1887

Abstract

Cachexia (CC) is a complex wasting syndrome that significantly affects life quality and life expectancy among cancer patients. Original studies, in which CC was induced in mouse models through inoculation with BaF and C26 tumour cells, demonstrated that CC development correlates with bacterial gut dysbiosis in these animals. In both cases, a common microbial signature was observed, based on the expansion of in the gut of CC animals. However, these two types of tumours induce unique microbial profiles, suggesting that different CC induction mechanisms significantly impact the outcome of gut dysbiosis. The present study sought to expand the scope of such analyses by characterizing the CC-associated dysbiosis that develops when mice are inoculated with Lewis lung carcinoma (LLC) cells, which constitutes one of the most widely employed mechanisms for CC induction. Interestingly, expansion is also observed in LLC-induced CC. However, the dysbiosis identified herein displays a more complex pattern, involving representatives from seven different bacterial phyla, which were consistently identified across successive levels of taxonomic hierarchy. These results are supported by a predictive analysis of gene content, which identified a series of functional/structural changes that potentially occur in the gut bacterial population of these animals, providing a complementary and alternative approach to microbiome analyses based solely on taxonomic classification.

Funding
This study was supported by the:
  • fundação de amparo à pesquisa do estado de são paulo (Award #2017/13197-8)
    • Principle Award Recipient: LuizR Nunes
  • fundação de amparo à pesquisa do estado de são paulo (Award #2017/08112-3)
    • Principle Award Recipient: DanielaLeite Jabes
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.001088
2021-10-01
2024-05-11
Loading full text...

Full text loading...

/deliver/fulltext/micro/167/10/mic001088.html?itemId=/content/journal/micro/10.1099/mic.0.001088&mimeType=html&fmt=ahah

References

  1. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers 2018; 4:1–18 [View Article]
    [Google Scholar]
  2. Evans WJ, Morley JE, Argilés J, Bales C, Baracos V et al. Cachexia: a new definition. Clin Nutr 2008; 27:793–799 [View Article]
    [Google Scholar]
  3. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12:489–495 [View Article]
    [Google Scholar]
  4. Gordon JN, Green SR, Goggin PM. Cancer cachexia. QJM 2005; 98:779–788 [View Article]
    [Google Scholar]
  5. Bruera E, Hui D. Conceptual models for integrating palliative care at cancer centers. J Palliat Med 2012; 15:1261–1269 [View Article]
    [Google Scholar]
  6. Bindels LB, Beck R, Schakman O, Martin JC, De Backer F et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS One 2012; 7:e37971 [View Article]
    [Google Scholar]
  7. Bindels LB, Neyrinck AM, Claus SP, Le Roy CI, Grangette C et al. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J 2016; 10:1456–1470 [View Article]
    [Google Scholar]
  8. Pötgens AS, Brossel H, Sboarina M, Catry E, Cani PD et al. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci Rep 2018; 8:12321 [View Article]
    [Google Scholar]
  9. Bindels LB, Neyrinck AM, Loumaye A, Catry E, Walgrave H et al. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. Oncotarget 2018; 9:18224–18238 [View Article]
    [Google Scholar]
  10. DeBoer MD. Animal models of anorexia and cachexia. Expert Opin Drug Discov 2009; 4:1145–1155 [View Article]
    [Google Scholar]
  11. Das SK, Eder S, Schauer S, Diwoky C, Temmel H et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011; 333:233–238 [View Article]
    [Google Scholar]
  12. Kir S, White JP, Kleiner S, Kazak L, Cohen P et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014; 513:100–104 [View Article]
    [Google Scholar]
