. Dis., 2016, 50: 10-17.

[34.] Huang Y, . Non-surgical periodontal treatment restored the gut microbiota and intestinal barrier in apolipoprotein E(-/-) mice with periodontitis. Front. Cell. Infect. Microbiol., 2020, 10: 498.

[35.] She YY, . Periodontitis and inflammatory bowel disease: a meta-analysis. BMC Oral Health, 2020, 20

[36.] Panda S, . Short-term effect of antibiotics on human gut microbiota. PloS One, 2014, 9: e95476.

[37.] Duan, H. et al. Antibiotic-induced gut dysbiosis and barrier disruption and the potential protective strategies. Crit. Rev. Food Sci. Nutr. 62, 1427–1452 (2020).

[38.] Schepper JD, . Probiotic Lactobacillus reuteri prevents postantibiotic bone loss by reducing intestinal dysbiosis and preventing barrier disruption. J. Bone Miner. Res., 2019, 34: 681-698.

[39.] Al Bander, Z., Nitert, M. D., Mousa, A. & Naderpoor, N. The gut microbiota and inflammation: an overview. Int. J. Environ. Res. Public Health 17, https://doi.org/10.3390/ijerph17207618 (2020).

[40.] Brandsma E, . A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ. Res., 2019, 124: 94-100.

[41.] Li, L. et al. Periodontitis may impair the homeostasis of systemic bone through regulation of gut microbiota in ApoE(-/-) mice. J. Clin. Periodontol. https://doi.org/10.1111/jcpe.13708 (2022).

[42.] Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000, 2014, 64: 57-80.

[43.] Hajishengallis G. The inflammophilic character of the periodontitis-associated microbiota. Mol. Oral. Microbiol., 2014, 29: 248-257.

[44.] Allam JP, . IL-23-producing CD68(+) macrophage-like cells predominate within an IL-17-polarized infiltrate in chronic periodontitis lesions. J. Clin. Periodontol., 2011, 38: 879-886.

[45.] Ernst CW, . Diminished forkhead box P3/CD25 double-positive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL+) T cells in bone resorption lesion of periodontal disease. Clin. Exp. Immunol., 2007, 148: 271-280.

[46.] O’Boyle C, . Ligature-induced periodontitis induces systemic inflammation but does not alter acute outcome after stroke in mice. Int. J. Stroke, 2020, 15: 175-187.

[47.] Rashidi, A., Ebadi, M., Weisdorf, D. J., Costalonga, M. & Staley, C. No evidence for colonization of oral bacteria in the distal gut in healthy adults. Proc. Natl Acad. Sci. USA 118, e2114152118 (2021).

[48.] Atarashi K, . Ectopic colonization of oral bacteria in the intestine drives T(H)1 cell induction and inflammation. Science, 2017, 358: 359-365.

[49.] Laudadio I, . Quantitative Assessment of Shotgun Metagenomics and 16S rDNA Amplicon Sequencing in the Study of Human Gut Microbiome. OMICS, 2018, 22: 248-254.

[50.] Yuan H, Gupte R, Zelkha S, Amar S. Receptor activator of nuclear factor kappa B ligand antagonists inhibit tissue inflammation and bone loss in experimental periodontitis. J. Clin. Periodontol., 2011, 38: 1029-1036.

[51.] Erben U, . A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int. J. Clin. Exp. Pathol., 2014, 7: 4557-4576.

Funding

2019 Chongqing Graduate Tutor Team Construction Project(dstd201903); National Natural Science Foundation of China (National Science Foundation of China)(82170968)