Effects of PCBs exposure on modulation of bile acid profile and intestinal microbiota in mice
Authors: Cheng Sunny Lihua , Fu Donna Zidong , Li Xueshu , Khayi Khakkhak , Lehmler Hans‐Joachim , Cui Julia Yue 
Published: November 2023

A major function of the gut microbiota is to convert primary bile acids (BAs), which are produced from cholesterol in liver, into secondary BAs generally thought to be more lipophilic and toxic. Key microbial reactions for BA metabolism include dehydroxylation and deconjugation. Accumulating evidence suggests that environmental exposure to xenobiotics may adversely impact various intermediary metabolism pathways. The goal of the present study was to investigate how oral exposure to polychlorinated biphenyls (PCBs), a class of persistent organic pollutants, impacts the BA homeostasis, and to what extent such interactions depend on gut microbiota. Ninety‐day‐old adult female conventional (CV) and germ‐free (GF) mice on a C57BL/6 background were orally exposed to corn oil (vehicle), or PCB mixture (Fox River Mix) at 6 or 30 mg/kg, once daily for 3‐consecutive days. The GF status was confirmed using 16S rRNA qPCR of universal bacteria in intestinal content of GF mice. Targeted BA metabolomics of 19 major BA metabolites was performed in liver, serum, small intestinal content (SIC), and large intestinal content (LIC) of these mice (n=5~6 per group). GF conditions markedly altered the BA homeostasis in various compartments. In liver and serum of GF mice, there was an increase in total BAs, conjugated BAs, as well as non‐12α‐OH BAs (which were produced through a Cyp8b1‐dependent pathway) compared to CV mice; conversely, total secondary BAs were diminished in GF mice. Intestinal compartment was influenced by GF conditions, with a marked increase in almost all host‐derived BAs but a decrease in microbial BAs (namely the total unconjugated and secondary BAs) in SIC and LIC (GF vehicle vs CV vehicle). PCBs did not affect the hepatic BA profiles or composition in CV or GF mice. However, PCBs at low dose increased serum total BAs, primary BAs, conjugated BAs, 12α‐OH BAs and non‐12α‐OH BAs in both CV and GF mice. PCBs at low dose also increased serum unconjugated BAs in CV mice but not in GF mice. PCBs at high dose did not affect serum BAs in either CV or GF mice. In SIC, PCBs at high dose also did not have any major effect on BA profiles in either CV or GF mice. However, PCBs at low dose increased total unconjugated and secondary BAs in a gut microbiota‐dependent manner. Although PCBs at low dose did not alter total BAs, primary BAs, conjugated BAs, and non‐12α‐OH BAs in SIC of CV mice, these BAs were increased in SIC of GF mice. In LIC, total conjugated BAs were increased by PCBs at both doses and in both strains of mice. In contrast, other types of BAs were not altered by PCBs in CV mice, but they were all markedly increased by PCBs at both doses in GF mice, suggesting that the lack of gut microbiota unmasked the PCB‐mediated effects on BA profiles. In summary, the present study has demonstrated that there is a novel interaction between PCB exposure and BA homeostasis that partially depends on the presence of gut microbiota. Whereas lack of gut microbiota alters the basal levels of BAs in multiple compartments of mice, both gut microbiota‐dependent and GF‐potentiation effects were observed on PCB‐mediated changes in BA homeostasis.Support or Funding InformationGrace Liejun Guo glg48@eohsi.rutgers.edu