1887

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Volume 72, Issue 6

Gut microbiota associated with the mitigation effect of synbiotics on adverse events of neoadjuvant chemotherapy in patients with esophageal cancer: A retrospective exploratory study Open Access

Abstract

Our synbiotics ( strain Shirota, strain Yakult, and galacto-oligosaccharides: LBG) helps mitigate serious adverse events such as febrile neutropenia (FN) and diarrhoea in oesophageal cancer patients receiving neoadjuvant chemotherapy (NAC). Unfortunately, LBG therapy does not benefit all patients.

Identification of the gut microbiota species involved in adverse events during chemotherapy could help predict the onset of adverse events. Identification of the gut microbiota that influence the efficacy of LBG could also help establish a diagnostic method to identify patients who will respond to LBG before the initiation of therapy.

To identify the gut microbiota involved in adverse events during NAC and that affect the efficacy of LBG therapy.

This study was ancillary to a parent randomized controlled trial in which 81 oesophageal cancer patients were recruited and administered either prophylactic antibiotics or LBG combined with enteral nutrition (LBG+EN). The study included 73 of 81 patients from whom faecal samples were collected both before and after NAC. The gut microbiota was analysed using 16S rRNA gene amplicon sequencing and compared based on the degree of NAC-associated adverse events. Furthermore, the association between the counts of identified bacteria and adverse events and the mitigation effect of LBG+EN was also analysed.

The abundance of and in patients with no FN or only mild diarrhoea was significantly higher (<0.05) compared to those with FN or severe diarrhoea. Moreover, subgroup analyses of patients receiving LBG+EN showed that the faecal count before NAC was significantly associated with a risk of developing FN (OR, 0.11; 95 % CI, 0.01–0.60, =0.019). The faecal count after NAC was positively correlated with intestinal concentrations of acetic acid (=0.0007) and butyric acid (=0.00005).

and may be involved in the ameliorating adverse events and can thus be used to identify beforehand patients that would benefit from LBG+EN during NAC. These results also suggest that LBG+EN would be useful in the development of measures to prevent adverse events during NAC.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): 16S rRNA gene amplicon sequencing , esophageal cancer , gut microbiota , neoadjuvant chemotherapy , real time RT-PCR and synbiotics
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2023-06-27
2024-05-17
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References