  13. Iwata Y, Suzuki N, Ohtake H, Kamauchi S, Hashimoto N al. Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2-independent mechanisms, unlike muscular dystrophy. J Cachexia Sarcopenia Muscle 2016; 7:366–376 [View Article]
    [Google Scholar]
  14. Macpherson AJ, McCoy K. Standardised animal models of host microbial mutualism. Mucosal Immunol 2015; 8:476–486 [View Article]
    [Google Scholar]
  15. Franklin CL, Ericsson AC. Microbiota and reproducibility of rodent models. Lab animal 2017; 46:114 [View Article]
    [Google Scholar]
  16. Voltarelli FA, Frajacomo FT, de Souza Padilha C, Testa MTJ, Cella PS et al. Syngeneic B16F10 melanoma causes cachexia and impairedskeletal muscle strength and locomotor activity in mice. Front Physiol 2017; 8:715 [View Article]
    [Google Scholar]
  17. Jabes DL, de Maria YNLF, Aciole Barbosa D, Santos KBNH, Carvalho LM et al. Fungal dysbiosis correlates with the development of tumor-induced cachexia in mice. J Fungi (Basel) 2020; 6:364 [View Article]
    [Google Scholar]
  18. Klindworth A, Pruesse E, Schweer T, Peplies J, Quast C et al. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res 2013; 41:e1 [View Article]
    [Google Scholar]
  19. Chong J, Liu P, Zhou G, Xia J. Using Microbiomeanalyst for comprehensive statistical, functional, and meta-analysis of microbiome data. Nat Protoc 2020; 15:799–821 [View Article]
    [Google Scholar]
  20. Cameron KA, Stibal M, Zarsky JD, Gözdereliler E, Schostag M et al. Supraglacial bacterial community structures vary across the Greenland ice sheet. FEMS Microbiol Ecol 2016; 92:fiv164 [View Article]
    [Google Scholar]
  21. Astudillo-García C, Bell JJ, Webster NS, Glasl B, Jompa J et al. Evaluating the core microbiota in complex communities: A systematic investigation. Environ Microbiol 2017; 19:1450–1462 [View Article]
    [Google Scholar]
  22. Flemer B, Gaci N, Borrel G, Sanderson IR, Chaudhary PP et al. Fecal microbiota variation across the lifespan of the healthy laboratory rat. Gut Microbes 2017; 8:428–439 [View Article]
    [Google Scholar]
  23. Björk JR, O’Hara RB, Ribes M, Coma R, Montoya JM. The dynamic core microbiome: Structure, dynamics and stability. bioRxiv 2018137885 [View Article]
    [Google Scholar]
  24. Toju H, Peay KG, Yamamichi M, Narisawa K, Hiruma K et al. Core microbiomes for sustainable agroecosystems. Nat Plants 2018; 4:247–257 [View Article]
    [Google Scholar]
  25. Russel J, Roesch L, Atkinson MA, Schatz D, Triplett EW et al. Genetic risk for type 1 diabetes profoundly influences the core gut microbiome in children. Diabetes 2018; 67:209–LB [View Article]
    [Google Scholar]
  26. Piampiano E, Pini F, Biondi N, Pastorelli R, Giovannetti L et al. Analysis of microbiota in cultures of the green microalga Tetraselmis suecica. Eur J Phycol 2019; 54:497–508 [View Article]
    [Google Scholar]
  27. Suenami S, Konishi Nobu M, Miyazaki R. Community analysis of gut microbiota in hornets, the largest eusocial wasps, Vespa mandarinia and V. simillima. Sci Rep 2019; 9:9830 [View Article]
    [Google Scholar]
  28. Wallace RJ, Sasson G, Garnsworthy PC, Tapio I, Gregson E et al. A heritable subset of the core rumen microbiome dictates dairy cow productivity and emissions. Sci Adv 2019; 5:eaav8391 [View Article]
    [Google Scholar]
  29. Clos-Garcia M, Andrés-Marin N, Fernández-Eulate G, Abecia L, Lavín JL et al. Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia. EBioMedicine 2019; 46:499–511 [View Article]
    [Google Scholar]
  30. Langille MGI, Zaneveld J, Caporaso JG, McDonald D, Knights D et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nature Biotechnol 2013; 31:814–821 [View Article]
    [Google Scholar]
  31. Anderson MJ, Walsh DCI. PERMANOVA, ANOSIM, and the Mantel test in the face of heterogeneous dispersions: What null hypothesis are you testing. Ecological Monographs 2013; 83:557–574 [View Article]
