Using Microbiome Genetics to Explore Microbe-Host Interaction at the Molecular Level

Dr. ChunJun Guo

Associate Professor of Microbiology & Immunology in Medicine,

Halvorsen Family Research Scholar in Metabolic Health

Jill Roberts Institute for Research in Inflammatory Bowel Disease

Weill Cornell Medicine

Changes in gut microbiota composition are often linked to host metabolic health, but the underlying mechanisms are poorly characterized. Driven by the idea that the gut microbiota acts as a ‘tractable’ auxiliary liver, Dr. Guo’s research focuses on innovatively designing and developing genetic tools to manipulate nonmodel gut bacteria. This allows them to explore their metabolic activity in vivo and study their profound impact on host metabolism and immunity.

The most precise format for interrogating a microbiota metabolic function is to manipulate the responsible gene in the host and compare phenotypes that differ only in this gene. To understand the critical role of the gut microbiota in human metabolic health, Dr. Guo’s journey began with tackling the challenge of the genetic inaccessibility of nonmodel gut bacteria. These bacteria harbor numerous genes believed to impact host metabolism but are challenging to study due to the lack of effective genetic tools.

In Dr. Guo’s first publication in Cell, he designed a genetic manipulation pipeline to expand the tractable territory of the human microbiome1. The pipeline efficiently identified gene transfer methods for over 80 nonmodel gut microbes. He applied this pipeline to study a microbiota gene for bile acid metabolism. Unexpectedly, while this gene has extremely low gastrointestinal abundance, it is metabolically active and drives the expansion of proinflammatory microbes, leading to worsened colon inflammation.

He then applied these toolsets to characterize the molecular mechanisms behind how dietary inulin fiber alters gut microbiota bile acid deconjugation and promotes type 2 inflammation. By precisely switching on/off this microbiota metabolic activity in the host, he and his colleagues demonstrated how this activity triggers type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells, and eosinophilia. These findings, published in Nature2, listed Dr. Guo as one of the corresponding authors.

In his third publication in Cell Host & Microbe3, he identified specific gut microbes and their genes that efficiently deplete dietary amino acids (AAs). Leveraging the genetic toolsets developed in his lab, they identified multiple gut microbiota metabolic genes responsible for depleting intestinal AAs via biochemical reactions similar to those in the liver. By precisely manipulating individual genes in the host, they demonstrated the causal effects of these microbial genes on host AA metabolism and glucose tolerance.

Two biological insights arise from their findings. First, the microbiome is highly diverse, and so are their barriers to DNA uptake. While it is unlikely to have a 'one-size-fits-all' solution, they showed that a generalizable pipeline could overcome some resistance and achieve gene transfer in over 40% of the 200 microbes tested. Second, the metabolic genes they studied redefine the gut microbiota as a ‘tractable’ auxiliary liver. These genes are frequently found in almost all humans, have an enormous physiological footprint, and a slight shift in their expression could lead to different downstream biological and disease outcomes.

The significance of Dr. Guo’s work lies in redefining the gut microbiota as a tractable 'metabolism' organ and demonstrating the potential of genetically engineering the microbiome for disease prevention and treatment. Moreover, they reveal an additional layer of modulation between dietary nutrients and diseasethe gut microbiota, providing molecular insights into the diet-microbiota-host biology crosstalk under the precision medicine paradigm.

Dr. Guo’s research reveals promising clinical applications for microbiota-based therapies, particularly targeting metabolic disorders like type 2 diabetes, obesity, and inflammatory bowel disease. By precisely manipulating microbial genes, they can develop personalized dietary interventions that optimize nutrient absorption and reduce proinflammatory responses, thus advancing precision nutrition. Moreover, engineering gut bacteria offers a potential method to regulate immune responses, addressing autoimmune and inflammatory conditions. This opens the door to next-generation probiotics designed to enhance beneficial microbial pathways or suppress harmful ones. Modulating gut microbiota-driven bile acid metabolism also shows promise for treating bile acid-related liver diseases and systemic metabolic disorders. This highlights the potential of integrating microbiota engineering into disease prevention and therapeutic strategies.

肠道菌群影响宿主生理功能的分子机制

肠道菌群的组成变化通常与宿主代谢健康密切相关，但其中的具体机制仍未完全阐明。郭教授实验室以肠道菌群作为“另一个肝脏”的概念为核心，创新开发遗传工具来操控非模式肠道细菌，从而在体内解析其代谢活动对宿主代谢和免疫的深远影响。

在其开创性研究中，他的实验室率先开发了一种遗传操控工作流程，能够识别超过80种非模式肠道细菌的基因转移方法。这项技术使他揭示出某些低丰度但代谢活跃的微生物基因对宿主健康的关键影响。例如，他发现一种胆汁酸代谢基因虽然在胃肠道中丰度极低，却能驱动促炎菌扩展，加重结肠炎症。此研究发表于《Cell》1。

此外，他利用这些工具深入研究膳食菊粉纤维如何改变肠道菌群的胆汁酸去结合活性，从而引发肠道和肺部的II型炎症。他们通过精确调控宿主中的微生物代谢活动，揭示了IL-33产生和II型固有淋巴细胞激活等分子机制。这些重要发现发表于《Nature》2。

在另一项发表于《Cell Host & Microbe》3的研究中，他鉴定了特定肠道微生物及其基因能够高效消耗膳食氨基酸，并通过精确操控这些基因，证明了它们对宿主氨基酸代谢和葡萄糖耐受性的因果作用。这些研究重新定义了肠道菌群为“可操控辅助肝脏”的角色，凸显其代谢基因在生理调控和疾病中的深远影响。

郭教授的研究不仅拓展了肠道微生物组作为“代谢器官”的理解，还展示了通过基因工程改造微生物组来预防和治疗疾病的潜力。他揭示了饮食、肠道微生物组和宿主代谢之间复杂的分子互作关系，为精准医学提供了重要启示。这些研究成果在临床应用中前景广阔，例如通过个性化饮食优化营养吸收、降低促炎反应，或通过设计下一代益生菌调节免疫反应，以治疗II型糖尿病、肥胖、IBD及胆汁酸相关的代谢紊乱。这些成果不仅为疾病防治提供了全新策略，还为整合微生物组工程与精准医学打开了大门。

References:

1. Jin, W.-B., Li, T.-T., Huo, D., Qu, S., Li, X.V., Arifuzzaman, M., Lima, S.F., Shi, H.-Q., Wang, A., Putzel, G.G., et al. (2022). Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome. Cell 185, 547-562.e22. https://doi.org/10.1016/j.cell.2021.12.035.

2. Arifuzzaman, M., Won, T.H., Li, T.-T., Yano, H., Digumarthi, S., Heras, A.F., Zhang, W., Parkhurst, C.N., Kashyap, S., Jin, W.-B., et al. (2022). Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation. Nature 611, 578–584. https://doi.org/10.1038/s41586-022-05380-y.

3. Li, T.-T., Chen, X., Huo, D., Arifuzzaman, M., Qiao, S., Jin, W.-B., Shi, H., Li, X.V., Iliev, I.D., Artis, D., et al. (2024). Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2024.04.004.