Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice.

Little is known about the pathogenesis of metabolic syndrome, although Toll-like receptor 4 (TLR4) has been implicated. We investigated whether TLR4 in the intestinal epithelium regulates metabolic syndrome by coordinating interactions between the luminal microbiota and host genes that regulate metabolism. Mice lacking TLR4 in the intestinal epithelium (TLR4ΔIEC), but not mice lacking TLR4 in myeloid cells nor mice lacking TLR4 globally, developed metabolic syndrome; these features were not observed in TLR4ΔIEC mice given antibiotics. Metagenomic analysis of the fecal microbiota revealed differences between TLR4ΔIEC and wild-type mice, while meta-transcriptome analysis of the microbiota showed that intestinal TLR4 affected the expression of microbial genes involved in the metabolism of lipids, amino acids, and nucleotides. Genes regulated by peroxisome proliferator-activated receptors (PPARs) and the antimicrobial peptide lysozyme were significantly downregulated in TLR4ΔIEC mice, suggesting a mechanism by which intestinal TLR4 could exert its effects on the microbiota and metabolic syndrome. Supportingly, antibiotics prevented both downregulation of PPAR genes and the development of metabolic syndrome, while PPAR agonists prevented development of metabolic syndrome in TLR4ΔIEC mice. Thus, intestinal epithelial TLR4 regulates metabolic syndrome through altered host-bacterial signaling, suggesting that microbial or PPAR-based strategies might have therapeutic potential for this disease.

Diet creates metabolic niches in the “inmature gut” that shapemicrobial communities

Although diet composition has been implicated as a major factor in the etiology of various gastrointestinal diseases, conclusive evidence remains elusive. This is particularly true in diseases such as necrotizing enterocolitis where breast milk as opposed to commercial formula appears to confer a ‘protective effect’ to the ‘immature gut’. Yet the mechanism by which this occurs continues to remain speculative. In the present study we hypothesize that the basic chemical composition of diet fundamentally selects for specific intestinal microbiota which may help explain disparate disease outcome and therapeutic direction. Complimentary animal and human studies were conducted on young piglets (21 d.)(n = 8)(IACUC protocols 08070 and 08015) and premature infants (adjusted gestational age 34-36 weeks) (n = 11)(IRB Protocol 15895A). In each study, cecal or stool contents from two groups (Breast milk-fed (BF) vs. Formulafed (FF)) were analyzed by gas chromatography/masss pectrometry (GC/MS) and comprehensive metabolic profiles generated and compared. Concurrently, bacterial community structure was assayed and respective representative microbiota of the groups determined by 16SrRNA gene amplicon pyrosequencing. Statistical modeling and analysis was done using SIMCA-P+ and R software. GC/MS metabolomics identified clear differences between BF and FF groups in the intestinal environment of piglets and humans. Sugars, amino-sugars, fatty acids, especially unsaturated fatty acids, and sterols were identified as being among the most important metabolites for distinguishing between BF and FF groups. Joint analysis (AU)

Aunque se ha implicado a la composición de la dieta como un factor principal en la etiología de varias enfermedades gastrointestinales, la evidencia concluyente sigue siendo esquiva. Esto es particularmente cierto en enfermedades como la enterocolitis necrosante en la que la leche materna, en contraposición de las fórmulas comerciales, parece conferir un ‘efecto protector’ para el ‘intestino inmaduro’ o el ecosistema intestinal juvenil del ‘intestino inmaduro’, si bien el mecanismo por el que esto ocurre sigue siendo una especulación. La hipótesis de nuestro estudio es que la composición química básica de la dieta selecciona fundamentalmente microbióticos intestinales específicos que pueden explicar los resultados dispares de la enfermedad y tener implicaciones terapéuticas. Se realizaron estudios adicionales en animales y humanos en lechones (21 d.) (n = 8) (protocolos IACUC08070 y 08015) y lactantes prematuros (edad gestacional ajustada de 34-36 semanas) (n = 11) (Protocolo IRB15895A). En cada estudio, se analizaron los contenidos cecales y fecales de ambos grupos (alimentación materna(AM) y alimentación con fórmula (AF)) mediante cromatografía de gases/espectrometría de masas (CG/EM) y se generaron y compararon perfiles metabólicos completos. De forma concurrente, se probó la estructura de la comunidad bacteriana y se determinaron los representantes (AU)

Diet creates metabolic niches in the "immature gut" that shape microbial communities.

Although diet composition has been implicated as a major factor in the etiology of various gastrointestinal diseases, conclusive evidence remains elusive. This is particularly true in diseases such as necrotizing enterocolitis where breast milk as opposed to commercial formula appears to confer a "protective effect" to the "immature gut." Yet the mechanism by which this occurs continues to remain speculative. In the present study we hypothesize that the basic chemical composition of diet fundamentally selects for specific intestinal microbiota which may help explain disparate disease outcome and therapeutic direction. Complimentary animal and human studies were conducted on young piglets (21 d.)(n = 8) (IACUC protocols 08070 and 08015) and premature infants (adjusted gestational age 34-36 weeks) (n = 11) (IRB Protocol 15895A). In each study, cecal or stool contents from two groups (Breast milk-fed (BF) vs. Formula-fed (FF)) were analyzed by gas chromatography/mass spectrometry (GC/MS) and comprehensive metabolic profiles generated and compared. Concurrently, bacterial community structure was assayed and respective representative microbiota of the groups determined by 16S rRNA gene amplicon pyrosequencing. Statistical modeling and analysis was done using SIMCA-P+ and R software. GC/MS metabolomics identified clear differences between BF and FF groups in the intestinal environment of piglets and humans. Sugars, amino-sugars, fatty acids, especially unsaturated fatty acids, and sterols were identified as being among the most important metabolites for distinguishing between BF and FF groups. Joint analysis of microbiota and metabolomics pinpointed specific sets of metabolites (p < 0.05) associated with the dominant bacterial taxa. The chemical composition of diet appears to have a significant role in defining the microbiota of the immature gut. Tandem analysis of intestinal microbial and metabolic profiles is potentially a powerful tool leading to better understanding of the role of diet in disease perhaps even leading to specific strategies to alter microbial behavior to improve clinical outcome.