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Long-term use of broad-spectrum antibiotics affects Ly6Chi monocyte recruitment and IL-17A and IL-22 production through the gut microbiota in tumor-bearing mice treated with chemotherapy

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Abstract

The protective effects of antibiotics against infection in cancer patients treated with chemotherapy remains unclear and related studies have been performed in healthy or pathogen-infected animal models. Here, we aimed to study the effects of antibiotic use on intestinal infection in tumor-bearing mice treated with chemotherapy and to determine the underlying mechanisms. Subcutaneous CT26 tumor-bearing mice were assigned to four groups: the control (Ctrl) group without any treatment, the antibiotic (ATB) group treated with a mixture of ampicillin, streptomycin, and colistin, the 5-fluorouracil (FU) group treated with four cycles of intraperitoneal injections of FU, and the ATB + FU group treated with the combination of ATB and FU. Gut microbial composition was determined and mesenteric lymph nodes (mLNs) were isolated for bacterial culturing. Intestinal permeability and integrity were assessed and the expression of cytokines was analyzed by quantitative PCR, ELISA, or flow cytometry (FCM). Monocytes in the colonic lamina propria (LP) were measured by FCM. Compared with the Ctrl and FU groups, the numbers of positive bacterial culturing results for mLNs were higher, and gut bacterial compositions were altered in the ATB and ATB + FU groups, with significantly decreased alpha diversity in the ATB + FU group. Intestinal integrity regarding the expression of tight junction proteins and intestinal permeability were not impaired significantly after treatments, but the colons were shorter in the ATB + FU group. The expression levels of intestinal IL-17A and IL-22, as well as the percentages of IL-17A+ cells in the colonic LP of the ATB + FU group, were lower than those in the FU group. The percentages of Ly6Chi monocytes in the colonic LP were lower, but those in the spleen were higher in the ATB + FU group than in the FU group. The mRNA levels of colonic CCL8 were reduced in the ATB + FU group. Antibiotic use is associated with an increased incidence of intestinal infections in tumor-bearing mice treated with chemotherapy, which might in turn be associated with a dysregulated gut microbiota that inhibits colonic monocyte recruitment and IL-17A and IL-22 production.

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Data availability

Data sets composing metagenomic sequencing of bacterial 16S rRNA were deposited in The National Center for Biotechnology Information Sequence Read Archive repository (PRJNA808794). Remaining data in the study will be available if requested.

References

  1. Culakova E, Thota R, Poniewierski MS, Kuderer NM, Wogu AF, Dale DC, Crawford J, Lyman GH. Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study. Cancer Med. 2014;3(2):434–44. https://doi.org/10.1002/cam4.200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J clin oncol. 2007;25(21):3158–67. https://doi.org/10.1200/JCO.2006.08.8823.

    Article  CAS  PubMed  Google Scholar 

  3. Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32. https://doi.org/10.1016/j.ejca.2010.10.013.

    Article  CAS  PubMed  Google Scholar 

  4. Weycker D, Chandler D, Barron R, Xu H, Wu H, Edelsberg J, Lyman GH. Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin’s lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice. J Oncol Pharm Pract. 2017;23(1):33–42. https://doi.org/10.1177/1078155215614997.

    Article  CAS  PubMed  Google Scholar 

  5. Sulis ML, Blonquist TM, Stevenson KE, Hunt SK, Kay-Green S, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, et al. Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2018;65(5):e26952. https://doi.org/10.1002/pbc.26952.

    Article  CAS  PubMed  Google Scholar 

  6. Felsenstein S, Orgel E, Rushing T, Fu C, Hoffman JA. Clinical and microbiologic outcomes of quinolone prophylaxis in children with acute myeloid leukemia. Pediatr Infect Dis J. 2015;34(4):e78-84. https://doi.org/10.1097/INF.0000000000000591.

    Article  PubMed  Google Scholar 

  7. Beyar-Katz O, Dickstein Y, Borok S, Vidal L, Leibovici L, Paul M. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017;6:CD003914. https://doi.org/10.1002/14651858.CD003914.pub4.

