Sequence variant analysis reveals poor correlations in microbial taxonomic abundance between humans and mice after gnotobiotic transfer

Abstract

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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Fig. 1: Multidimensional scaling of microbial communities from human fecal samples, slurries, and mouse fecal pellets.
Fig. 2: Retention of SVs from human stool in slurries.
Fig. 3: Relationship between relative abundance of SVs in a human fecal sample-slurry pairs.
Fig. 4: Retention of SVs from slurries in recipient mice.
Fig. 5: Relationship between relative abundances of SVs in a slurry-mouse fecal pellet pairs 1 week after colonization.
Fig. 6: Transfer efficiency across different bacterial taxa.

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Acknowledgements

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.

Funding

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).

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Correspondence to Anthony A. Fodor or Ian M. Carroll.

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CMB has served on advisory boards for Shire and receives royalties from Pearson. IMC and AAF have previously served as consultants for Salix Pharmaceuticals.

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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

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