Microbiota milieu and mechanisms of intestinal Toll Like Receptors (TLRs) involved in chemotherapy induced mucositis

Authors

  • Aradhana Marathe
  • Gayathri M. Rao
  • Sharada Rai

DOI:

https://doi.org/10.51248/.v42i5.2275

Keywords:

Microbiota, Gut, Toll like receptors, Commensal and pathogenic bacteria, TLR-2, TLR-4, TLR-5, TLR-9

Abstract

Gut is not only of digestive but also of immunological importance because of the residing microbiota milieu. Pathological or certain therapeutic condition may modify the normal commensal microflora. Mucositis, the most common untoward effect of chemotherapy, can also lead to this microbiotic imbalance. This shift leads to various molecular cascades which in turn trigger the action of Pattern Recognition Receptors (PRR’s). Toll like receptor (TLR) is one such pattern recognition receptor. In the human body there are about 13 types of TLRs out of which TLR-2, TLR-4, TLR-5 and TLR-9 are intestinal specific. They respond through ligands such as bacterial derivatives like flagellin, Lipoteichoic acid, Lipopolysaccharides, microbial antigen or genetic material of the viru. In turn via adaptor molecules, TLRs alter the signalling mechanisms and further induct the activation of pro or anti-inflammatory cytokines based on the immunological need. Several of the studies have described the involvement of under twined mechanisms of TLRs during chemotherapy. Therefore, agonists and/or antagonists of these strategic molecules may play a key role in pathological and therapeutic aspects. Thus, this review is an attempt to focus on the involvement of TLRs and microbiota to different chemotherapeutic agents and thereby track the available mechanisms of functionality.

Author Biographies

Aradhana Marathe

Department of Biochemistry, Kasturba Medical College, Mangalore
Manipal Academy of Higher Education, Manipal, India

Gayathri M. Rao

Department of Biochemistry, Kasturba Medical College, Mangalore
Manipal Academy of Higher Education, Manipal, India

Sharada Rai

Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India

References

Sonis, S.T., Elting, L.S., Keefe, D., Peterson, D.E., Schubert, M., Hauer-Jensen, M., et al., Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004; 100:1995-2025. DOI: https://doi.org/10.1002/cncr.20162

Dahlgren, D., Sjoblom, M., Hellstrom, M., Lennernas, H. Chemotherapeutics-induced intestinal mucositis: Pathophysiology and potential treatment strategies. Front pharma. 2021; 12: 681417. https://doi.org/10.3389/fphar.2021.681417 DOI: https://doi.org/10.3389/fphar.2021.681417

Rowland, I., Gibson, G., Heinken, A., Scott, K., Swann, J., Thiele, I., Tuohy, K. Gut microbiota functions: metabolism of nutrients and other food components. Euro J Nutri. 2018;57(1): 1-24. DOI: https://doi.org/10.1007/s00394-017-1445-8

Sender, R., Fuchs, S., Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2017:14:e1002533. https://10.1371/journal.pbio.1002533 DOI: https://doi.org/10.1371/journal.pbio.1002533

Chen, F. The role of gastrointestinal microbiome in chemotherapy, radiotherapy and immunotherapy for cancer and its mechanism. Chin J Cancer Biother. 2019; 26:810–816.

Panebianco, C., Andriulli, A., Pazienza, V. Pharmacomicrobiomics: Exploiting the drug-microbiota interactions in anticancer therapies. Microbiome. 2018 6:92. doi: 10.1186/s40168-018-0483-7. DOI: https://doi.org/10.1186/s40168-018-0483-7

Julie,M.D., Faye,C., Raylene, A.R., Jan-Willem,H., Mohamad, B., Katherine,A.P., et al., The chemo-gut study: investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol. BMC Cancer. 2019;19: 1243. https://doi.org/10.1186/s12885-019-6473-8 DOI: https://doi.org/10.1186/s12885-019-6473-8

Beutler, B. Pathogens, Commensals, and immunity: From the perspective of the urinary bladder. Pathogens. 2016; 5(1): 5. https://doi:10.3390/pathogens5010005 DOI: https://doi.org/10.3390/pathogens5010005

Kho, Z.Y., Lal, S.K. The Human Gut Microbiome – A potential controller of wellness and disease. Front. Microbiol. 2018; 9:1835. https://doi:10.3389/fmicb.2018.01835 DOI: https://doi.org/10.3389/fmicb.2018.01835

