Systemic multicompartmental effects of the gut microbiome on mouse metabolic phenotypes

To characterize the impact of gut microbiota on host metabolism, we investigated the multicompartmental metabolic profiles of a conventional mouse strain (C3H/HeJ) ( n =5) and its germ‐free (GF) equivalent ( n =5). We confirm that the microbiome strongly impacts on the metabolism of bile acids through the enterohepatic cycle and gut metabolism (higher levels of phosphocholine and glycine in GF liver and marked higher levels of bile acids in three gut compartments). Furthermore we demonstrate that (1) well‐defined metabolic differences exist in all examined compartments between the metabotypes of GF and conventional mice: bacterial co‐metabolic products such as hippurate (urine) and 5‐aminovalerate (colon epithelium) were found at reduced concentrations, whereas raffinose was only detected in GF colonic profiles. (2) The microbiome also influences kidney homeostasis with elevated levels of key cell volume regulators (betaine, choline, myo ‐inositol and so on) observed in GF kidneys. (3) Gut microbiota modulate metabotype expression at both local (gut) and global (biofluids, kidney, liver) system levels and hence influence the responses to a variety of dietary modulation and drug exposures relevant to personalized health‐care investigations. Synopsis The gut microbiota (microbiome) form a complex and dynamic ecosystem that constantly interacts with host metabolism (Dunne, 2001 ; Hooper and Gordon, 2001 ; Bourlioux et al , 2003 ). The microbiome provides trophic (Hooper and Gordon, 2001 ) and protective (Umesaki and Setoyama, 2000 ) functions and impact on the host's energy metabolism (Savage, 1986 ), facilitating the absorption of complex carbohydrates (fiber breakdown) and influencing the homeostasis of amino acids (Hooper et al , 2002 ). But despite their evident important contribution to host biology and function, some bacterial species contained in the gut also have the potential to generate carcinogens or can be the source of opportunistic infections (Berg, 1996 ). We have recently demonstrated a close relationship between the metabolism of gut microbiota and the susceptibility of rodents to insulin resistance in high‐fat diet studies (Dumas et al , 2006a ). In this context, recent investigations have shown that even subtle changes in the gut microbiota have an impact on the host phenotype (Holmes and Nicholson, 2005 ; Robosky et al , 2005 ; Rohde et al , 2007 ). Germ‐free (GF) animal studies have been widely used as a source of knowledge on the gut mic