    Article  PubMed  Google Scholar 

  8. Lewis JD, Chen EZ, Baldassano RN, Otley AR, Griffiths AM, Lee D, Bittinger K, Bailey A, Friedman ES, Hoffmann C, et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease. Cell Host Microbe. 2015;18(4):489–500. https://doi.org/10.1016/j.chom.2015.09.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Keith JW, Pamer EG. Enlisting commensal microbes to resist antibiotic-resistant pathogens. J Exp Med. 2019;216(1):10–9. https://doi.org/10.1084/jem.20180399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dessein R, Gironella M, Vignal C, Peyrin-Biroulet L, Sokol H, Secher T, Lacas-Gervais S, Gratadoux JJ, Lafont F, Dagorn JC, et al. Toll-like receptor 2 is critical for induction of Reg3 beta expression and intestinal clearance of Yersinia pseudotuberculosis. Gut. 2009;58(6):771–6. https://doi.org/10.1136/gut.2008.168443.

    Article  CAS  PubMed  Google Scholar 

  11. Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T, Fleisher M, Schnabl B, DeMatteo RP, Pamer EG. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008;455(7214):804–7. https://doi.org/10.1038/nature07250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. https://doi.org/10.1016/j.cell.2009.09.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sorbara MT, Pamer EG. Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. Mucosal Immunol. 2019;12(1):1–9. https://doi.org/10.1038/s41385-018-0053-0.

    Article  CAS  PubMed  Google Scholar 

  14. Potgens SA, Brossel H, Sboarina M, Catry E, Cani PD, Neyrinck AM, Delzenne NM, Bindels LB. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci Rep. 2018;8(1):12321. https://doi.org/10.1038/s41598-018-30569-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Taur Y, Pamer EG. The intestinal microbiota and susceptibility to infection in immunocompromised patients. Curr Opin Infect Dis. 2013;26(4):332–7. https://doi.org/10.1097/QCO.0b013e3283630dd3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cole GT, Halawa AA, Anaissie EJ. The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside. Clin Infect Dis. 1996;22(Suppl 2):S73-88. https://doi.org/10.1093/clinids/22.supplement_2.s73.

    Article  PubMed  Google Scholar 

  17. Hecht JR, Pillai M, Gollard R, Heim W, Swan F, Patel R, Dreiling L, Mo M, Malik I. A randomized, placebo-controlled phase ii study evaluating the reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving pegfilgrastim with every-2-week chemotherapy. Clin Colorectal Cancer. 2010;9(2):95–101. https://doi.org/10.3816/CCC.2010.n.013.

    Article  CAS  PubMed  Google Scholar 

  18. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6. https://doi.org/10.1038/nmeth.f.303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glockner FO. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013;41(Database issue):D590-596. https://doi.org/10.1093/nar/gks1219.

    Article  CAS  PubMed  Google Scholar 

  20. Ganta VC, Cromer W, Mills GL, Traylor J, Jennings M, Daley S, Clark B, Mathis JM, Bernas M, Boktor M, et al. Angiopoietin-2 in experimental colitis. Inflamm Bowel Dis. 2010;16(6):1029–39. https://doi.org/10.1002/ibd.21150.

    Article  PubMed  Google Scholar 

  21. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6. https://doi.org/10.1126/science.1240537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Qiu Z, Sheridan BS. Isolating lymphocytes from the mouse small intestinal immune system. Journal of visualized experiments: JoVE. 2018;(132):e57281. https://doi.org/10.3791/57281

  23. Richard P, Amador Del Valle G, Moreau P, Milpied N, Felice MP, Daeschler T, Harousseau JL, Richet H. Viridans streptococcal bacteraemia in patients with neutropenia. Lancet. 1995;345(8965):1607–9. https://doi.org/10.1016/s0140-6736(95)90117-5.

