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Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice.

ABSTRACT: The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4^-/-) NOD mice. In 70-90-day-old normoglycemic (prediabetic) female NOD TLR4^+/+ and NOD TLR4^-/- mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo Compared with NOD TLR4^+/+ mice, NOD TLR4^-/- animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance-related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.

SUBMITTER: Simon MC

PROVIDER: S-EPMC6983849 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice.

Simon Marie-Christine MC Reinbeck Anna Lena AL Wessel Corinna C Heindirk Julia J Jelenik Tomas T Kaul Kirti K Arreguin-Cano Juan J Strom Alexander A Blaut Michael M Bäckhed Fredrik F Burkart Volker V Roden Michael M

The Journal of biological chemistry 20191210 4

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes de ...[more]

PMID: 31822562

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Project description:Altered gut microbiota has been connected to hepatocellular carcinoma (HCC) occurrence and advancement. This study was conducted to identify a gut microbiota signature in differentiating between viral-related HCC (Viral-HCC) and non-hepatitis B-, non-hepatitis C-related HCC (NBNC-HCC). Fecal specimens were obtained from 16 healthy controls, 33 patients with viral-HCC (17 and 16 cases with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, respectively), and 18 patients with NBNC-HCC. Compositions of fecal microbiota were assessed by 16S rRNA sequencing. Bioinformatic analysis was performed by the DADA2 pipeline in the R program. Significantly different genera from the top 50 relative abundance were used to classify between subgroups of HCC by the Random Forest algorithm. Our data demonstrated that the HCC group had a significantly decreased alpha-diversity and changed microbial composition in comparison with healthy controls. Within the top 50 relative abundance, there were 11 genera including Faecalibacterium, Agathobacter, and Coprococcus that were significantly enhanced in Viral-HCC, while 5 genera such as Bacteroides, Streptococcus, Ruminococcus gnavus group, Parabacteroides, and Erysipelatoclostridium were enhanced in NBNC-HCC. Compared to Viral-HCC, the NBNC-HCC subgroup significantly reduced various short-chain fatty acid-producing bacteria, as well as declined fecal butyrate but elevated plasma surrogate markers of microbial translocation. Based on the machine learning algorithm, a high diagnostic accuracy to classify HCC subgroups was achieved with an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.94. Collectively, these data revealed that gut dysbiosis was distinct according to etiological factors of HCC, which might play an essential role in hepatocarcinogenesis. These findings underscore the possible use of a gut microbiota signature for the diagnosis and therapeutic approaches regarding different subgroups of HCC. KEY POINTS: • Gut dysbiosis is connected to hepatocarcinogenesis and can be used as a novel biomarker. • Gut microbiota composition is significantly altered in different etiological factors of HCC. • Microbiota-based signature can accurately distinguish between Viral-HCC and NBNC-HCC.

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Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice.

Publications

Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice.

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