2,534
Views
4
CrossRef citations to date
0
Altmetric
Research Paper

Longitudinal flux balance analyses of a patient with episodic colonic inflammation reveals microbiome metabolic dynamics

, , , , , , , & ORCID Icon show all
Article: 2226921 | Received 16 Dec 2022, Accepted 14 Jun 2023, Published online: 12 Jul 2023

References

  • Heinken A, Hertel J, Thiele I. Metabolic modelling reveals broad changes in gut microbial metabolism in inflammatory bowel disease patients with dysbiosis. NPJ Syst Biol Appl. 2021;7(1):19. doi:10.1038/s41540-021-00178-6.
  • Almeida A, Nayfach S, Boland M, Strozzi F, Beracochea M, Shi ZJ, Pollard KS, Sakharova E, Parks DH, Hugenholtz P, et al. A unified catalog of 204,938 reference genomes from the human gut microbiome. Nat Biotechnol. 2021;39(1):105–25. doi:10.1038/s41587-020-0603-3.
  • Schippa S, Conte MP. Dysbiotic events in gut microbiota: impact on human health. Nutrients [Internet] 2014;6(12):5786–5805. [accessed 2022 Nov 11]. https://www.mdpi.com/2072-6643/6/12/5786.
  • Cheng M, Ning K. Stereotypes about enterotype: the old and new ideas. Genomics, Proteomics & Bioinf. 2019;17(1):4–12. doi:10.1016/j.gpb.2018.02.004.
  • Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13(4):260–270. doi:10.1038/nrg3182.
  • Lopez RN, Leach ST, Lemberg DA, Duvoisin G, Gearry RB, Day AS. Fecal biomarkers in inflammatory bowel disease. J Gastroen Hepatol [Internet]. 2017;32(3):577–582. [accessed 2022 Aug 6]. https://onlinelibrary.wiley.com/doi/abs/.10.1111/jgh.13611
  • Yoo JY, Groer M, Dutra SVO, Sarkar A, McSkimming DI. Gut microbiota and immune system interactions. Microorganisms [Internet]. 2020;8(10):1587. [accessed 2022 Sep 21]. https://www.mdpi.com/2076-2607/8/10/1587.
  • Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387(10014):156–167. doi:10.1016/S0140-6736(15)00465-1.
  • Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z, Järnerot G, Tysk C, Jansson JK, Engstrand L. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139(6):1844–1854.e1. doi:10.1053/j.gastro.2010.08.049.
  • Yazdani M, Taylor BC, Debelius JW, Li W, Knight R, Smarr L. Using machine learning to identify major shifts in human gut microbiome protein family abundance in disease. In: 2016 IEEE International Conference on Big Data (Big Data); 2016 December 5-8; Washington D.C., USA. p. 1272–1280.
  • Heinken A, Basile A, Thiele I. Advances in constraint-based modelling of microbial communities. Current Opinion Sys Biol. [Internet] 2021;27:100346. https://www.sciencedirect.com/science/article/pii/S2452310021000317.
  • Basile A, Campanaro S, Kovalovszki A, Zampieri G, Rossi A, Angelidaki I, Valle G, Treu L. Revealing metabolic mechanisms of interaction in the anaerobic digestion microbiome by flux balance analysis. Metab Eng. 2020;62:138–149. doi:10.1016/j.ymben.2020.08.013.
  • Thiele I, Heinken A, Fleming RMT. A systems biology approach to studying the role of microbes in human health. Curr Opin Biotechnol. 2013;24(1):4–12. doi:10.1016/j.copbio.2012.10.001.
  • Heinken A, Basile A, Hertel J, Thinnes C, Thiele I. Genome-scale metabolic modeling of the human microbiome in the era of personalized medicine. Annu Rev Microbiol. 2021;75(1):199–222. doi:10.1146/annurev-micro-060221-012134.
  • Orth JD, Thiele I, Palsson BØ. What is flux balance analysis? Nat Biotechnol. 2010;28(3):245–248. doi:10.1038/nbt.1614.