    Article  CAS  PubMed  Google Scholar 

  24. Li HL, Lu L, Wang XS, Qin LY, Wang P, Qiu SP, Wu H, Huang F, Zhang BB, Shi HL, et al. Alteration of gut microbiota and inflammatory cytokine/chemokine profiles in 5-fluorouracil induced intestinal mucositis. Front Cell Infect Microbiol. 2017;7:455. https://doi.org/10.3389/fcimb.2017.00455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pappu R, Ramirez-Carrozzi V, Sambandam A. The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology. 2011;134(1):8–16. https://doi.org/10.1111/j.1365-2567.2011.03465.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim M, Galan C, Hill AA, Wu WJ, Fehlner-Peach H, Song HW, Schady D, Bettini ML, Simpson KW, Longman RS, et al. Critical role for the microbiota in CX3CR1(+) intestinal mononuclear phagocyte regulation of intestinal T cell responses. Immunity. 2018;49(1):151-163 e155. https://doi.org/10.1016/j.immuni.2018.05.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bain CC, Bravo-Blas A, Scott CL, Perdiguero EG, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014;15(10):929–37. https://doi.org/10.1038/ni.2967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xiong H, Keith JW, Samilo DW, Carter RA, Leiner IM, Pamer EG. Innate lymphocyte/Ly6C(hi) monocyte crosstalk promotes klebsiella pneumoniae clearance. Cell. 2016;165(3):679–89. https://doi.org/10.1016/j.cell.2016.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612–6. https://doi.org/10.1126/science.1175202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamouda N, Sano T, Oikawa Y, Ozaki T, Shimakawa M, Matsumoto K, Amagase K, Higuchi K, Kato S. Apoptosis, Dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice. Basic Clin Pharmacol Toxicol. 2017;121(3):159–68. https://doi.org/10.1111/bcpt.12793.

    Article  CAS  PubMed  Google Scholar 

  31. Sougiannis AT, VanderVeen BN, Enos RT, Velazquez KT, Bader JE, Carson M, Chatzistamou I, Walla M, Pena MM, Kubinak JL, et al. Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota. Brain Behav Immun. 2019;80:44–55. https://doi.org/10.1016/j.bbi.2019.02.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pickard JM, Zeng MY, Caruso R, Nunez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev. 2017;279(1):70–89. https://doi.org/10.1111/imr.12567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ducarmon QR, Zwittink RD, Hornung BVH, van Schaik W, Young VB, Kuijper EJ. Gut microbiota and colonization resistance against bacterial enteric infection. Microbiology and molecular biology reviews: MMBR. 2019;83(3):e00007–19. https://doi.org/10.1128/MMBR.00007-19

  34. Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med. 2016;22(6):458–78. https://doi.org/10.1016/j.molmed.2016.04.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Taur Y, Pamer EG. Microbiome mediation of infections in the cancer setting. Genome medicine. 2016;8(1):40. https://doi.org/10.1186/s13073-016-0306-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, Hase K, Yang CS, Lim HS, Kim MS, et al. Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol. 2017;10(1):104–16. https://doi.org/10.1038/mi.2016.42.

    Article  CAS  PubMed  Google Scholar 

  37. Yanagibashi T, Hosono A, Oyama A, Tsuda M, Suzuki A, Hachimura S, Takahashi Y, Momose Y, Itoh K, Hirayama K, et al. IgA production in the large intestine is modulated by a different mechanism than in the small intestine: bacteroides acidifaciens promotes IgA production in the large intestine by inducing germinal center formation and increasing the number of IgA+ B cells. Immunobiology. 2013;218(4):645–51. https://doi.org/10.1016/j.imbio.2012.07.033.

    Article  CAS  PubMed  Google Scholar 

  38. Jacobson A, Lam L, Rajendram M, Tamburini F, Honeycutt J, Pham T, Van Treuren W, Pruss K, Stabler SR, Lugo K, et al. A gut commensal-produced metabolite mediates colonization resistance to salmonella infection. Cell host & microbe. 2018;24(2):296-307 e297. https://doi.org/10.1016/j.chom.2018.07.002.