    [Google Scholar]
  32. Mallick H, Ma S, Franzosa EA, Vatanen T, Morgan XC et al. Experimental design and quantitative analysis of microbial community multiomics. Genome Biol 2017228 [View Article]
    [Google Scholar]
  33. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L et al. Metagenomic biomarker discovery and explanation. Genome Biol 2011; 12:R60 [View Article]
    [Google Scholar]
  34. Bindels LB, Thissen JP. Nutrition in cancer patients with cachexia: A role for the gut microbiota?. Clin Nutr Exp 2016; 6:74–82 [View Article]
    [Google Scholar]
  35. Herremans KM, Riner AN, Cameron ME, Trevino JG. The microbiota and cancer cachexia. Int J Mol Sci 2019; 20:E6267 [View Article]
    [Google Scholar]
  36. Yang JY, Lee YS, Kim Y, Lee SH, Ryu S et al. Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol 2017; 10:104–116 [View Article]
    [Google Scholar]
  37. Kanehisa M, Goto SK. Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28:27–30 [View Article]
    [Google Scholar]
  38. Tatusov RL, Galperin MY, Natale DA, Koonina EV. The COG database: a tool for genome-scale analysis of protein functions and evolution. Nucleic Acids Res 2000; 28:33–36 [View Article]
    [Google Scholar]
  39. Kanehisa M. Toward understanding the origin and evolution of cellular organisms. Protein Sci 2019; 28:1947–1951 [View Article]
    [Google Scholar]
  40. Kanehisa M, Sato Y, Furumichi M, Morishima K, Anabe M. New approach for understanding genome variations in KEGG. Nucleic Acids Res 2019; 47:D590–D595 [View Article]
    [Google Scholar]
  41. Ebner N, Anker SD, Haehling S. Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference. J Cachexia Sarcopenia Muscle 2019; 10:218–225 [View Article]
    [Google Scholar]
  42. Reikvam DH, Erofeev A, Sandvik A, Grcic V, Jahnsen FL et al. Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS One 2011; 6:e17996 [View Article]
    [Google Scholar]
  43. Hoban AE, Moloney RD, Golubeva AV, McVey Neufeld KA, O’Sullivan O et al. Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience 2016; 339:463–477 [View Article]
    [Google Scholar]
  44. Wang H, Ji Y, Yin C et al. Differential analysis of gut microbiota correlated with oxidative stress in sows with high or low litter performance during lactation. Front Microbiol 2018; 9:1665 [View Article]
    [Google Scholar]
  45. Guirro M, Costa A, Gual-Grau A, Herrero P, Torrell H et al. Effects from diet-induced gut microbiota dysbiosis and obesity can be ameliorated by fecal microbiota transplantation: A multiomics approach. PLoS One 2019; 14:e0218143 [View Article]
    [Google Scholar]
  46. Brenner SR. Blue-green algae or cyanobacteria in the intestinal micro-flora may produce neurotoxins such as Beta-N-Methylamino-L-Alanine (BMAA) which may be related to development of amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson-Dementia-Complex in humans and Equine Motor Neuron Disease in horses. Med Hypotheses 2013; 80:103 [View Article]
    [Google Scholar]
  47. Roy Sarkar S, Banerjee S. Gut microbiota in neurodegenerative disorders. J Neuroimmunol 2019; 328:98–104 [View Article]
    [Google Scholar]
  48. Ohko Y, Nagao Y, Okano K, Sugiura N, Fukuda A et al. Prevention of Phormidium tenue Biofilm Formation by TiO(2) Photocatalysis. Microbes Environ 2009; 24:241–245 [View Article]
    [Google Scholar]
  49. Camilleri M, Nadeau A, Lamsam J, Nord SL, Ryks M et al. Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion. Neurogastroenterol Motil 2010; 22:e15-26 [View Article]
    [Google Scholar]
  50. Christie R, North E, Parkin BJ. Criteria of pathogenicity in staphylococci. Aust J Exp Biol Med Sci 1946; 24:73–78 [View Article]
    [Google Scholar]
  51. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444:1027–1031 [View Article]
    [Google Scholar]