Negi, S., Das, D.K., Pahari, S., Nadeem, S., Agrewala, J. N. Potential role of gut microbiota in induction and regulation of innate immune memory. Front Immunol. 2019;10: 2441. https://doi:10.3389/fimmu.2019.02441 DOI: https://doi.org/10.3389/fimmu.2019.02441

Peng, C., Ouyang,Y., Lu, N., Li, N. The NF-kB Signaling pathway, the microbiota, and gastrointestinal tumorigenesis: Recent advances. Front Immunol. 2020;11:1387. https://doi:10.3389/fimmu.2020.01387 DOI: https://doi.org/10.3389/fimmu.2020.01387

Liu, C., Han, C., Liu, J. The Role of Toll-Like receptors in oncotherapy. Oncol Res. 2019;27:965-978. DOI: https://doi.org/10.3727/096504019X15498329881440

Weaver, L.K., Minichino, D., Biswas, C., Chu, N., Lee, J.J., Bittinger, K., et al.,Microbiota-dependent signals are required to sustain TLR-mediated immune responses. JCI Insight. 2019;4(1):e124370. doi: 10.1172/jci.insight.124370. Epub ahead of print. PMID: 30626747; DOI: https://doi.org/10.1172/jci.insight.124370

Zheng, C., Chen, J., Chu, F., Zhu, J., Jin, T. Inflammatory Role of TLR-MyD88 Signaling in multiple sclerosis. Front. Mol. Neurosci. 2020; 12:314. doi:10.3389/fnmol.2019.00314 DOI: https://doi.org/10.3389/fnmol.2019.00314

Beukema, M., Jermendi, É., van den Berg, M. A., Faas, M. M., Schols, H. A., de Vos, P. The impact of the level and distribution of methyl-esters of pectins on TLR2-1 dependent anti-inflammatory responses. Carbohydrate Polymers. 2021; 251:117093. https://doi.org/10.1016/j.carbpol.2020.117093 DOI: https://doi.org/10.1016/j.carbpol.2020.117093

Martin, B., Éva, J., Taco, K., Kohji, K., Bart, J., van den Berg, M. A., et al., Attenuation of Doxorubicin-Induced Small Intestinal Mucositis by Pectins is Dependent on Pectin's Methyl-Ester Number and Distribution Molecular Nutrition and Food Research. Mol. Nutr. Food Res. 2021; 65: 2100222. https://doi.org/10.1002/mnfr.202100222 DOI: https://doi.org/10.1002/mnfr.202100222

Ribeiro, R.A., Wanderley, C.W., Wong, D.V., Mota, J.M., Leite, C.A., Souza, M.H. et al., Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol. 2016; 78(5):881-893. DOI: https://doi.org/10.1007/s00280-016-3139-y

Cario, E. Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity, Curr Opi Supp Palli Care. 2016;10 (2): 157-164. DOI: https://doi.org/10.1097/SPC.0000000000000202

Wang, L., Chen, Q., Qi, H., Wang, C., Zhang, J., Dong, L. Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res. 2016;76(22):6631-6642. DOI: https://doi.org/10.1158/0008-5472.CAN-15-3034

Kim, S.J., Kim, H.M. Dynamic lipopolysaccharide transfer cascade to TLR4/MD2 complex via LBP and CD14. BMB reports. 2017; 50(2):55-57. DOI: https://doi.org/10.5483/BMBRep.2017.50.2.011

Khan, S., Wardill, H.R., Bowen, J.M. Role of toll-like receptor 4 (TLR4)-mediated interleukin-6 (IL-6) production in chemotherapy-induced mucositis. Cancer Chemother Pharmacol. 2018; 82: 31-37. DOI: https://doi.org/10.1007/s00280-018-3605-9

Reeh, H., Rudolph, N., Billing, U., Christen, H., Streif, S., Bullinger,E., et al., Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor alpha to gp130 expression: fusing experimental insights and dynamic modelling. Cell Commun Signal. 2019;1: 46. https://doi.org/10.1186/s12964-019-0356-0 DOI: https://doi.org/10.1186/s12964-019-0356-0

Nyati, K.K., Masuda, K., Zaman, M.M., Dubey, P.K., Millrine, D., Chalise, J.P., et al., TLR4-induced NF-kB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a. Nucleic Acids Res. 2017;45(5):2687-2703. DOI: https://doi.org/10.1093/nar/gkx064