  • Norsigian CJ, Fang X, Seif Y, Monk JM, Palsson BO. A workflow for generating multi-strain genome-scale metabolic models of prokaryotes. Nat Protoc. 2020;15(1):1–14. doi:10.1038/s41596-019-0254-3.
  • Feist AM, Palsson BO. The biomass objective function. Curr Opin Microbiol [Internet]. 2010; 13(3):344–349. doi:10.1016/j.mib.2010.03.003.
  • Baldini F, Hertel J, Sandt E, Thinnes CC, Neuberger-Castillo L, Pavelka L, Betsou F, Krüger R, Thiele I, Consortium N-P. Parkinson’s disease-associated alterations of the gut microbiome predict disease-relevant changes in metabolic functions. BMC Biol. 2020;18:62. doi:10.1186/s12915-020-00775-7.
  • Hertel J, Harms AC, Heinken A, Baldini F, Thinnes CC, Glaab E, Vasco DA, Pietzner M, Stewart ID, Wareham NJ, et al. Integrated analyses of microbiome and longitudinal metabolome data reveal microbial-host interactions on sulfur metabolism in Parkinson’s Disease. Cell Rep. 2019;29(7):1767–1777.e8. doi:10.1016/j.celrep.2019.10.035.
  • Fang X, Vázquez-Baeza Y, Elijah E, Vargas F, Ackermann G, Humphrey G, Lau R, Weldon KC, Sanders JG, Panitchpakdi M, et al. Gastrointestinal surgery for inflammatory bowel disease persistently lowers microbiome and metabolome diversity. Inflamm Bowel Dis. 2021;27(5):603–616. doi:10.1093/ibd/izaa262.
  • Fang X, Monk JM, Nurk S, Akseshina M, Zhu Q, Gemmell C, Gianetto-Hill C, Leung N, Szubin R, Sanders J, et al. Metagenomics-based, strain-level analysis of Escherichia coli from a time-series of microbiome samples from a crohn’s disease patient. Front Microbiol. 2018;9:2559. doi:10.3389/fmicb.2018.02559.
  • Fang X, Monk JM, Mih N, Du B, Sastry AV, Kavvas E, Seif Y, Smarr L, Palsson BO. Escherichia coli B2 strains prevalent in inflammatory bowel disease patients have distinct metabolic capabilities that enable colonization of intestinal mucosa. BMC Syst Biol. 2018;12(1):66. doi:10.1186/s12918-018-0587-5.
  • Magnúsdóttir S, Heinken A, Kutt L, Ravcheev DA, Bauer E, Noronha A, Greenhalgh K, Jäger C, Baginska J, Wilmes P, et al. Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota. Nat Biotechnol. 2017;35(1):81–89. doi:10.1038/nbt.3703.
  • Heinken A, Hertel J, Acharya G, Ravcheev DA, Nyga M, Okpala OE, Hogan M, Magnúsdóttir S, Martinelli F, Nap B, et al. Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine. Nat Biotechnol. 2023: 1–12. doi:10.1038/s41587-022-01628-0
  • Heinken A, Ravcheev DA, Baldini F, Heirendt L, Fleming RMT, Thiele I. Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease. Microbiome. 2019;7(1):75. doi:10.1186/s40168-019-0689-3.
  • Thiele I, Sahoo S, Heinken A, Hertel J, Heirendt L, Aurich MK, Fleming RM. Personalized whole-body models integrate metabolism, physiology, and the gut microbiome. Mol Syst Biol. 2020;16(5):e8982. doi:10.15252/msb.20198982.
  • Wu S, Li W, Smarr L, Nelson K, Yooseph S, Torralba M Large memory high performance computing enables comparison across human gut microbiome of patients with autoimmune diseases and healthy subjects [Internet]. In: Proceedings of the Conference on Extreme Science and Engineering Discovery Environment: Gateway to Discovery. New York, NY, USA: Association for Computing Machinery; 2013:1–6. doi:10.1145/2484762.2484828.
  • Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, Bonazzi V, McEwen JE, Wetterstrand KA, NIH HMP Working Group, et al. The NIH human microbiome project. Genome Res. 2009;19(12):2317–2323. doi:10.1101/gr.096651.109.
  • Mills RH, Vázquez-Baeza Y, Zhu Q, Jiang L, Gaffney J, Humphrey G, Smarr L, Knight R, Gonzalez DJ. Evaluating metagenomic prediction of the metaproteome in a 4.5-year study of a patient with Crohn’s disease. mSystems. 2019;4:e00337–18. doi:10.1128/mSystems.00337-18.
  • Smarr L, Hyde ER, McDonald D, Sandborn WJ, Knight R. Tracking human gut microbiome changes resulting from a colonoscopy. Methods Inf Med. 2017;56(6):442–447. doi:10.3414/ME17-01-0036.
  • Schembri J, Bonello J, Christodoulou DK, Katsanos KH, Ellul P. Segmental colitis associated with diverticulosis: is it the coexistence of colonic diverticulosis and inflammatory bowel disease? Ann Gastroenterol. 2017;30:257–261. [accessed 2023 Apr 19]. doi:10.20524/aog.2017.0126.
  • Integrative HMP (iHMP) research network consortium. The integrative human microbiome project. Nature. 2019;569(7758):641–648. doi:10.1038/s41586-019-1238-8.
  • Chibani CM, Mahnert A, Borrel G, Almeida A, Werner A, Brugère J-F, Gribaldo S, Finn RD, Schmitz RA, Moissl-Eichinger C. A catalogue of 1,167 genomes from the human gut archaeome. Nat Microbiol [Internet]. 2022;7(1):48–61. [Internet] doi:10.1038/s41564-021-01020-9.
  • Callahan BJ, Sankaran K, Fukuyama JA, McMurdie PJ, Holmes SP. Bioconductor workflow for microbiome data analysis: from raw reads to community analyses. F1000Res. 2016;5:1492. doi:10.12688/f1000research.8986.2.
  • Noronha A, Modamio J, Jarosz Y, Guerard E, Sompairac N, Preciat G, Daníelsdóttir AD, Krecke M, Merten D, Haraldsdóttir HS, et al. The virtual metabolic human database: integrating human and gut microbiome metabolism with nutrition and disease. Nucleic Acids Res. 2019;47(D1):D614–24. doi:10.1093/nar/gky992.
  • Shah A, Morrison M, Burger D, Martin N, Rich J, Jones M, Koloski N, Walker MM, Talley NJ, Holtmann GJ. Systematic review with meta-analysis: the prevalence of small intestinal bacterial overgrowth in inflammatory bowel disease. Aliment Pharmacol Ther. 2019;49(6):624–635. doi:10.1111/apt.15133.
  • Dridi B, Raoult D, Drancourt M. Archaea as emerging organisms in complex human microbiomes. Anaerobe. 2011;17(2):56–63. doi:10.1016/j.anaerobe.2011.03.001.
  • Henson MA, Phalak P. Microbiota dysbiosis in inflammatory bowel diseases: in silico investigation of the oxygen hypothesis. BMC Syst Biol. 2017;11(1):145. doi:10.1186/s12918-017-0522-1.
  • Winter SE, Lopez CA, Bäumler AJ. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 2013;14(4):319–327. doi:10.1038/embor.2013.27.
  • Wilson A, Teft WA, Morse BL, Choi Y-H, Woolsey S, DeGorter MK, Hegele RA, Tirona RG, Kim RB. Trimethylamine-N-oxide: a novel biomarker for the identification of inflammatory bowel disease. Dig Dis Sci Available from. 2015;60(12):3620–3630. doi:10.1007/s10620-015-3797-3.
  • Pickard JM, Zeng MY, Caruso R, Núñez G. Gut microbiota: role in pathogen colonization, immune responses and inflammatory disease. Immunol Rev. 2017 [[cited 2022 Nov 10]];279(1):70–89. doi:10.1111/imr.12567.
