Transplanting human gut microbiotas into germ-free (GF) mice is a popular approach to disentangle cause-and-effect relationships between enteric microbes and disease. Algorithm development has enabled sequence variant (SV) identification from 16S rRNA gene sequence data. SV analyses can identify which donor taxa colonize recipient GF mice, and how SV abundance in humans is replicated in these mice. Fecal microbiotas from 8 human subjects were used to generate 77 slurries, which were transplanted into 153 GF mice. Strong correlations between fecal and slurry microbial communities were observed; however, only 42.15 ± 9.95% of SVs successfully transferred from the donor to the corresponding recipient mouse. Firmicutes had a particularly low transfer rate and SV abundance was poorly correlated between donor and recipient pairs. Our study confirms human fecal microbiotas colonize formerly GF mice, but the engrafted community only partially resembles the input human communities. Our findings emphasize the importance of reporting a standardized transfer rate and merit the exploration of other animal models or in silico tools to understand the relationships between human gut microbiotas and disease.
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Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718–23.
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–3.
Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.
Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.
Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE. 2010;5:e9085.
Wang T, Cai G, Qiu Y, Fei N, Zhang M, Pang X, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012;6:320–9.
Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4:293–305.
De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8:e76993.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341:1241214–10.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.
Hintze KJ, Cox JE, Rompato G, Benninghoff AD, Ward RE, Broadbent J, et al. Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer. Gut Microbes. 2014;5:183–91.
Zhang L, Bahl MI, Roager HM, Fonvig CE, Hellgren LI, Frandsen HL, et al. Environmental spread of microbes impacts the development of metabolic phenotypes in mice transplanted with microbial communities from humans. ISME J. 2017;11:676–90.
Fouladi F, Brooks AE, Fodor AA, Carroll IM, Bulik-Sullivan EC, Tsilimigras MCB, et al. The role of the gut microbiota in sustained weight loss following Roux-en-Y gastric bypass surgery. Obes Surg. 2019;29:1259–67.
Tremaroli V, Karlsson F, Werling M, Ståhlman M, Kovatcheva-Datchary P, Olbers T, et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 2015;22:228–38.
Staley C, Kaiser T, Beura LK, Hamilton MJ, Weingarden AR, Bobr A, et al. Stable engraftment of human microbiota into mice with a single oral gavage following antibiotic conditioning. Microbiome. 2017;5:87.
Wos-Oxley M, Bleich A, Oxley AP, Kahl S, Janus LM, Smoczek A, et al. Comparative evaluation of establishing a human gut microbial community within rodent models. Gut Microbes. 2012;3:234–49.
Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell. 2012;149:1578–93.
Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1:6ra14.
Rawls JF, Mahowald MA, Ley RE, Gordon JI. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell. 2006;127:423–33.
Arrieta MC, Walter J, Finlay BB. Human microbiota-associated mice: a model with challenges. Cell Host Microbe. 2016;19:575–8.
Campbell JH, Foster CM, Vishnivetskaya T, Campbell AG, Yang ZK, Wymore A, et al. Host genetic and environmental effects on mouse intestinal microbiota. ISME J. 2012;6:2033–44.
McCafferty J, Muhlbauer M, Gharaibeh RZ, Arthur JC, Perez-Chanona E, Sha W, et al. Stochastic changes over time and not founder effects drive cage effects in microbial community assembly in a mouse model. ISME J. 2013;7:2116–25.
Le Roy T, Debedat J, Marquet F, Da-Cunha C, Ichou F, Guerre-Millo M, et al. Comparative evaluation of microbiota engraftment following fecal microbiota transfer in mice models: age, kinetic and microbial status matter. Front Microbiol. 2018;9:3289.
Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3.
Edgar RC UNOISE2: improved error-correction for Illumina 16S and ITS amplicon sequencing. bioRxiv. 2016. https://doi.org/10.1101/081257.