    Article  CAS  Google Scholar 

  39. Ray N, Jeong H, Kwon D, Kim J, Moon Y. Antibiotic exposure aggravates bacteroides-linked uremic toxicity in the gut-kidney axis. Front Immunol. 2022;13:737536. https://doi.org/10.3389/fimmu.2022.737536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lo BC, Shin SB, Canals Hernaez D, Refaeli I, Yu HB, Goebeler V, Cait A, Mohn WW, Vallance BA, McNagny KM. IL-22 preserves gut epithelial integrity and promotes disease remission during chronic salmonella infection. J Immunol. 2019;202(3):956–65. https://doi.org/10.4049/jimmunol.1801308.

    Article  CAS  PubMed  Google Scholar 

  41. Kim S, Covington A, Pamer EG. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens. Immunol Rev. 2017;279(1):90–105. https://doi.org/10.1111/imr.12563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kayama H, Okumura R, Takeda K. Interaction between the microbiota, epithelia, and immune cells in the intestine. Annu Rev Immunol. 2020;38:23–48. https://doi.org/10.1146/annurev-immunol-070119-115104.

    Article  CAS  PubMed  Google Scholar 

  43. Mendes V, Galvao I, Vieira AT. Mechanisms by which the gut microbiota influences cytokine production and modulates host inflammatory responses. J Interferon Cytokine Res. 2019;39(7):393–409. https://doi.org/10.1089/jir.2019.0011.

    Article  CAS  PubMed  Google Scholar 

  44. Joeris T, Muller-Luda K, Agace WW, Mowat AM. Diversity and functions of intestinal mononuclear phagocytes. Mucosal Immunol. 2017;10(4):845–64. https://doi.org/10.1038/mi.2017.22.

    Article  CAS  PubMed  Google Scholar 

  45. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500. https://doi.org/10.1038/nri2785.

    Article  CAS  PubMed  Google Scholar 

  46. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71–82. https://doi.org/10.1016/s1074-7613(03)00174-2.

    Article  CAS  PubMed  Google Scholar 

  47. Guilliams M, Mildner A, Yona S. Developmental and functional heterogeneity of monocytes. Immunity. 2018;49(4):595–613. https://doi.org/10.1016/j.immuni.2018.10.005.

    Article  CAS  PubMed  Google Scholar 

  48. Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, Guilliams M, Malissen B, Agace WW, Mowat AM. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013;6(3):498–510. https://doi.org/10.1038/mi.2012.89.

    Article  CAS  PubMed  Google Scholar 

  49. Sanchez-Tarjuelo R, Cortegano I, Manosalva J, Rodriguez M, Ruiz C, Alia M, Prado MC, Cano EM, Ferrandiz MJ, de la Campa AG, et al. The TLR4-MyD88 signaling axis regulates lung monocyte differentiation pathways in response to Streptococcus pneumoniae. Front Immunol. 2020;11:2120. https://doi.org/10.3389/fimmu.2020.02120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jin L, Getahun A, Knowles HM, Mogan J, Akerlund LJ, Packard TA, Perraud AL, Cambier JC. STING/MPYS mediates host defense against Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration. J Immunol. 2013;190(6):2835–43. https://doi.org/10.4049/jimmunol.1201788.

    Article  CAS  PubMed  Google Scholar 

  51. Kim YG, Kamada N, Shaw MH, Warner N, Chen GY, Franchi L, Nunez G. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity. 2011;34(5):769–80. https://doi.org/10.1016/j.immuni.2011.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leuschner F, Rauch PJ, Ueno T, Gorbatov R, Marinelli B, Lee WW, Dutta P, Wei Y, Robbins C, Iwamoto Y, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012;209(1):123–37. https://doi.org/10.1084/jem.20111009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jones GR, Bain CC, Fenton TM, Kelly A, Brown SL, Ivens AC, Travis MA, Cook PC, MacDonald AS. Dynamics of colon monocyte and macrophage activation during colitis. Front Immunol. 2018;9:2764. https://doi.org/10.3389/fimmu.2018.02764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang Z, Clarke TB, Weiser JN. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Investig. 2009;119(7):1899–909. https://doi.org/10.1172/JCI36731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. De Trez C, Magez S, Akira S, Ryffel B, Carlier Y, Muraille E. iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS Pathog. 2009;5(6):e1000494. https://doi.org/10.1371/journal.ppat.1000494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, Franchini F, Chomka A, Ilott NE, Johnston DGW, Pires E, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. 2019;50(2):432 e437-445. https://doi.org/10.1016/j.immuni.2018.12.018.