  • Sánchez-Pérez S, Comas-Basté O, Duelo A, Veciana-Nogués MT, Berlanga M, Latorre-Moratalla ML, Vidal-Carou MC. Intestinal dysbiosis in patients with histamine intolerance. Nutrients. 2022;14(9):1774. [accessed 2022 Sep 22]. https://www.mdpi.com/2072-6643/14/9/1774.
  • Liu Y, Dai M. Trimethylamine N-Oxide generated by the gut microbiota is associated with vascular inflammation: new insights into atherosclerosis. Mediators Inflamm. 2020;2020:4634172. doi:10.1155/2020/4634172.
  • Kelly D, Yang L, Gut Microbiota PZ. Fusobacteria, and colorectal cancer. Diseases [Internet]. 2018;6(4):109. https://www.mdpi.com/2079-9721/6/4/109.
  • Cao Y-N, Feng L-J, Wang B-M, Jiang K, Li S, Xu X, Wang W-Q, Zhao J-W, Wang Y-M. Lactobacillus acidophilus and Bifidobacterium longum supernatants upregulate the serotonin transporter expression in intestinal epithelial cells. Saudi J Gastroenterol. 2018;24(1):59–66. doi:10.4103/sjg.SJG_333_17.
  • Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol. 2004;141(8):1285–1293. doi:10.1038/sj.bjp.0705762.
  • Minderhoud IM, Oldenburg B, Schipper MEI, Ter LindeJJM, Samsom M, Ter Linde JJM. Serotonin synthesis and uptake in symptomatic patients with Crohn’s disease in remission. Clin Gastroenterol Hepatol. 2007;5(6):714–720. doi:10.1016/j.cgh.2007.02.013.
  • Heinken A, Thiele I. Systems biology of host–microbe metabolomics. Wiley Interdiscip Rev Syst Biol Med. 2015;7(4):195–219. doi:10.1002/wsbm.1301.
  • Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32(18):2847–2849. doi:10.1093/bioinformatics/btw313.
  • de Vladar HP, de Vladar HP. Amino acid fermentation at the origin of the genetic code. Biol Direct. 2012;7(1):6. doi:10.1186/1745-6150-7-6.
  • Theriot CM, Fletcher JR. Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment. J Clin Invest. 2019;129(9):3539–3541. doi:10.1172/JCI130008.
  • Levitt MD, Furne J, Olsson S. The relation of passage of gas an abdominal bloating to colonic gas production. Ann Intern Med. 1996;124(4):422–424. doi:10.7326/0003-4819-124-4-199602150-00006.
  • Freudenberg MA, Merlin T, Gumenscheimer M, Kalis C, Landmann R, Galanos C. Role of lipopolysaccharide susceptibility in the innate immune response to Salmonella typhimurium infection: lPS, a primary target for recognition of gram-negative bacteria. Microbes Infect. 2001;3(14–15):1213–1222. doi:10.1016/S1286-4579(01)01481-2.
  • Gronbach K, Flade I, Holst O, Lindner B, Ruscheweyh HJ, Wittmann A, Menz S, Schwiertz A, Adam P, Stecher B, et al. Endotoxicity of lipopolysaccharide as a determinant of T-Cell−Mediated colitis induction in mice. Gastroenterology. 2014;146(3):765–775. doi:10.1053/j.gastro.2013.11.033.
  • Deng Z, Liu S. Inflammation-responsive delivery systems for the treatment of chronic inflammatory diseases. Drug Deliv Transl Res. 2021;11(4):1475–1497. doi:10.1007/s13346-021-00977-8.
  • Magro DO, Kotze PG, Martinez CAR, Camargo MG, Guadagnini D, Calixto AR, Vasques ACJ, de LS AM, Geloneze B, Pareja JC, et al. Changes in serum levels of lipopolysaccharides and CD26 in patients with Crohn’s disease. Intest Res. 2017;15:352–357. doi:10.5217/ir.2017.15.3.352.
  • Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012;489(7415):231–241. doi:10.1038/nature11551.
  • Segain JP, Raingeard de la Blétière D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottière HM, Galmiche JP. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease. Gut. 2000;47(3):397–403. doi:10.1136/gut.47.3.397.
  • Sassone-Corsi M, Nuccio S-P, Liu H, Hernandez D, Vu CT, Takahashi AA, Edwards RA, Raffatellu M. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature. 2016;540(7632):280–283. doi:10.1038/nature20557.
  • Matthews RG, Neidhardt FC. Elevated serine catabolism is associated with the heat shock response in Escherichia coli. J Bacteriol. 1989;171(5):2619–2625. doi:10.1128/jb.171.5.2619-2625.1989.
  • Kitamoto S, Alteri CJ, Rodrigues M, Nagao-Kitamoto H, Sugihara K, Himpsl SD, Bazzi M, Miyoshi M, Nishioka T, Hayashi A, et al. Dietary L-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut. Nature Microbiology. 2020;5(1):116–125. doi:10.1038/s41564-019-0591-6.
  • Zeng MY, Inohara N, Nuñez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 2017;10(1):18–26. doi:10.1038/mi.2016.75.
  • Stecher B, Conway T, Cohen P. The roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection. Microbiol Spectr. 2015;3(3):3. doi:10.1128/microbiolspec.MBP-0008-2014.
  • Sawers G. The anaerobic degradation of L-serine and L-threonine in enterobacteria: networks of pathways and regulatory signals. Arch Microbiol. 1998;171(1):1–5. doi:10.1007/s002030050670.
  • Connolly JPR, Gabrielsen M, Goldstone RJ, Grinter R, Wang D, Cogdell RJ, Walker D, Smith DGE, Roe AJ, Mulvey MA. A highly conserved bacterial d-serine uptake system links host metabolism and virulence. PLoS Pathog. 2016;12(1):e1005359. doi:10.1371/journal.ppat.1005359.
  • Duboc H, Rajca S, Rainteau D, Benarous D, Maubert M-A, Quervain E, Thomas G, Barbu V, Humbert L, Despras G, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut. 2013;62(4):531–539. doi:10.1136/gutjnl-2012-302578.
  • Li N, Koester ST, Lachance DM, Dutta M, Cui JY, Dey N. Microbiome-encoded bile acid metabolism modulates colonic transit times. iScience [Internet]. 2021; 24:102508. doi:10.1016/j.isci.2021.102508.
  • Kean IRL, Wagner J, Wijeyesekera A, De Goffau M, Thurston S, Clark JA, White DK, Ridout J, Agrawal S, Kayani R, et al. Profiling gut microbiota and bile acid metabolism in critically ill children. Sci Rep [Internet]. 2022; 12:10432. doi:10.1038/s41598-022-13640-0.
  • Diener C, Gibbons SM, Resendis-Antonio O, Chia N. MICOM: metagenome-scale modeling to infer metabolic interactions in the gut microbiota. mSystems. 2020;5(1):e00606–19. doi:10.1128/mSystems.00606-19.
  • Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60:631–637. doi:10.1136/gut.2010.223263.
  • Tsune I, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Takei Y, Sato N. Dietary glycine prevents chemical-induced experimental colitis in the rat. Gastroenterology. 2003;125(3):775–785. doi:10.1016/S0016-5085(03)01067-9.
  • Mirsepasi-Lauridsen HC, Vallance BA, Krogfelt KA, Petersen AM. Escherichia coli pathobionts associated with inflammatory bowel disease. Clin Microbiol Rev. 2019;32(2):e00060–18. doi:10.1128/CMR.00060-18.
  • Ghoshal U, Shukla R, Srivastava D, Ghoshal UC. Irritable bowel syndrome, particularly the constipation-predominant form, involves an increase in methanobrevibacter smithii, which is associated with higher methane production. Gut Liver. 2016;10(6):932–938. doi:10.5009/gnl15588.
