Study Title:

Gut Contents influence Liver Metabolism

Study Abstract

The gut microbiota enhances the host’s metabolic capacity for processing nutrients and drugs and modulate the activities of multiple pathways in a variety of organ systems. We have probed the systemic metabolic adaptation to gut colonization for 20 days following exposure of axenic mice (n = 35) to a typical environmental microbial background using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy to analyze urine, plasma, liver, kidney, and colon (5 time points) metabolic profiles. Acquisition of the gut microbiota was associated with rapid increase in body weight (4%) over the first 5 days of colonization with parallel changes in multiple pathways in all compartments analyzed. The colonization process stimulated glycogenesis in the liver prior to triggering increases in hepatic triglyceride synthesis. These changes were associated with modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites, including taurocholate and tauromuricholate, which are essential regulators of lipid absorption. Expression and activity of major drug-metabolizing enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated. Remarkably, statistical modeling of the interactions between hepatic metabolic profiles and microbial composition analyzed by 16S rRNA gene pyrosequencing revealed strong associations of the Coriobacteriaceae family with both the hepatic triglyceride, glucose, and glycogen levels and the metabolism of xenobiotics. These data demonstrate the importance of microbial activity in metabolic phenotype development, indicating that microbiota manipulation is a useful tool for beneficially modulating xenobiotic metabolism and pharmacokinetics in personalized health care.

IMPORTANCE Gut bacteria have been associated with various essential biological functions in humans such as energy harvest and regulation of blood pressure. Furthermore, gut microbial colonization occurs after birth in parallel with other critical processes such as immune and cognitive development. Thus, it is essential to understand the bidirectional interaction between the host metabolism and its symbionts. Here, we describe the first evidence of an in vivo association between a family of bacteria and hepatic lipid metabolism. These results provide new insights into the fundamental mechanisms that regulate host-gut microbiota interactions and are thus of wide interest to microbiological, nutrition, metabolic, systems biology, and pharmaceutical research communities. This work will also contribute to developing novel strategies in the alteration of host-gut microbiota relationships which can in turn beneficially modulate the host metabolism.

From press release:

Bacteria in the human gut may not just be helping digest food but also could be exerting some level of control over the metabolic functions of other organs, like the liver, according to research published this week in the online journal mBio®. These findings offer new understanding of the symbiotic relationship between humans and their gut microbes and how changes to the microbiota can impact overall health.

"The gut microbiota enhances the host's metabolic capacity for processing nutrients and drugs and modulates the activities of multiple pathways in a variety of organ systems," says Sandrine Claus of the Imperial College of London, a researcher on the study.

Claus and her colleagues exposed germ-free mice to bedding that had previously been used by conventional mice with normal microbiota and followed their metabolic profiles for 20 days to observe changes as they became colonized with gut bacteria.

Over the first 5 days after exposure, the mice exhibited a rapid increase in weight (4%). Colonization also triggered a number of processes in the liver in which sugars (glucose) are converted to starch (glycogen) and fat (triglycerides) for short-term and long-term energy storage. Statistical modeling between liver metabolic functions and microbial populations determined that the levels of glucose, glycogen and triglycerides in the liver were strongly associated with a single family of bacteria called Coriobacteriaceae.

"Here we describe the first evidence of an in vivo association between a family of bacteria and hepatic lipid metabolism. These results provide new insights into the fundamental mechanisms that regulate host-gut microbiota interactions and are of wide interest to microbiological, nutrition, metabolic, systems biology and pharmaceutical research communities," says Claus.

Another important finding in the paper, according to Claus, is that gut colonization strongly stimulated the expression and activity of the cytochrome P450 3A11, an essential enzyme in drug-detoxification pathways.

Although she warns about being careful to extrapolate the specific findings from mice to humans, Claus notes the results of this research will provide a basis to further develop new strategies to beneficially modulate host metabolism by altering microbial communities in the gut.

Study Information

S. P. Claus, S. L. Ellero, B. Berger, L. Krause, A. Bruttin, J. Molina, A. Paris, E. J. Want, I. de Waziers, O. Cloarec, S. E. Richards, Y. Wang, M.-E. Dumas, A. Ross, S. Rezzi, S. Kochhar, P. Van Bladeren, J. C. Lindon, E. Holmes, J. K. Nicholson
Colonization-Induced Host-Gut Microbial Metabolic Interaction.
mBio
2011 March
Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.

Full Study

http://mbio.asm.org/content/2/2/e00271-10.full