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Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

ABSTRACT: Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:

SUBMITTER: Cox LM

PROVIDER: S-EPMC4134513 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

Cox Laura M LM Yamanishi Shingo S Sohn Jiho J Alekseyenko Alexander V AV Leung Jacqueline M JM Cho Ilseung I Kim Sungheon G SG Li Huilin H Gao Zhan Z Mahana Douglas D Zárate Rodriguez Jorge G JG Rogers Arlin B AB Robine Nicolas N Loke P'ng P Blaser Martin J MJ

Cell 20140801 4

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficie ...[more]

PMID: 25126780

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Project description:Background & aimsIntestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity.MethodsWe performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/flox mice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls).ResultsMice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months.ConclusionsIn analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.

Project description:Chitosan oligosaccharides (COS) play a prebiotic role in many ways, whereas its function on microbiota is not fully understood. In this study, the effects of COS on metabolic syndrome were initially investigated by testing changes in the physiological indicators after adding COS to the diet of mice with high fat (group H) and low fat (group L). The results showed that COS markedly inhibited the accumulation of body weight and liver fat induced by high-fat diet, as well as restored the elevated concentration of blood glucose and fasting insulin to normal levels. Next, changes of the murine intestinal microbiota were examined. The results exhibited that COS reduced with-in-sample diversity, while the between-sample microbial diversity enhanced. Specifically, COS enriched Clostridium paraputrificum and Clostridium ramosum in the mice on a high-fat diet, while the abundance of Clostridium cocleatum was reduced. As a comparison, Parabacteroides goldsteinii and Bacteroides uniformis increased their abundance in response to COS in the low-fat diet group. Noticeably, a large amount of Akkermansia muciniphila was enriched in both high-fat or low-fat diet groups. Among the differential fecal bacteria, Clostridium ramosume was found to be positively interacted with Faecalibacterim prausnitzii and Clostridium paraputrificum; Clostridium paraputrificum had a positive interactions with Lactococcus chungangensis and Bifidobacterium mongoliense, suggesting that COS probably ameliorate metabolic syndrome through the microbiota in view of the lipid-lowering effects of these interacted bacteria. Furthermore, the gene expression data revealed that COS improved the functions related to intestinal barrier and glucose transport, which could be the trigger and consequence of the variations in gut microbiota induced by COS. Additionally, correlation analysis found that intestinal bacteria are related to physiological parameters, which further supports the mediating role of gut microbiota in the beneficial effect of COS. In summary, our research results provide new evidence for the prebiotic effects of COS.

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Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

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Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

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