Amir A, McDonald D, Navas-Molina JA, Kopylova E, Morton JT, Zech Xu Z, et al. Deblur rapidly resolves single-nucleotide community sequence patterns. mSystems. 2017;2:e00191–16.
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.
Feeding and eating disorders. In: AE Kazdin, editor. Diagnostic and statistical manual of mental disorders, 5th edn. Washington DC; American Psychiatric Association; 2013.
Kleiman SC, Bulik-Sullivan EC, Glenny EM, Zerwas SC, Huh EY, Tsilimigras MCB, et al. The gut-brain axis in healthy females: lack of significant association between microbial composition and diversity with psychiatric measures. PLoS ONE. 2017;12:e0170208.
Kleiman SC, Watson HJ, Bulik-Sullivan EC, Huh EY, Tarantino LM, Bulik CM, et al. The intestinal microbiota in acute anorexia nervosa and during renourishment: relationship to depression, anxiety, and eating disorder psychopathology. Psychosom Med. 2015;77:969–81.
Carroll IM, Ringel-Kulka T, Keku TO, Chang Y-H, Packey CD, Sartor RB, et al. Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2011;301:G799–807.
Kleiman SC, Glenny EM, Bulik-Sullivan EC, Huh EY, Tsilimigras MCB, Fodor AA, et al. Daily changes in composition and diversity of the intestinal microbiota in patients with anorexia nervosa: a series of three cases. Eur Eat Disord Rev. 2017;25:423–7.
Parker KD, Albeke SE, Gigley JP, Goldstein AM, Ward NL. Microbiome composition in both wild-type and disease model mice is heavily influenced by mouse facility. Front Microbiol. 2018;9:1598.
Choo JM, Leong LE, Rogers GB. Sample storage conditions significantly influence faecal microbiome profiles. Sci Rep. 2015;5:16350.
Kim D, Hofstaedter CE, Zhao C, Mattei L, Tanes C, Clarke E, et al. Optimizing methods and dodging pitfalls in microbiome research. Microbiome. 2017;5:52.
Tedjo DI, Jonkers DM, Savelkoul PH, Masclee AA, van Best N, Pierik MJ, et al. The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. PLoS ONE. 2015;10:e0126685.
Pollock J, Glendinning L, Wisedchanwet T, Watson M. The madness of microbiome: attempting to find consensus “best practice” for 16S microbiome studies. Appl Environ Microbiol. 2018;84;e02627–17.
McLaren MR, Willis AD, Callahan BJ. Consistent and correctable bias in metagenomic sequencing experiments. Elife. 2019;8:e46923.
The authors thank the nurses in the UNC Center of Excellence for Eating Disorders for their invaluable assistance collecting fecal samples from patients, Eun Young Huh and Yesel Trillo-Ordonez for providing technical assistance, the National Gnotobiotic Rodent Resource Center (NIH P30DK034987) for providing the germ-free mice, the UNC-Chapel Hill High-Throughput Sequencing Facility for performing the high-throughput sequencing, and the Lineberger Animal Studies Core (supported in part by an NCI Center Core Support Grant (CA16086)) for their assistance with rodent procedures. Finally, this study was supported by NIDDK grant P30DK056350 to the UNC Nutrition Obesity Research Center.
This work was funded by the National Institute of Mental Health (R01 MH105684: PI Carroll). CMB acknowledges funding from the Swedish Research Council (Vetenskapsrådet, award: 538-2013-8864).
Conflict of interest
CMB has served on advisory boards for Shire and receives royalties from Pearson. IMC and AAF have previously served as consultants for Salix Pharmaceuticals.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Fouladi, F., Glenny, E.M., Bulik-Sullivan, E.C. et al. Sequence variant analysis reveals poor correlations in microbial taxonomic abundance between humans and mice after gnotobiotic transfer. ISME J 14, 1809–1820 (2020). https://doi.org/10.1038/s41396-020-0645-z