  1. Leng XF, Daiko H, Han YT, Mao YS. Optimal preoperative neoadjuvant therapy for resectable locally advanced esophageal squamous cell carcinoma. Ann N Y Acad Sci 2020; 1482:213–224 [View Article] [PubMed]
     [Google Scholar]
  2. Watanabe M, Otake R, Kozuki R, Toihata T, Takahashi K et al. Recent progress in multidisciplinary treatment for patients with esophageal cancer. Surg Today 2020; 50:12–20 [View Article]
     [Google Scholar]
  3. Yamasaki M, Yasuda T, Yano M, Hirao M, Kobayashi K et al. Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003). Ann Oncol 2017; 28:116–120 [View Article] [PubMed]
     [Google Scholar]
  4. Sugimura K, Yamasaki M, Yasuda T, Yano M, Hirao M et al. Long-term results of a randomized controlled trial comparing neoadjuvant Adriamycin, cisplatin, and 5-fluorouracil vs docetaxel, cisplatin, and 5-fluorouracil followed by surgery for esophageal cancer (OGSG1003). Ann Gastroenterol Surg 2021; 5:75–82 [View Article] [PubMed]
     [Google Scholar]
  5. Miyata H, Yano M, Yasuda T, Hamano R, Yamasaki M et al. Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer. Clinical Nutrition 2012; 31:330–336 [View Article]
     [Google Scholar]
  6. Motoori M, Fujitani K, Sugimura K, Miyata H, Nakatsuka R et al. Skeletal muscle loss during neoadjuvant chemotherapy is an independent risk factor for postoperative infectious complications in patients with advanced esophageal cancer. Oncology 2018; 95:281–287 [View Article] [PubMed]
     [Google Scholar]
  7. Liu T, Xiong Q, Li L, Hu Y. Intestinal microbiota predicts lung cancer patients at risk of immune-related diarrhea. Immunotherapy 2019; 11:385–396 [View Article] [PubMed]
     [Google Scholar]
  8. Rattanathammethee T, Tuitemwong P, Thiennimitr P, Sarichai P, Na Pombejra S et al. Gut microbiota profiles of treatment-naïve adult acute myeloid leukemia patients with neutropenic fever during intensive chemotherapy. PLoS One 2020; 15:e0236460 [View Article] [PubMed]
     [Google Scholar]
  9. Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S et al. Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia. Clin Infect Dis 2018; 67:541–548 [View Article] [PubMed]
     [Google Scholar]
  10. Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G et al. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nat Rev Gastroenterol Hepatol 2020; 17:687–701 [View Article] [PubMed]
     [Google Scholar]
  11. Cruz BCS, Sarandy MM, Messias AC, Gonçalves RV, Ferreira C et al. Preclinical and clinical relevance of probiotics and synbiotics in colorectal carcinogenesis: a systematic review. Nutr Rev 2020; 78:667–687 [View Article] [PubMed]
     [Google Scholar]
  12. Chowdhury AH, Adiamah A, Kushairi A, Varadhan KK, Krznaric Z et al. Perioperative probiotics or synbiotics in adults undergoing elective abdominal surgery: a systematic review and meta-analysis of randomized controlled trials. Ann Surg 2020; 271:1036–1047 [View Article] [PubMed]
     [Google Scholar]
  13. Chen Y, Qi A, Teng D, Li S, Yan Y et al. Probiotics and synbiotics for preventing postoperative infectious complications in colorectal cancer patients: a systematic review and meta-analysis. Tech Coloproctol 2022; 26:425–436 [View Article]
     [Google Scholar]
  14. Arab A, Karimi E, Bagherniya M, Sathyapalan T, Sahebkar A. The effect of probiotic and synbiotic consumption on the most prevalent chemotherapy-related complications: a systematic review of current literature. Curr Med Chem 2022; 29:5462–5473 [View Article] [PubMed]
     [Google Scholar]
  15. Motoori M, Yano M, Miyata H, Sugimura K, Saito T et al. Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on adverse events in esophageal cancer patients. Clin Nutr 2017; 36:93–99 [View Article] [PubMed]
     [Google Scholar]
  16. Motoori M, Sugimura K, Tanaka K, Shiraishi O, Kimura Y et al. Comparison of synbiotics combined with enteral nutrition and prophylactic antibiotics as supportive care in patients with esophageal cancer undergoing neoadjuvant chemotherapy: a multicenter randomized study. Clin Nutr 2022; 41:1112–1121 [View Article] [PubMed]
     [Google Scholar]
  17. National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE). n.d https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm accessed 22 May 2023
  18. Kubota H, Tsuji H, Matsuda K, Kurakawa T, Asahara T et al. Detection of human intestinal catalase-negative, Gram-positive cocci by rRNA-targeted reverse transcription-PCR. Appl Environ Microbiol 2010; 76:5440–5451 [View Article] [PubMed]
     [Google Scholar]
  19. Sugimoto T, Shima T, Amamoto R, Kaga C, Kado Y et al. Impacts of habitual diets intake on gut microbial counts in healthy Japanese adults. Nutrients 2020; 12:2414 [View Article] [PubMed]
     [Google Scholar]
  20. Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol 2019; 37:852–857 [View Article]
     [Google Scholar]
