Objective To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. Design 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. Results 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. Conclusion Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation. Trial registration number NCT01731366; Results.

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 ¹ H 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.

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][1]; [Hooper and Gordon, 2001][2]; [Bourlioux et al , 2003][3]). The microbiome provides trophic ([Hooper and Gordon, 2001][2]) and protective ([Umesaki and Setoyama, 2000][4]) functions and impact on the host's energy metabolism ([Savage, 1986][5]), facilitating the absorption of complex carbohydrates (fiber breakdown) and influencing the homeostasis of amino acids ([Hooper et al , 2002][6]). 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][7]). 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][8]). 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][9]; [Robosky et al , 2005][10]; [Rohde et al , 2007][11]). Germ‐free (GF) animal studies have been widely used as a source of knowledge on the gut microbiota contributions to host homeostatic controls ([Wostmann, 1981][12]). GF mice display unusual gut morphology, as well as physiological and immunological abnormalities. However, despite the extensive use of GF models, the exact mechanisms involved in the morphologic, physiologic and immunologic modifications in GF animals remain unclear. The characterization of the metabolic differences between conventional and GF mice is, therefore, an essential step toward better understanding the interaction between host and gut microbiota. Metabonomic approaches combining spectroscopic profiling techniques with pattern recognition analysis have proved useful in the assessment of the systemic metabolic responses of organisms to drugs or nutrients ([Nicholson et al , 2002][13]; [Lindon et al , 2004][14]; [Dumas et al , 2006b][15]; [Rezzi et al , 2007][16]). In the current study, we employed a high‐resolution 1H NMR spectroscopic approach to investigate the metabolic phenotype, or metabotype ([Gavaghan et al , 2000][17]), of GF mice from urine and tissues (gut, liver and kidney) and to determine the biochemical consequences of the absent microbiome on these biological matrices. In the current study, we demonstrate that the metabolic impact of the microbiota extended beyond the intestinal tissue and biofluids to major organs such as the liver and kidney. In the gut, metabolic variations in response to microbial activity were observed in the biochemical profiles of intestinal tissue extracts with increasing effect along the continuous gastrointestinal tract. It was observed that duodenum and jejunum displayed fewer metabolic differences between GF and conventional mice, whereas ileum and particularly colon were the most affected. This reflects the higher microbial loads found in ileum and colon. The metabolite profiles of duodenum, jejunum and ileum were all characterized by a higher concentration of tauro‐conjugated bile acids in GF mice, which is not apparent in the colon profile. In conventional animals, tauro‐ and glycine‐conjugated bile acids are deconjugated by gut microbiota, facilitating their fecal elimination. Here, in the absence of microorganisms, primary bile acids are reabsorbed into the enterohepatic cycle, without deconjugation. This increased recycling of bile acids was also suggested by the significantly higher level of phosphocholine and by the observed trend of higher concentration of bile acids in the liver metabolic profile of GF mice. The colonic metabolite profile in GF mice was characterized by lower levels of choline and its phosphorylated derivatives, glycerophosphocholine and phosphocholine. This is likely due to the disturbance of the membrane of colonocytes in GF animals. We also observed raffinose accumulation in these cells, which is probably another consequence of the membrane disruption. Raffinose is an oligosaccharide that is only digested by the gut microbiota, as monogastric animals do not express pancreatic α‐galactosidase ([LeBlanc et al , 2004][18]). In GF animals, it seems that this trisaccharide is able to cross the epithelial membrane and accumulates in colonocytes where it induces a rise in osmotic pressure. This phenomenon provokes a well‐described signaling cascade that leads to the release of the mobile osmolytes GPC, myo ‐inositol and scyllo...

Background: Whole grains are recognized for their potential role in preventing cardiovascular diseases; however, results from randomized controlled st