    Article  CAS  Google Scholar 

  57. Rubino SJ, Geddes K, Girardin SE. Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol. 2012;33(3):112–8. https://doi.org/10.1016/j.it.2012.01.003.

    Article  CAS  PubMed  Google Scholar 

  58. Wilharm A, Tabib Y, Nassar M, Reinhardt A, Mizraji G, Sandrock I, Heyman O, Barros-Martins J, Aizenbud Y, Khalaileh A, et al. Mutual interplay between IL-17-producing gammadeltaT cells and microbiota orchestrates oral mucosal homeostasis. Proc Natl Acad Sci USA. 2019;116(7):2652–61. https://doi.org/10.1073/pnas.1818812116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cypowyj S, Picard C, Marodi L, Casanova JL, Puel A. Immunity to infection in IL-17-deficient mice and humans. Eur J Immunol. 2012;42(9):2246–54. https://doi.org/10.1002/eji.201242605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chen YS, Chen IB, Pham G, Shao TY, Bangar H, Way SS, Haslam DB. IL-17-producing gammadelta T cells protect against Clostridium difficile infection. J Clin Investig. 2020;130(5):2377–90. https://doi.org/10.1172/JCI127242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693–700. https://doi.org/10.1136/gutjnl-2011-301668.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang HJ, Xu B, Wang H, Xu B, Wang GD, Jiang MZ, Lei C, Ding ML, Yu PF, Nie YZ, et al. IL-17 is a protection effector against the adherent-invasive Escherichia coli in murine colitis. Mol Immunol. 2018;93:166–72. https://doi.org/10.1016/j.molimm.2017.11.020.

    Article  CAS  PubMed  Google Scholar 

  63. Basu R, O’Quinn DB, Silberger DJ, Schoeb TR, Fouser L, Ouyang W, Hatton RD, Weaver CT. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity. 2012;37(6):1061–75. https://doi.org/10.1016/j.immuni.2012.08.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282–9. https://doi.org/10.1038/nm1720.

    Article  CAS  PubMed  Google Scholar 

  65. Matsunaga Y, Clark T, Wanek AG, Bitoun JP, Gong Q, Good M, Kolls JK. Intestinal IL-17R signaling controls secretory IgA and oxidase balance in Citrobacter rodentium infection. J Immunol. 2021;206(4):766–75. https://doi.org/10.4049/jimmunol.2000591.

    Article  CAS  PubMed  Google Scholar 

  66. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70. https://doi.org/10.1126/science.1240527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM. Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis. 1999;20(8):1425–31. https://doi.org/10.1093/carcin/20.8.1425.

    Article  CAS  PubMed  Google Scholar 

  68. Zhu HC, Jia XK, Fan Y, Xu SH, Li XY, Huang MQ, Lan ML, Xu W, Wu SS. Alisol B 23-Acetate ameliorates azoxymethane/dextran sodium sulfate-induced male murine colitis-associated colorectal cancer via modulating the composition of gut microbiota and improving intestinal barrier. Front Cell Infect Microbiol. 2021;11:640225. https://doi.org/10.3389/fcimb.2021.640225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fong W, Li Q, Yu J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene. 2020;39(26):4925–43. https://doi.org/10.1038/s41388-020-1341-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chin KF, Kallam R, O’Boyle C, MacFie J. Bacterial translocation may influence the long-term survival in colorectal cancer patients. Dis Colon Rectum. 2007;50(3):323–30. https://doi.org/10.1007/s10350-006-0827-4.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Shanghai Personalbio Technology Co., Ltd. for cooperation with the 16S rRNA sequencing work and Dr. Xiaokang Dong, Jing Chen, and Xingli Tang for their technical supports in microbial culturing and identification.

Funding

This work was supported by Scientific Research Foundation of the Higher Education Institute of Anhui Province (Grant number, KJ2019A0425) and Scientific Research Foundation of Key Program of Wannan Medical College (grant number, WK201905).