  21. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA et al. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods 2016; 13:581–583 [View Article] [PubMed]
     [Google Scholar]
  22. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 1997; 25:4876–4882 [View Article] [PubMed]
     [Google Scholar]
  23. Tsuji H, Matsuda K, Nomoto K. Counting the countless: bacterial quantification by targeting rRNA molecules to explore the human gut microbiota in health and disease. Front Microbiol 2018; 9:1417 [View Article] [PubMed]
     [Google Scholar]
  24. Sato J, Kanazawa A, Ikeda F, Yoshihara T, Goto H et al. Gut dysbiosis and detection of “live gut bacteria” in blood of Japanese patients with type 2 diabetes. Diabetes Care 2014; 37:2343–2350 [View Article] [PubMed]
     [Google Scholar]
  25. Niikura M, Atobe S, Takahashi A, Kado Y, Sugimoto T et al. Development of a rapid and sensitive analytical system for Pseudomonas aeruginosa based on reverse transcription quantitative PCR targeting of rRNA molecules. Emerg Microbes Infect 2021; 10:677–686 [View Article] [PubMed]
     [Google Scholar]
  26. Matsuda K, Tsuji H, Asahara T, Kado Y, Nomoto K. Sensitive quantitative detection of commensal bacteria by rRNA-targeted reverse transcription-PCR. Appl Environ Microbiol 2007; 73:32–39 [View Article] [PubMed]
     [Google Scholar]
  27. Kurakawa T, Ogata K, Tsuji H, Kado Y, Takahashi T et al. Establishment of a sensitive system for analysis of human vaginal microbiota on the basis of rRNA-targeted reverse transcription-quantitative PCR. J Microbiol Methods 2015; 111:93–104 [View Article] [PubMed]
     [Google Scholar]
  28. Nagpal R, Kurakawa T, Tsuji H, Takahashi T, Kawashima K et al. Evolution of gut Bifidobacterium population in healthy Japanese infants over the first three years of life: a quantitative assessment. Sci Rep 2017; 7:10097 [View Article] [PubMed]
     [Google Scholar]
  29. Jansen GJ, Wildeboer-Veloo AC, Tonk RH, Franks AH, Welling GW. Development and validation of an automated, microscopy-based method for enumeration of groups of intestinal bacteria. J Microbiol Methods 1999; 37:215–221 [View Article] [PubMed]
     [Google Scholar]
  30. Asahara T, Takahashi A, Yuki N, Kaji R, Takahashi T et al. Protective effect of a synbiotic against multidrug-resistant Acinetobacter baumannii in a murine infection model. Antimicrob Agents Chemother 2016; 60:3041–3050 [View Article] [PubMed]
     [Google Scholar]
  31. Fernandes AD, Reid JN, Macklaim JM, McMurrough TA, Edgell DR et al. Unifying the analysis of high-throughput sequencing datasets: characterizing RNA-seq, 16S rRNA gene sequencing and selective growth experiments by compositional data analysis. Microbiome 2014; 2:15 [View Article] [PubMed]
     [Google Scholar]
  32. Yi Y, Shen L, Shi W, Xia F, Zhang H et al. Gut microbiome components predict response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a prospective, longitudinal study. Clin Cancer Res 2021; 27:1329–1340 [View Article] [PubMed]
     [Google Scholar]
  33. Allen-Vercoe E, Daigneault M, White A, Panaccione R, Duncan SH et al. Anaerostipes hadrus comb. nov., a dominant species within the human colonic microbiota; reclassification of Eubacterium hadrum Moore et al. 1976. Anaerobe 2012; 18:523–529 [View Article]
     [Google Scholar]
  34. Wong JMW, de Souza R, Kendall CWC, Emam A, Jenkins DJA. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006; 40:235–243 [View Article] [PubMed]
     [Google Scholar]
  35. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504:446–450 [View Article] [PubMed]
     [Google Scholar]
  36. Matsuki T, Watanabe K, Fujimoto J, Kado Y, Takada T et al. Quantitative PCR with 16S rRNA-gene-targeted species-specific primers for analysis of human intestinal bifidobacteria. Appl Environ Microbiol 2004; 70:167–173 [View Article]
     [Google Scholar]
  37. The HC, Florez de Sessions P, Jie S, Pham Thanh D, Thompson CN et al. Assessing gut microbiota perturbations during the early phase of infectious diarrhea in Vietnamese children. Gut Microbes 2018; 9:38–54 [View Article]
     [Google Scholar]
  38. Moratalla A, Caparrós E, Juanola O, Portune K, Puig-Kröger A et al. Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis. J Hepatol 2016; 64:135–145 [View Article] [PubMed]
     [Google Scholar]
  39. Moratalla A, Gómez-Hurtado I, Moya-Pérez Á, Zapater P, Peiró G et al. Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis. Eur J Nutr 2016; 55:197–206 [View Article] [PubMed]
     [Google Scholar]
  40. Pérez-Reytor D, Puebla C, Karahanian E, García K. Use of short-chain fatty acids for the recovery of the intestinal epithelial barrier affected by bacterial toxins. Front Physiol 2021; 12:650313 [View Article]
     [Google Scholar]
  41. Caballero-Flores G, Pickard JM, Núñez G. Microbiota-mediated colonization resistance: mechanisms and regulation. Nat Rev Microbiol 2023; 21:347–360 [View Article] [PubMed]
     [Google Scholar]
