Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.

Gut Microbiota in Health and Disease

Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIbeta and RegIIIgamma, in colonic epithelial cells. Exogenous mouse or human RegIIIgamma substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.

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Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens

It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver

The cellular and signaling networks linking the immune system and metabolism in disease

The GLUT4 Glucose Transporter

Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.

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Insulin sensitivity: modulation by nutrients and inflammation.

Non-caloric artificial sweeteners (NASs) provide sweet tastes to food without adding calories or glucose NASs can be used as alternative sweeteners for controlling blood glucose levels and weight gain Although the consumption of NASs has increased over the past decade in Japan and other countries, whether these sweeteners affect the composition of the gut microbiome is unclear In the present study, we examined the effects of sucralose or acesulfame-K ingestion (at most the maximum acceptable daily intake (ADI) levels, 15 mg/kg body weight) on the gut microbiome in mice Consumption of sucralose, but not acesulfame-K, for 8 weeks reduced the relative amount of Clostridium cluster XIVa in feces Meanwhile, sucralose and acesulfame-K did not increase food intake, body weight gain or liver weight, or fat in the epididymis or cecum Only sucralose intake increased the concentration of hepatic cholesterol and cholic acid Moreover, the relative concentration of butyrate and the ratio of secondary/primary bile acids in luminal metabolites increased with sucralose consumption in a dose-dependent manner These results suggest that daily intake of maximum ADI levels of sucralose, but not acesulfame-K, affected the relative amount of the Clostridium cluster XIVa in fecal microbiome and cholesterol bile acid metabolism in mice

/pdf/effects-of-low-dose-non-caloric-sweetener-consumption-on-gut-30oyr1pb2z.pdf

Effects of Low-Dose Non-Caloric Sweetener Consumption on Gut Microbiota in Mice

An integrated circuit device (100) includes a substrate (110) having a top surface including substrate pads (112), and a through-substrate via (115) die including a semiconductor substrate (105) including a top semiconductor surface (106) having active circuitry and a bottom surface (106). The top semiconductor surface (107) includes bonding connectors (109) that are coupled to the substrate pads on the top surface of the substrate. A plurality of through- substrate vias (TSVs) include an inner metal core (125) that extends from the top side semiconductor surface to protruding TSV tips (121) which extend out from the bottom surface. At least one of the plurality of TSVs is a dummy TSV (120) that has its protruding TSV tip exclusive of any electrically connection thereto and that provides additional surface area to enhance heat dissipation from the bottom side of the TSV die.

Protruding TSV tips for enhanced heat dissipation for IC devices

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2801%2903088-5

Production of β‐defensin‐2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein

The gut microbiota produce hundreds of bioactive compounds, including B-vitamins, which play significant physiological roles in hosts by supporting the fitness of symbiotic species and suppressing the growth of competitive species. B-vitamins are also essential to the host and certain gut bacterium. Although dietary B-vitamins are mainly absorbed from the small intestine, excess B-vitamins unable to be absorbed in the small intestine are supplied to the distal gut. In addition, B-vitamins are supplied from biosynthesis by distal gut microbiota. B-vitamins in the distal colon may perform many important functions in the body. They act as 1) nutrients for a host and their microbiota, 2) regulators of immune cell activity, 3) mediators of drug efficacy, 4) supporters of survival, or the fitness of certain bacterium, 5) suppressors of colonization by pathogenic bacteria, and 6) modulators of colitis. Insights into basic biophysical principles, including the bioavailability of B-vitamins and their derivatives in the distal gut are still not fully elucidated. Here, the function of single B-vitamin in the distal gut including their roles in relation to bacteria are briefly reviewed. The prospect of extending analytical methods to better understand the role of B-vitamins in the gut is also explored.

/pdf/functional-roles-of-b-vitamins-in-the-gut-and-gut-microbiome-1z9t256tmq.pdf

Functional Roles of B-Vitamins in the Gut and Gut Microbiome.

OBJECTIVE— c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action. In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action. RESEARCH DESIGN AND METHODS— C57BL/6 (Cbl-b +/+ ) or Cbl-b-deficient (Cbl-b −/− ) mice were subjected to insulin and glucose tolerance tests and a hyperinsulinemic-euglycemic clamp test. Infiltration of macrophages into white adipose tissue (WAT) was assessed by immunohistochemistry and flow cytometry. We examined macrophage activation using co-cultures of 3T3-L1 adipocytes and peritoneal macrophages. RESULTS— Elderly Cbl-b −/− mice developed glucose intolerance and peripheral insulin resistance; serum insulin concentrations after a glucose challenge were always higher in elderly Cbl-b −/− mice than age-matched Cbl-b +/+ mice. Deficiency of the Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, whereas fatty liver was apparent in elderly Cbl-b −/− mice. Cbl-b deficiency was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein (MCP)-1. Co-culture of Cbl-b −/− macrophages with 3T3-L1 adipocytes induced leptin expression and dephosphorylation of insulin receptor substrate 1, leading to impaired glucose uptake in adipocytes. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b −/− macrophages compared with Cbl-b +/+ macrophages. Treatment with a neutralizing anti–MCP-1 antibody improved peripheral insulin resistance and macrophage infiltration into WAT in elderly Cbl-b −/− mice. CONCLUSIONS— Cbl-b is a negative regulator of macrophage infiltration and activation, and macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages.

https://diabetes.diabetesjournals.org/content/diabetes/56/10/2511.full.pdf

Kazuaki Mawatari

Papers

Effects of Low-Dose Non-Caloric Sweetener Consumption on Gut Microbiota in Mice

Protruding TSV tips for enhanced heat dissipation for IC devices

Production of β‐defensin‐2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein

Functional Roles of B-Vitamins in the Gut and Gut Microbiome.

Deficiency of Cbl-b Gene Enhances Infiltration and Activation of Macrophages in Adipose Tissue and Causes Peripheral Insulin Resistance in Mice