Author information

Authors and Affiliations

  1. Department of Medical Microbiology and Immunology, Wannan Medical College, Wuhu, Anhui, China

    Yanhong Wu, Tao Zhu, Hui Liu, Yanjing Xiong & Xiaoxuan Zuo

  2. Basic Medical Laboratory, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China

    Xiaolei Tang

  3. Department of Blood Transfusion, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China

    Feng Hu

  4. The Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu, Anhui, China

    Aiping Xu

  5. Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

    Xiufen Zhuang

Authors
  1. Yanhong Wu
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  2. Xiaolei Tang
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  3. Feng Hu
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  4. Tao Zhu
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  5. Hui Liu
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  6. Yanjing Xiong
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  7. Xiaoxuan Zuo
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  8. Aiping Xu
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  9. Xiufen Zhuang
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Corresponding authors

Correspondence to Aiping Xu or Xiufen Zhuang.

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The animal study was reviewed and approved by the Animal Care and Ethics Committee of Wannan Medical College.

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Supplementary Information

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12026_2022_9313_MOESM1_ESM.jpg

Supplementary file1 The composition of gut bacteria in cecal contents at the species level, as assessed by 16S rRNA gene sequencing. Abundances of species that ranked top 10 are shown. (JPG 74 KB)

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Supplementary file2 Quantitative PCR analysis of inflammatory cytokines in mesenteric lymph nodes (mLNs) 24 hrs (A) and 7 days (B) after the last FU treatment. * P < 0.05, ** P < 0.01, *** P < 0.001. (JPG 92 KB)

12026_2022_9313_MOESM3_ESM.jpg

Supplementary file3 Reduced percentages of IL-17A+ cells in the mLNs after ATB+FU treatment. Flow cytometry (FCM) analyses of percentages of IL-17A+ cells (A,B), and IL-22+ cells (C) were performed by gating on living cells that were isolated from mLNs 7 days after the last FU treatment and stimulated with phorbol myristate acetate and ionomycin for 6 hrs. ** P < 0.01, *** P < 0.001. (JPG 120 KB)

12026_2022_9313_MOESM4_ESM.jpg

Supplementary file4 Few CD11c+ cells and F4/80+ in the colonic LP. Representative FCM profiles of percentages of CD11c+ cells and F4/80+ cells in the four groups (A) and statitical analyses of CD11c+ cells (B) F4/80+ cells (B). Gating on CD45+ cells that were isolated from the colonic LP 7 days after the last FU treatment. (JPG 114 KB)

12026_2022_9313_MOESM5_ESM.jpg

Supplementary file5 Decreased percentages of Ly6Chi monocytes in the mLNs after FU treatment. Representative FCM profiles of percentages of F4/80+ cells and CD11b+ cells in the four groups (A). Statitical analyses of percentages of F4/80+ cells (B) and CD11b+ cells (C) and proportions of Ly6Chi monocytes in the CD11b+ mLN cells (D). Gating on living cells that were isolated from the mLNs 7 days after the last FU treatment. *** P < 0.001. (JPG 140 KB)

12026_2022_9313_MOESM6_ESM.jpg

Supplementary file6 Increased percentages of Ly6Chi monocytes in the spleen after ATB+FU treatment. Representative FCM profiles of percentages of F4/80+ cells and CD11b+ cells in the four groups (A). Statitical analyses of percentages of F4/80+ cells (B) and CD11b+ cells (C) and proportions of Ly6Chi monocytes in the CD11b+ spleen cells (D). Gating on living cells that were isolated from the spleen 7 days after the last FU treatment. * P < 0.05, ** P < 0.01, *** P < 0.001. (JPG 143 KB)

Supplementary file7 (DOCX 17 KB)

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Wu, Y., Tang, X., Hu, F. et al. Long-term use of broad-spectrum antibiotics affects Ly6Chi monocyte recruitment and IL-17A and IL-22 production through the gut microbiota in tumor-bearing mice treated with chemotherapy. Immunol Res 70, 829–843 (2022). https://doi.org/10.1007/s12026-022-09313-9

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