Profiling How the Gut Microbiome Modulates Host Xenobiotic Metabolism in Response to Benzo[a]pyrene and 1‑Nitropyrene Exposure

The gut microbiome is a key contributor
to xenobiotic metabolism.
Polycyclic aromatic hydrocarbons (PAHs) are an abundant class of environmental
contaminants that have varying levels of carcinogenicity depending
on their individual structures. Little is known about how the gut
microbiome affects the rates of PAH metabolism. This study sought
to determine the role that the gut microbiome has in determining the
various aspects of metabolism in the liver, before and after exposure
to two structurally different PAHs, benzo­[a]­pyrene
and 1-nitropyrene. Following exposures, the metabolic rates of PAH
metabolism were measured, and activity-based protein profiling was
performed. We observed differences in PAH metabolism rates between
germ-free and conventional mice under both unexposed and exposed conditions.
Our activity-based protein profiling (ABPP) analysis showed that,
under unexposed conditions, there were only minor differences in total
P450 activity in germ-free mice relative to conventional mice. However,
we observed distinct activity profiles in response to corn oil vehicle
and PAH treatment, primarily in the case of 1-NP treatment. This study
revealed that the repertoire of active P450s in the liver is impacted
by the presence of the gut microbiome, which modifies PAH metabolism
in a substrate-specific fashion.

肠道微生物组是异生物代谢的关键贡献者。多环芳烃（PAHs）是一类在环境中广泛存在的污染物，其致癌性因个体结构的不同而异。关于肠道微生物组如何影响PAH代谢速率的知识甚少。本研究旨在确定肠道微生物组在肝脏代谢多个方面所起的作用，包括在接触两种结构不同的PAHs——苯并[a]芘和1-硝基芘前后的作用。在暴露后，测量了PAH代谢的速率，并进行了基于活性的蛋白质组学分析。我们发现，在未暴露和暴露条件下，无菌小鼠和常规小鼠在PAH代谢速率上存在差异。我们的基于活性的蛋白质组学（ABPP）分析显示，在未暴露条件下，无菌小鼠与常规小鼠相比，总P450活性仅有微小差异。然而，我们观察到在玉米油溶剂和PAH处理下的不同活性图谱，尤其是在1-NP处理的情况下。本研究揭示了肝脏中活性P450的库受肠道微生物组的存在所影响，该微生物组以底物特异性的方式调节PAH代谢。