Wong Matthew K, Armstrong Eric, Heirali Alya A, Schneeberger Pierre H H, Chen Helen, Cochrane Kyla, Sherriff Keith, Allen-Vercoe Emma, Siu Lillian L, Spreafico Anna, Coburn Bryan
Department of Immunology, University of Toronto, Toronto, Canada.
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
bioRxiv. 2025 Mar 11:2025.03.11.642547. doi: 10.1101/2025.03.11.642547.
Composition and function of the gut microbiome is associated with diverse health conditions and treatment responses. Human microbiota-associated (HMA) mouse models are used to establish causal links for these associations but have important limitations. We assessed the fidelity of HMA mouse models to recapitulate ecological responses to a microbial consortium using stools collected from a human clinical trial. HMA mice were generated using different routes of consortium exposure and their ecological features were compared to human donors by metagenomic sequencing. HMA mice were more similar in gut composition to other mice than their respective human donors, with taxa including and species enriched in mouse recipients. A limited repertoire of microbes was able to engraft into HMA mice regardless of route of consortium exposure. In publicly available HMA mouse datasets from four distinct health conditions, we confirmed our observation that a taxonomically restricted set of microbes reproducibly engrafts in HMA mice and observed that stool microbiome composition of HMA mice were more like other mice than their human donor. Our data suggest that HMA mice are limited models to assess the ecological impact of microbial consortia, with ecological effects in HMA mice being more strongly associated with host species than donor stool ecology or ecological responses to treatment in humans. Comparisons to published studies suggest this may be due to comparatively large host-species effects that overwhelm ecological effects of treatment in humans that HMA models aim to recapitulate.
肠道微生物群的组成和功能与多种健康状况及治疗反应相关。人类微生物群相关（HMA）小鼠模型用于建立这些关联的因果联系，但存在重要局限性。我们使用从一项人体临床试验收集的粪便，评估了HMA小鼠模型在重现对微生物群落生态反应方面的逼真度。通过不同的群落暴露途径生成HMA小鼠，并通过宏基因组测序将它们的生态特征与人类供体进行比较。与各自的人类供体相比，HMA小鼠的肠道组成与其他小鼠更为相似，在小鼠受体中富集的分类群包括[具体分类群1]和[具体分类群2]物种。无论群落暴露途径如何，有限种类的微生物能够植入HMA小鼠体内。在来自四种不同健康状况的公开可用HMA小鼠数据集中，我们证实了我们的观察结果，即一组分类学上受限的微生物可重复植入HMA小鼠体内，并观察到HMA小鼠的粪便微生物群组成与其他小鼠更为相似，而非与其人类供体相似。我们的数据表明，HMA小鼠是评估微生物群落生态影响的有限模型，HMA小鼠中的生态效应与宿主物种的关联比与供体粪便生态或人类对治疗的生态反应更强。与已发表研究的比较表明，这可能是由于相对较大的宿主物种效应压倒了HMA模型旨在重现的人类治疗的生态效应。
