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ABSTRACT
Precision engineering of the gut microbiome holds promise as an effective therapeutic approach for diseases associated with a disruption in this microbial community. Engrafting a live biotherapeutic product (LBP) in a predictable, controllable manner is key to the consistent success of this approach and has remained a challenge for most LBPs under development. We recently demonstrated high-level engraftment of Bifidobacterium longum subsp. infantis (B. infantis) in adults when co-dosed with a specific prebiotic, human milk oligosaccharides (HMO). Here, we present a cellular kinetic-pharmacodynamic approach, analogous to pharmacokinetic-pharmacodynamic-based analyses of small molecule- and biologic-based drugs, to establish how HMO controls expansion, abundance, and metabolic output of B. infantis in a human microbiota-based model in gnotobiotic mice. Our data demonstrate that the HMO dose controls steady-state abundance of B. infantis in the microbiome, and that B. infantis together with HMO impacts gut metabolite levels in a targeted, HMO-dependent manner. We also found that HMO creates a privileged niche for B. infantis expansion across a 5-log range of bacterial inocula. These results demonstrate remarkable control of both B. infantis levels and the microbiome community metabolic outputs using this synbiotic approach, and pave the way for precision engineering of desirable microbes and metabolites to treat a range of diseases.
Acknowledgments
We would like to thank Shuning Rook Zheng, Richard Lavin, Aislinn Rowan-Nash, Chloe Autran, David Rechtman, Biranchi Patra, Shao-Hung Fred Tsen, Huiyu Jannela Xia, Kim Thu Tran, Tin Huynh, Thanhvan Vanessa Nguyen, Anita Wong, Jorge Ramirez, Gildardo Inzunza, Yesenia Martinez, and Mike Garelick for their support of and contributions to this study.
Author contributions
ALR, JEB, GJM designed experiments. CMC developed methods. ALR, RS, OT performed experiments. ALR, SLB, and MLL analyzed data. ALR wrote the paper. AKS provided materials.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article.
Disclosure statement
Prolacta Bioscience employees are also shareholders in the company. U.S. Patent No. 8,927,027, U.S. Patent Application No. 20200054035, International Application Pub. Nos. WO 2021/061991 and WO 2022/036225, and their corresponding family member patents and applications relate to aspects of this work.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.