  52. Koliada A, Syzenko G, Moseiko V, Budovska L, Puchkov K et al. Association between body mass index and Firmicutes/Bacteroidetes ratio in an adult Ukrainian population. BMC microbiol 2017; 17:120 [View Article]
    [Google Scholar]
  53. Castaner O, Goday A, Park YM, Lee SH, Magkos F et al. The gut microbiome profile in obesity: a systematic review. Int J Endocrinol 20181–9 [View Article]
    [Google Scholar]
  54. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2018; 3:213–223 [View Article]
    [Google Scholar]
  55. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013; 54:2325–2340 [View Article]
    [Google Scholar]
  56. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015; 11:577–591 [View Article]
    [Google Scholar]
  57. Tahara Y, Yamazaki M, Sukigara H, Motohashi H, Sasaki H et al. Gut microbiota-derived short chain fatty acids induce circadian clock entrainment in mouse peripheral tissue. Sci Rep 2018; 8:1395 [View Article]
    [Google Scholar]
  58. Silva YP, Bernardi A, Frozza RNL. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol (Lausanne) 2020; 11:25 [View Article]
    [Google Scholar]
  59. Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M et al. Gut microbiota and metabolic syndrome. World J Gastroenterol 2014; 20:16079–16094 [View Article]
    [Google Scholar]
  60. Moreno-Indias I, Sánchez-Alcoholado L, García-Fuentes E, Cardona F, Queipo-Ortuño MI et al. Insulin resistance is associated with specific gut microbiota in appendix samples from morbidly obese patients. Am J Transl Res 2016; 8:5672–5684 [PubMed]
    [Google Scholar]
  61. Belizário JE, Faintuch J, Garay-Malpartida M. Gut microbiome dysbiosis and immunometabolism: new frontiers for treatment of metabolic diseases. Mediators Inflamm 20182037838 [View Article]
    [Google Scholar]
  62. Shin NR, Whon TW, Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 2015; 33:496–503 [View Article]
    [Google Scholar]
  63. DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 2016; 22:1137–1150 [View Article]
    [Google Scholar]
  64. Zhang C, Zhang M, Wang S, Han R, Cao Y et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J 2010; 4:232–241 [View Article]
    [Google Scholar]
  65. Cani PD. Gut microbiota and obesity: lessons from the microbiome. Brief Funct Genomics 2013; 12:381–387 [View Article]
    [Google Scholar]
  66. Rinninella E, Raoul P, Cintoni M, Franceschi F, Miggiano G et al. What is the healthy gut microbiota composition? a changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019; 7:14 [View Article]
    [Google Scholar]
  67. Kuehbacher T, Rehman A, Lepage P, Hellmig S, Fölsch UR et al. Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease. J Med Microbiol 2008; 57:1569–1576 [View Article]
    [Google Scholar]
  68. Rowan F, Docherty NG, Murphy M, Murphy B, Calvin Coffey J et al. Desulfovibrio bacterial species are increased in ulcerative colitis. Dis Colon Rectum 2010; 53:1530–1536 [View Article]
    [Google Scholar]
  69. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL. IBD-what role do Proteobacteria play. Nat Rev Gastroenterol Hepatol 2012; 9:219–230 [View Article]
    [Google Scholar]
  70. Jakobsson HE, Rodriguez-Pineiro AM, Schutte A, Ermund A, Boysen P et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep 2015; 16:164–177 [View Article]
    [Google Scholar]
  71. Zeng M, Inohara N, Nuñez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol 2017; 10:18–26 [View Article]
    [Google Scholar]
  72. Hughes ER, Winter MG, Duerkop BA, Spiga L, Furtado de Carvalho T et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 2017; 21:208–219 [View Article]
    [Google Scholar]
  73. da Silva SM, Pimentel C, Valente FM, Rodrigues-Pousada C, Pereira IA. Tungsten and molybdenum regulation of formate dehydrogenase expression in Desulfovibrio vulgaris Hildenborough. J Bacteriol 2011; 193:2909–2916 [View Article]
    [Google Scholar]
