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Fecal and blood samples of infants with autism spectrum disorders (ASD) and healthy infants were analyzed to investigate the association of altered gut microbiota and ASD development. 16S rRNA gene-based sequencing found that, unlike those of healthy infants, feces of ASD infants had significantly higher and lower abundance of genera Faecalibacterium and Blautia, respectively. Moreover, DNA microarray analysis of peripheral blood mononuclear cells (PBMC) detected more highly than low expressed genes in ASD infants than in healthy infants. Gene Ontology analysis revealed that differentially expressed genes between ASD and healthy infants were involved in interferon (IFN)-γ and type-I IFN signaling pathways. Finally, strong positive correlations between expression of IFN signaling-associated genes in PBMC and fecal abundance of Faecalibacterium were found. Our results strongly suggested that altered gut microbiota in infants resulted from ASD development and was associated with systemic immunity dysregulation, especially chronic inflammation.

Gluconic acid reaches the large intestine to stimulate lactic acid bacteria. However, the fermentation pattern of gluconic acid has yet to be elucidated. Accordingly, we examined the fermentation properties induced by gluconic acid in the pig cecal digesta in vitro. We also tested sorbitol and glucose, substrates for which the fermentation rate and patterns are known. The gluconic acid-utilizing bacteria were further isolated from pig cecal digesta and identified to examine the effect of gluconic acid on hind gut fermentation. Gluconic acid was fermented more slowly than were the other two substrates. Gluconic acid stimulated butyrate production; the butyrate molar percentage reached 26%, which is considered a high butyrate production. The majority of gluconic acid fermenters were identified as lactic acid bacteria, such as Lactobacillus reuteri and L. mucosae, and acid-utilizing bacteria, such as Megasphaera elsdenii and Mitsuokella multiacida. The gluconic acid fermented by lactic acid bacteria, and the lactate and acetate that were produced were used to form butyrate by acid-utilizing bacteria, such as M. elsdenii. Gluconic acid may be useful as a prebiotic to stimulate butyrate production in the large intestine.

Abstract-Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue. Importantly, ATF3, when induced by saturated fatty acids, can transcriptionally repress tumor necrosis factor-␣ production in macrophages in vitro. Chromatin immunoprecipitation assay revealed that ATF3 is recruited to the region containing the activator protein-1 site of the endogenous tumor necrosis factor-␣ promoter. Furthermore, transgenic overexpression of ATF3 specifically in macrophages results in the marked attenuation of proinflammatory M1 macrophage activation in the adipose tissue from genetically obese KKA y mice fed high-fat diet. This study provides evidence that ATF3, which is induced in obese adipose tissue, acts as a transcriptional repressor of saturated fatty acids/TLR4 signaling, thereby revealing the negative feedback mechanism that attenuates obesity-induced macrophage activation. Our data also suggest that activation of ATF3 in macrophages offers a novel therapeutic strategy to prevent or treat obesity-induced adipose tissue inflammation. (Circ Res. 2009;105:25-32.) Key Words: adipocytes Ⅲ ATF3 Ⅲ fatty acids Ⅲ inflammation Ⅲ macrophages Ⅲ TLR4 K nown as the metabolic syndrome, the cluster of wellestablished risk factors for cardiovascular disease (visceral fat obesity, impaired glucose metabolism, atherogenic dyslipidemia, and blood pressure elevation), is an increasing health problem worldwide. [1][2][3] The pathophysiology underlying the metabolic syndrome is not fully understood and visceral fat obesity appears to be an important component. 4 There is considerable evidence that obesity is a state of chronic low-grade inflammation, which may play a critical role in the pathophysiology of the metabolic syndrome. [1][2][3] Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. 5 Using an in vitro coculture system composed of adipocytes and macrophages, we have provided evidence that a paracrine loop involving saturated fatty acids and tumor necrosis factor (TNF)␣ derived from adipocytes and macrophages, respectively, establishes a vicious cycle that augment the inflammatory change in obese adipose tissue. 6 Recent studies have also poin...