Wong, D.V.T., Holanda, R.B.F., Cajado, A.G., Bandeira, A.M., Pereira, J.F.B., Amorim, J. O., et al., TLR4 deficiency upregulates TLR9 expression andenhances irinotecan-related intestinal mucositis and late-onset diarrhoea. British Journal of Pharmacology, 2021;1-17. DOI: https://doi.org/10.1111/bph.15609

Matam, V.K., Jesse, D.A., Amrita, K., Andrew, S.N., Satoshi, U., Shizuo, A., et al., Toll-Like receptor 5-deficient mice have dysregulated intestinal gene expression and nonspecific resistance to salmonella-induced typhoid-like disease. Infec Immun. 2020; 76 (3):1276-1281. DOI: https://doi.org/10.1128/IAI.01491-07

Yang, J., Yan, H.TLR5: beyond the recognition of flagellin. Cell Molecular Immu. 2017; 14(12), 1017-1019. DOI: https://doi.org/10.1038/cmi.2017.122

Suprabhat, M., Subhajit, K., Santi, P.S.B. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braj Infect Dis. 2016; 20(2):193-204 DOI: https://doi.org/10.1016/j.bjid.2015.10.011

Haderski, G.J., Kandar, B.M., Brackett, C.M., Toshkov, I.M., Johnson,C.P., Paszkiewicz, G..M, et al., TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects. PLoS ONE. 2020; 15(2): e0227940. https://doi.org/10.1371/journal.pone.0227940 DOI: https://doi.org/10.1371/journal.pone.0227940

Mett, V., Kurnasov, O.V., Bespalov, I.A., Molodtsov, I., Brackett, C.M., Burdelya, L.G., et al., A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications. Commun Biol. 2021; Apr 12;4(1):466. doi: 10.1038/s42003-021-01978-6. DOI: https://doi.org/10.1038/s42003-021-01978-6

Ohto, U., Hanako, I., Takuma, S., Ryota, S., Kensuke, M., Toshiyuki, S. Toll-like Receptor 9 contains two dna binding sites that function cooperatively to promote receptor dimerization and activation. Immunity. 2018; 48: 649-658. DOI: https://doi.org/10.1016/j.immuni.2018.03.013

Chuang, Y.C., Tseng, J.C., Huang, L.R., Huang, C.M., Huang, C.F., Chuang, T.H. Adjuvant effect of Toll-like receptor 9 activation on cancer immunotherapy using checkpoint blockade. Front Immunol. 2020; 11:1075. https://doi:10.3389/fimmu.2020.01075 DOI: https://doi.org/10.3389/fimmu.2020.01075

Babdor, J., Descamps,D., Adiko,A.C., Tohme,M., Maschalidi, S., Evnouchidou,I., et al., IRAP+ endosomes restrict TLR9 activation and signaling. Nat Immunol. 2017; 05; 18(5):509-518 DOI: https://doi.org/10.1038/ni.3711

Marongiu, L., Gornati, L., Artuso, I., Zanoni, I., Granucci, F. Below the surface: The inner lives of TLR4 and TLR9. J Leukoc. Biol.2019;106:147-160–https://doi.org/10.1002/JLB.3MIR1218-483RR DOI: https://doi.org/10.1002/JLB.3MIR1218-483RR

Lind, N.A., Rael, V. E.,, Pestal K., Liu, B., Barton, G.M. Regulation of the nucleic acid- sensing Toll-like receptors. Nature rev Immunol. 2021; 1-12. DOI: https://doi.org/10.1038/s41577-021-00577-0

Hajam, I.A., Dar, P.A., Shahnawaz, I., Jaume, J.C., Lee, J.H. Bacterial flagellin-a potent immunomodulatory agent. Exp Mol Med. 2017; 49(9):e373. doi: 10.1038/emm.2017.172. PMID: 28860663; PMCID: PMC5628280. DOI: https://doi.org/10.1038/emm.2017.172

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Published

2022-11-14

How to Cite

1.
Marathe A, M. Rao G, Rai S. Microbiota milieu and mechanisms of intestinal Toll Like Receptors (TLRs) involved in chemotherapy induced mucositis. Biomedicine [Internet]. 2022 Nov. 14 [cited 2022 Nov. 27];42(5):856-62. Available from: https://biomedicineonline.org/home/article/view/2275

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