  • Loubinoux J, Bronowicki J-P, Pereira IAC, Mougenel J-L, Faou AE. Sulfate-reducing bacteria in human feces and their association with inflammatory bowel diseases. FEMS Microbiol Ecol. 2002;40(2):107–112. doi:10.1111/j.1574-6941.2002.tb00942.x.
  • Magee EA, Edmond LM, Tasker SM, Kong SC, Curno R, Cummings JH. Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis. Nutr J. 2005;4(1):7. doi:10.1186/1475-2891-4-7.
  • Eng A, Borenstein E. Taxa-function robustness in microbial communities. Microbiome. 2018;6(1):45. doi:10.1186/s40168-018-0425-4.
  • Jimenez Loayza JJ, Berendsen EM, Teh J-J, Hoedt EC, Zhang J, Liu Q, Hamilton AL, Wilson-O’Brien A, Trakman GL, Lin W, et al. P837 the common food additives sodium sulfite and polysorbate 80 have a profound inhibitory effect on the commensal, anti-inflammatory bacterium Faecalibacterium prausnitzii: the ENIGMA study. Journal Of Crohn’s And Colitis. 2019;13(Supplement_1):S542–3. doi:10.1093/ecco-jcc/jjy222.961.
  • Devkota S, Chang EB. Interactions between diet, bile acid metabolism, gut microbiota, and inflammatory bowel diseases. Dig Dis [Internet] Available from. 2015; 33:351–356. doi:10.1159/000371687.
  • Keller A, Schink B, Müller N. Alternative pathways of acetogenic ethanol and methanol degradation in the thermophilic anaerobe thermacetogenium phaeum. Front Microbiol. 2019;10:423. doi:10.3389/fmicb.2019.00423.
  • Bertsch J, Siemund AL, Kremp F, Müller V. A novel route for ethanol oxidation in the acetogenic bacterium Acetobacterium woodii: the acetaldehyde/ethanol dehydrogenase pathway. Environ Microbiol. 2016;18(9):2913–2922. doi:10.1111/1462-2920.13082.
  • Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (N Y). [Internet] 2011 Available from. cited 2022 Apr 28.7. 235–241.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127025/.
  • Wallace JL. Prostaglandin biology in inflammatory bowel disease. Gastroenterol Clin North Am. 2001;30(4):971–980. doi:10.1016/S0889-8553(05)70223-5.
  • Tromm A, Griga T, May B. Oral mesalazine for the treatment of Crohn’s disease: clinical efficacy with respect to pharmacokinetic properties. Hepatogastroenterology. 1999;46:3124–3135.
  • Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr. 2004;24(1):539–577. doi:10.1146/annurev.nutr.24.012003.132418.
  • Walker A, Schmitt-Kopplin P. The role of fecal sulfur metabolome in inflammatory bowel diseases. Int J Med Microbiol. 2021;311(5):151513. doi:10.1016/j.ijmm.2021.151513.
  • Heinken A, Thiele I, Wren J. Microbiome Modelling Toolbox 2.0: efficient, tractable modelling of microbiome communities. Bioinformatics Available from. 2022;38(8):2367–2368. [[cited 2023 Mar 28]]. doi:10.1093/bioinformatics/btac082.
  • Heirendt L, Arreckx S, Pfau T, Mendoza SN, Richelle A, Heinken A, Haraldsdóttir HS, Wachowiak J, Keating SM, Vlasov V, et al. Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0. Nat Protoc. 2019;14(3):639–702. doi:10.1038/s41596-018-0098-2.
  • Baldini F, Heinken A, Heirendt L, Magnusdottir S, Fleming RMT, Thiele I, Wren J. The microbiome modeling toolbox: from microbial interactions to personalized microbial communities. Bioinformatics. 2019;35(13):2332–2334. doi:10.1093/bioinformatics/bty941.
  • Clarke KR, Warwick RM. The taxonomic distinctness measure of biodiversity: weighting of step lengths between hierarchical levels. Mar Ecol Prog Ser. 1999;184:21–29. doi:10.3354/meps184021.