title: Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases.
abstract: OBJECTIVE
  A common side effect of chemotherapy treatment is diarrhoea. Unfortunately, the underlying mechanisms of chemotherapy-induced diarrhoea (CD) are poorly understood. We aimed to determine if faecal microbes of CD patients were displaced, if faecal calprotectin increased during CD and if there were alterations in circulating matrix metalloproteinases, nuclear factor kappa B (NF-κB), IL-1β and TNF.
  
  
  METHODS
  Twenty-six cancer patients receiving chemotherapy were enrolled and requested to provide stool samples and blood samples at various times during their chemotherapy cycle. Stool samples were analysed using conventional culture techniques and qRT-PCR. ELISA kits determined faecal calprotectin levels, levels of circulating matrix metalloproteinases and circulating NF-κB, IL-1β and TNF.
  
  
  RESULTS
  The majority of patients with CD showed decreases in Lactobacillus spp., Bifidobacterium spp., Bacteroides spp. and Enterococcus spp. Increases were observed in Escherichia coli and Staphylococcus spp. Methanogenic archaea were also quantified, with all patients except one showing a decrease. Faecal calprotectin levels were increased in 81.25 % of patients with CD. Circulating MMP-3 and MMP-9 significantly increased following chemotherapy. Circulating levels of NF-κB, IL-1β and TNF were increased following chemotherapy, although this did not reach significance.
  
  
  CONCLUSIONS
  We demonstrated that CD is associated with marked changes in intestinal microflora, methanogenic archaea, matrix metalloproteinase and serum levels of NF-κB, IL-1β and TNF. These changes may result in diminished bacterial functions within the gut, altering gut function and initiating intestinal damage, resulting in the onset of diarrhoea. More importantly, these changes may provide clinicians with a possible new target for biomarkers of toxicity.
authors: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors: Andrea M
authors: AM
authors: Stringer
authors: Noor
authors: N
authors: Al-Dasooqi
authors: Joanne M
authors: JM
authors: Bowen
authors: Thean H
authors: TH
authors: Tan
authors: Maryam
authors: M
authors: Radzuan
authors: Richard M
authors: RM
authors: Logan
authors: Bronwen
authors: B
authors: Mayo
authors: Dorothy M K
authors: DM
authors: Keefe
authors: Rachel J
authors: RJ
authors: Gibson
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced* / Q000201:enzymology / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood*; D064307:Microbiota / Q000187:drug effects*; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced* / Q000201:enzymology / Q000382:microbiology; D016328:NF-kappa B / Q000097:blood; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases
references: J Support Oncol. 2007 Jun;5(6):259-67
references: 17624050
references: Nat Rev Cancer. 2004 Apr;4(4):277-84
references: 15057287
references: Toxicol In Vitro. 2006 Mar;20(2):163-75
references: 16271446
references: Cancer Chemother Pharmacol. 2007 Feb;59(3):337-48
references: 16799812
references: Support Care Cancer. 2006 Sep;14(9):890-900
references: 16604351
references: Exp Biol Med (Maywood). 2009 Apr;234(4):430-41
references: 19176868
references: Cancer Treat Rev. 2007 Aug;33(5):448-60
references: 17507164
references: Cancer Chemother Pharmacol. 2008 Jun;62(1):33-41
references: 17703303
references: Exp Biol Med (Maywood). 2007 Jan;232(1):96-106
references: 17202590
references: J Appl Bacteriol. 1988 Sep;65(3):241-7
references: 2852666
references: J Gastroenterol Hepatol. 2003 Sep;18(9):1095-100
references: 12911669
references: Int J Med Microbiol. 2003 Apr;293(1):77-86
references: 12755368
references: Science. 2001 Jul 13;293(5528):293-7
references: 11452123
references: Pediatr Blood Cancer. 2009 Dec 15;53(7):1188-94
references: 19688831
references: FEMS Microbiol Lett. 2005 Feb 1;243(1):141-7
references: 15668012
references: Exp Biol Med (Maywood). 2010 Oct;235(10):1244-56
references: 20682600
references: Cancer. 2005 Jan 1;103(1):191-9
references: 15573372
references: J Antimicrob Chemother. 2006 Jul;58(1):85-94
references: 16698847
references: Dig Liver Dis. 2003 Sep;35(9):607-9
references: 14563180
references: Pathol Res Pract. 2010 Apr 15;206(4):241-7
references: 20092959
references: Cancer Chemother Pharmacol. 2009 Jun;64(1):1-9
references: 19305997
references: J Clin Oncol. 1997 Aug;15(8):2981-95
references: 9256143
references: Appl Environ Microbiol. 2006 Jun;72(6):4214-24
references: 16751534
references: Cancer. 2003 Oct 1;98(7):1531-9
references: 14508842
references: J Appl Microbiol. 2004;97(6):1166-77
references: 15546407
references: Aliment Pharmacol Ther. 2008 May;27(10):980-7
references: 18315578
references: Microbes Infect. 2002 Mar;4(3):309-17
references: 11909741
references: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references: 17318226
references: Clin Lab. 2008;54(11-12):473-84
references: 19216253
references: Cell Host Microbe. 2008 Jun 12;3(6):340-1
references: 18541208
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16767-72
references: 18931303
references: Dig Dis Sci. 2004 Jan;49(1):84-7
references: 14992440
references: Cancer. 2007 Mar 1;109(5):820-31
references: 17236223
references: Appl Environ Microbiol. 2004 Dec;70(12):7220-8
references: 15574920
references: Gut. 2005 Mar;54(3):364-8
references: 15710984
references: BMC Microbiol. 2008 May 20;8:79
references: 18492229
references: EMBO J. 2007 Oct 31;26(21):4457-66
references: 17914462
references: Clin Exp Med. 2005 Mar;4(4):188-95
references: 15750766
references: Appl Environ Microbiol. 1996 Dec;62(12):4608-13
references: 8953730
references: J Clin Microbiol. 2001 Sep;39(9):3047-51
references: 11526126
references: Cancer Treat Rev. 2011 Oct;37(6):487-93
references: 21689887
references: J Pathol. 2008 Oct;216(2):183-92
references: 18729068
references: Cancer. 2004 May 1;100(9 Suppl):1995-2025
references: 15108222
references: Clin Microbiol Rev. 2007 Oct;20(4):593-621
references: 17934076