  74. Plugge CM, Zhang W, Scholten JC, Stams AJ. Metabolic flexibility of sulfate-reducing bacteria. Front Microbiol 2011; 2:81 [View Article]
    [Google Scholar]
  75. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 2004; 127:412–421 [View Article]
    [Google Scholar]
  76. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G et al. Host-gut microbiota metabolic interactions. Science 2012; 336:1262–1267 [View Article]
    [Google Scholar]
  77. Gevers D, Kugathasan S, Denson LA, Vázquez-Baeza Y, Van Treuren W et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 2014; 15:382–392 [View Article]
    [Google Scholar]
  78. Craig L, Forest KT, Maier B. Type IV pili: dynamics, biophysics and functional consequences. Nat Rev Microbiol 2019; 17:429–440 [View Article]
    [Google Scholar]
  79. Stecher B, Hapfelmeier S, Müller C, Kremer M, Stallmach T et al. Flagella and chemotaxis are required for efficient induction of Salmonella enterica serovar Typhimurium colitis in streptomycin-pretreated mice. Infect Immun 2004; 72:4138–4150 [View Article]
    [Google Scholar]
  80. Grimes L, Doyle A, Miller AL, Pyles RB, Olah G et al. Intraluminal flagellin differentially contributes to gut dysbiosis and systemic inflammation following burn injury. PloS One 2016; 11:e0166770 [View Article]
    [Google Scholar]
  81. Barocchi MA, Ries J, Zogaj X, Hemsley C, Albiger B et al. A pneumococcal pilus influences virulence and host inflammatory responses. Proc Natl Acad Sci U S A 2006; 103:2857–2862 [View Article]
    [Google Scholar]
  82. Winter SE, Thiennimitr P, Nuccio SP, Haneda T, Winter MG et al. Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype typhimurium infection. Infect Immun 2009; 77:1904–1916 [View Article]
    [Google Scholar]
  83. Chassaing B, Ley RE, Gewirtz AT. Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 2014; 147:1363–1377 [View Article]
    [Google Scholar]
  84. Tran HQ, Ley RE, Gewirtz AT, Chassaing B. Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases. Nat Commun 2019; 10:5650 [View Article]
    [Google Scholar]
  85. Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K et al. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci U S A 2012; 109:8334–8339 [View Article]
    [Google Scholar]
  86. Granado-Serrano AB, Martín-Garí M, Sánchez V, Riart Solans M, Berdún R et al. Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Sci Rep 20199 [View Article]
    [Google Scholar]
  87. Nørskov-Lauritsen N. Classification, identification, and clinical significance of Haemophilus and Aggregatibacter species with host specificity for humans. Clin Microbiol Rev 2014; 27:214–240 [View Article]
    [Google Scholar]
  88. Angelakis E, Armougom F, Carrière F, Bachar D, Laugier R et al. A metagenomic investigation of the duodenal microbiota reveals links with obesity. PLoS One 2015; 10:e0137784 [View Article]
    [Google Scholar]
  89. Castro JF, Nouioui I, Asenjo JA, Andrews B, Bull AT et al. New genus-specific primers for PCR identification of Rubrobacter strains. Antonie van Leeuwenhoek 2019; 112:1863–1874 [View Article]
    [Google Scholar]
  90. Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiology Rev 2007; 20:593–621 [View Article]
    [Google Scholar]
  91. Xu J, Saunders CW, Hu P, Grant RA, Boekhout T et al. Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens. Proc Natl Acad Sci U S A 2007; 104:18730–18735 [View Article]
    [Google Scholar]
  92. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010; 59:3049–3057 [View Article]
    [Google Scholar]
  93. Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B et al. Gut microbiota and obesity: a role for probiotics. Nutrients 2019; 11:2690 [View Article]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.001088
Loading
/content/journal/micro/10.1099/mic.0.001088
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error