  42. Asahara T, Shimizu K, Nomoto K, Hamabata T, Ozawa A et al. Probiotic bifidobacteria protect mice from lethal infection with Shiga toxin-producing Escherichia coli O157:H7. Infect Immun 2004; 72:2240–2247 [View Article] [PubMed]
     [Google Scholar]
  43. Nishigaki E, Abe T, Yokoyama Y, Fukaya M, Asahara T et al. The detection of intraoperative bacterial translocation in the mesenteric lymph nodes is useful in predicting patients at high risk for postoperative infectious complications after esophagectomy. Ann Surg 2014; 259:477–484 [View Article] [PubMed]
     [Google Scholar]
  44. Sakaguchi S, Saito M, Tsuji H, Asahara T, Takata O et al. Bacterial rRNA-targeted reverse transcription-PCR used to identify pathogens responsible for fever with neutropenia. J Clin Microbiol 2010; 48:1624–1628 [View Article] [PubMed]
     [Google Scholar]
  45. Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 2009; 139:1619–1625 [View Article] [PubMed]
     [Google Scholar]
  46. Carvalho PLA, Andrade MER, Trindade LM, Leocádio PCL, Alvarez-Leite JI et al. Prophylactic and therapeutic supplementation using fructo-oligosaccharide improves the intestinal homeostasis after mucositis induced by 5- fluorouracil. Biomed Pharmacother 2021; 133:111012 [View Article] [PubMed]
     [Google Scholar]
  47. Lkhagvadorj E, Nagata S, Wada M, Bian L, Wang C et al. Anti-infectious activity of synbiotics in a novel mouse model of methicillin-resistant Staphylococcus aureus infection. Microbiol Immunol 2010; 54:265–275 [View Article] [PubMed]
     [Google Scholar]
  48. Barboza M, Sela DA, Pirim C, Locascio RG, Freeman SL et al. Glycoprofiling bifidobacterial consumption of galacto-oligosaccharides by mass spectrometry reveals strain-specific, preferential consumption of glycans. Appl Environ Microbiol 2009; 75:7319–7325 [View Article] [PubMed]
     [Google Scholar]
  49. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28:1368–1379 [View Article] [PubMed]
     [Google Scholar]
  50. Gao J, Yan K-T, Wang J-X, Dou J, Wang J et al. Gut microbial taxa as potential predictive biomarkers for acute coronary syndrome and post-STEMI cardiovascular events. Sci Rep 2020; 10:2639 [View Article] [PubMed]
     [Google Scholar]
  51. Yamamura K, Izumi D, Kandimalla R, Sonohara F, Baba Y et al. Intratumoral Fusobacterium nucleatum levels predict therapeutic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma. Clin Cancer Res 2019; 25:6170–6179 [View Article] [PubMed]
     [Google Scholar]
  52. Kanazawa H, Nagino M, Kamiya S, Komatsu S, Mayumi T et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390:104–113 [View Article] [PubMed]
     [Google Scholar]
  53. Sugawara G, Nagino M, Nishio H, Ebata T, Takagi K et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006; 244:706–714 [View Article] [PubMed]
     [Google Scholar]
  54. Usami M, Miyoshi M, Kanbara Y, Aoyama M, Sakaki H et al. Effects of perioperative synbiotic treatment on infectious complications, intestinal integrity, and fecal flora and organic acids in hepatic surgery with or without cirrhosis. JPEN J Parenter Enteral Nutr 2011; 35:317–328 [View Article] [PubMed]
     [Google Scholar]
  55. Yokoyama Y, Nishigaki E, Abe T, Fukaya M, Asahara T et al. Randomized clinical trial of the effect of perioperative synbiotics versus no synbiotics on bacterial translocation after oesophagectomy. Br J Surg 2014; 101:189–199 [View Article] [PubMed]
     [Google Scholar]
  56. Yokoyama Y, Miyake T, Kokuryo T, Asahara T, Nomoto K et al. Effect of perioperative synbiotic treatment on bacterial translocation and postoperative infectious complications after pancreatoduodenectomy. Dig Surg 2016; 33:220–229 [View Article]
     [Google Scholar]
  57. Hayakawa M, Asahara T, Ishitani T, Okamura A, Nomoto K et al. Synbiotic therapy reduces the pathological gram-negative rods caused by an increased acetic acid concentration in the gut. Dig Dis Sci 2012; 57:2642–2649 [View Article] [PubMed]
     [Google Scholar]
  58. Shimizu K, Yamada T, Ogura H, Mohri T, Kiguchi T et al. Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial. Crit Care 2018; 22:239 [View Article] [PubMed]
     [Google Scholar]
  59. Tanaka K, Yano M, Motoori M, Kishi K, Miyashiro I et al. Impact of perioperative administration of synbiotics in patients with esophageal cancer undergoing esophagectomy: a prospective randomized controlled trial. Surgery 2012; 152:832–842 [View Article] [PubMed]
     [Google Scholar]
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Gut microbiota associated with the mitigation effect of synbiotics on adverse events of neoadjuvant chemotherapy in patients with esophageal cancer: A retrospective exploratory study
J. Med. Microbiol. 72, 001723 (2023); https://doi.org/10.1099/jmm.0.001723
/content/journal/jmm/10.1099/jmm.0.001723
/content/journal/jmm/10.1099/jmm.0.001723
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