Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver

BACKGROUND: The liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates. PRINCIPAL FINDINGS: By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group. CONCLUSION: Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver

Worms need microbes too: microbiota, health and aging in Caenorhabditis elegans

Many animal species live in close association with commensal and symbiotic microbes (microbiota). Recent studies have revealed that the status of gastrointestinal tract microbiota can influence nutrition‐related syndromes such as obesity and type‐2 diabetes, and perhaps aging. These morbidities have a profound impact in terms of individual suffering, and are an increasing economic burden to modern societies. Several theories have been proposed for the influence of microbiota on host metabolism, but these largely remain to be proven. In this article we discuss how microbiota may be manipulated (via pharmacology, diet, or gene manipulation) in order to alter metabolism, immunity, health and aging in the host. The nematode Caenorhabditis elegans in combination with one microbial species is an excellent, defined model system to investigate the mechanisms of host–microbiota interactions, particularly given the combined power of worm and microbial genetics. We also discuss the multifaceted nature of the worm–microbe relationship, which likely encompasses predation, commensalism, pathogenicity and necromeny

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction

Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogen-detoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR