- Email: [email protected]
Hold the Door: Role of the Gut Barrier in Diabetes
Cell Metabolism
Previews bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381. Krall, A.S., Xu, S., Graeber, T.G., Braas, D., and Christofk, H.R. (2016). Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457. Krebs, A.M., Mitschke, J., Lasierra Losada, M., Schmalhofer, O., Boerries, M., Busch, H., Boettcher, M., Mougiakakos, D., Reichardt, W., Bronsert, P., et al. (2017). The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529. Liao, J., Liu, P.P., Hou, G., Shao, J., Yang, J., Liu, K., Lu, W., Wen, S., Hu, Y., and Huang, P. (2017). Regulation of stem-like cancer cells by glutamine through b-catenin pathway mediated by redox signaling. Mol. Cancer 16, 51. Liu, S., Cong, Y., Wang, D., Sun, Y., Deng, L., Liu, Y., Martin-Trevino, R., Shang, L., McDermott, S.P.,
Landis, M.D., et al. (2013). Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78–91.
Thompson, C.B., and Zhang, J. (2018). As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438.e5.
Mani, S.A., Guo, W., Liao, M.J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F., Zhang, C.C., Shipitsin, M., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715.
Stankic, M., Pavlovic, S., Chin, Y., Brogi, E., Padua, D., Norton, L., Massague´, J., and Benezra, R. (2013). TGF-b-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 5, 1228– 1242.
Ocan˜a, O.H., Co´rcoles, R., Fabra, A., MorenoBueno, G., Acloque, H., Vega, S., Barrallo-Gimeno, A., Cano, A., and Nieto, M.A. (2012). Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724. Pavlova, N.N., and Thompson, C.B. (2016). The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47. Pavlova, N.N., Hui, S., Ghergurovich, J.M., Fan, J., Intlekofer, A.M., White, R.M., Rabinowitz, J.D.,
Vander Heiden, M.G., and DeBerardinis, R.J. (2017). Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669. Zhang, J., Fan, J., Venneti, S., Cross, J.R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E.H., Judkins, A.R., et al. (2014). Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218.
Hold the Door: Role of the Gut Barrier in Diabetes Anthony Martin1 and Suzanne Devkota1,2,* 1Inflammatory
Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.04.017 2Department
While metabolic tissues such as adipose, liver, muscle, and pancreas have been extensively studied in dysmetabolism, the contribution of the gut remains poorly understood. In a recent Science article, Thaiss et al. (2018) unravel mechanisms underlying intestinal permeability observed in obesity and link barrier dysfunction and risk for infection with hyperglycemia. The list of features that characterize ‘‘metabolic syndrome’’ or pre-diabetes continues to evolve in line with the growing appreciation for cardiometabolic risk phenotypes. While hallmark features include insulin resistance, high blood pressure, and dyslipidemia (Miranda et al., 2005), a recent study by Thaiss et al. (2018) suggests that increased intestinal permeability and systemic exposure to bacterial antigen should be used to further define metabolic syndrome. Compromised small or large intestinal barrier function involves the weakening of tight junction and adhesion proteins between intestinal epithelial cells, resulting in increased diffusion of bacterial components into the blood, lymph, and extra-intestinal tissues (Winer et al., 2016; Randolph et al., 2016). Loss of barrier integrity has been proposed as a driver
of chronic low-grade inflammation seen in obesity (Cani et al., 2007), but an additional, underappreciated consequence involves an increased risk for pathogenic infections (Kaspersen et al., 2015). The exact culprit(s) or biochemical basis for gut permeability continues to be investigated, but the strongest candidates include diet, gut microbiota-derived metabolites, or a combination of the two (Desai et al., 2016; Zhao et al., 2018). Thaiss et al. hypothesized that some central feature of dysmetabolism is responsible for persistent intestinal permeability. Through use of several wellestablished rodent models of obesity and diabetes, the study dissects potential roles for leptin, gut microbiota, and obesity itself as possible mediators of intestinal permeability. However, the authors ultimately conclude that dysregulated intracellular
glucose metabolism in intestinal epithelial cells, mediated by the insulin-independent glucose transporter GLUT2, drives barrier dysfunction (Figure 1). To identify which metabolic abnormalities drive gut permeability, the authors first explored the role of the satiety hormone leptin. They found that obese leptin receptor (LepR) knockout (db/db) or leptin-deficient (ob/ob) mice exhibit diminished barrier function and increased intestinal permeability in comparison to wild-type littermates. When orally challenged with Citrobacter rodentium, an established model mimicking human Escherichia coli enteric infection, db/db and ob/ob mice displayed an inability to clear the intestinally colonized pathogen. Whole-body disruption of leptin signaling appeared to enhance C. rodentium invasion, so the authors wanted to
Cell Metabolism 27, May 1, 2018 ª 2018 Elsevier Inc. 949
Cell Metabolism
Previews Tight Junction Glucose GLUT2 Transporter C. rodentium Bacterial Product
Systemic Circulation
Elevated Blood Glucose
Blood Vessel Insulin GLUT2 Ablation
XX
Basal
↑ Glucose Influx ↑ Glucose Metabolism ↑ Intestinal Permeability Glucose Metabolism
2-DG
Intestinal Epithelial Cell
Apical
↓ Barrier Function ↑ C. rodentium Colonization Intestine
Figure 1. Hyperglycemia Disrupts Intestinal Epithelial Cell Barrier Integrity Persistent vascular transport of glucose into intestinal epithelial cells via the insulin-independent GLUT2 transporter mediates aberrant intracellular glucose metabolism. This results in increased intestinal permeability, permissive translocation of bacterial products into systemic circulation, and sustained colonization of Citrobacter rodentium infection in the intestine. However, administration of insulin, genetic ablation of GLUT2, or inhibition of glucose metabolism with 2-deoxyglucose (2-DG) can reverse the consequential loss in barrier integrity and dissemination of bacterial products to systemic tissues.
identify the tissue-specific mediator of LepR-driven protection against infection. However, knocking out LepR in intestinal epithelial cells, hepatocytes, or specific regions of the hypothalamus did not enhance infection. Furthermore, to determine whether the permeability effects were due to obesity, the authors pair-fed db/db and ob/ob mice to match wildtype consumption and found that in the absence of obesity, barrier permeability and infection persisted. Additionally, non-obese, wild-type mice treated with a leptin antagonist also demonstrated persistent barrier dysfunction and C. rodentium infection. Thus, while providing evidence for the association of leptin deficiency and obesity with barrier dysfunction, the authors concluded there was no causative link. However, there was a consistent observation across all of the mouse models that put into focus an alternative mecha950 Cell Metabolism 27, May 1, 2018
nism driving the permeability phenotype. All mice displaying increased permeability and persistent infection were hyperglycemic regardless of leptin or obesity status. Therefore, a feasible approach to test the role of hyperglycemia on barrier function was to ablate insulin-producing beta cells to drive hyperglycemic blood glucose levels. Streptozotocin (STZ), a commonly used beta cell toxin, was administered to induce hyperglycemia in wild-type mice. Interestingly, elevation of blood glucose alone could recapitulate barrier dysfunction and susceptibility to C. rodentium infection. RNA sequencing of intestinal epithelial cells isolated from STZ-treated mice demonstrated a robust transcriptional shift toward abrogation of pathways involved in normal barrier function. Remarkably, reintroduction of insulin to STZ-treated mice protected against hyperglycemia and restored the tight junctions. This resulted in decreased
microbial byproducts in the blood and greater clearance of C. rodentium from the intestine. The developing body of evidence presented thus far suggested that risk for enteric infection due to intestinal barrier dysfunction might be resolved by disrupting epithelial uptake of glucose or intracellular glucose metabolism. Indeed, 2-deoxyglucose-mediated pharmacologic inhibition of glycolysis in isolated epithelial cells from hyperglycemic mice restored barrier integrity. Moreover, conditional genetic ablation of GLUT2 in intestinal epithelial cells rescued STZtreated mice from the deleterious consequences of impaired barrier function. Blood glucose remained elevated in the absence of GLUT2 in STZ-treated mice, implying the requirement for the intracellular transport of glucose into intestinal epithelial cells to render the barrier dysfunction phenotype. Surprisingly, the authors concluded there was no link between the gut microbiota and altered barrier function under hyperglycemic conditions. While microbiota community shifts were observed in STZtreated mice compared to wild-type, and treatment with insulin attenuated these shifts, fecal microbiota transfer (FMT) of the hyperglycemic microbiota into germfree mice did not result in transfer of the hyperglycemic phenotype or greater susceptibility to C. rodentium infection. Unfortunately, transference of phenotypes upon FMT is more often the exception than the rule and should not be used to rule out the role of the microbiota. However, in the current study the various manipulations of glucose uptake and metabolism appeared to consistently alter barrier integrity while the gut microbiota changes were variable with no apparent signatures. Upon extensive characterization of dysmetabolism and intestinal permeability in rodents, the authors wanted to determine if similar patterns are observed in humans. The authors recruited 27 healthy subjects to look for a correlation between TLR4 ligands in the blood and 45 clinical parameters collected on each individual ranging from body mass index to neutrophil counts. The highest correlation observed was with glycated hemoglobin levels (HbA1c), generally indicative of an individual’s 3-month blood glucose concentration, supporting their rodent data implicating hyperglycemia in barrier dysfunction.
Cell Metabolism
Previews This work provides compelling evidence demonstrating the link between glycemic levels and intestinal barrier function in the etiology of obesity and diabetes. The authors describe a novel mechanistic role for intracellular hyperglycemia in the intestinal epithelia, independent of the microbiome, in driving intestinal permeability. The result is subsequent dissemination of microbial antigen coupled with increased risk for enteric infection. This work contributes meaningful new insights into our multifactorial model of metabolic disease and makes a convincing case for redefining metabolic syndrome to include intestinal permeability and risk for infections. These lessons in glucose toxicity remind us of the negative impact certain dietary behaviors can confer, and the importance of glucose control in diabetic individuals. Moreover, this study
places the gut at the center of metabolic syndrome and supports the hypothesis that metabolic derangements may begin there. REFERENCES Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A.M., Fava, F., Tuohy, K.M., Chabo, C., et al. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772. Desai, M.S., Seekatz, A.M., Koropatkin, N.M., Kamada, N., Hickey, C.A., Wolter, M., Pudlo, N.A., Kitamoto, S., Terrapon, N., Muller, A., et al. (2016). A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21. Kaspersen, K.A., Pedersen, O.B., Petersen, M.S., Hjalgrim, H., Rostgaard, K., Møller, B.K., JuulSørensen, C., Kotze´, S., Dinh, K.M., Erikstrup, L.T., et al. (2015). Obesity and risk of infection: results from the Danish Blood Donor Study. Epidemiology 26, 580–589.
Miranda, P.J., DeFronzo, R.A., Califf, R.M., and Guyton, J.R. (2005). Metabolic syndrome: definition, pathophysiology, and mechanisms. Am. Heart J. 149, 33–45. Randolph, G.J., Bala, S., Rahier, J.-F., Johnson, M.W., Wang, P.L., Nalbantoglu, I., Dubuquoy, L., Chau, A., Pariente, B., Kartheuser, A., et al. (2016). Lymphoid aggregates remodel lymphatic collecting vessels that serve mesenteric lymph nodes in Crohn disease. Am. J. Pathol. 186, 3066–3073. Thaiss, C.A., Levy, M., Grosheva, I., Zheng, D., Soffer, E., Blacher, E., Braverman, S., Tengeler, A.C., Barak, O., Elazar, M., et al. (2018). Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359, 1376–1383. Winer, D.A., Luck, H., Tsai, S., and Winer, S. (2016). The intestinal immune system in obesity and insulin resistance. Cell Metab. 23, 413–426. Zhao, L., Zhang, F., Ding, X., Wu, G., Lam, Y.Y., Wang, X., Fu, H., Xue, X., Lu, C., Ma, J., et al. (2018). Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359, 1151–1156.
Cold Temperatures Fire up Circadian Neurons Annika F. Barber1,* and Amita Sehgal1 1Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.04.016
Circadian clocks monitor both light and temperature cycles to entrain behavior and physiology to the environment. Recently in Nature, Yadlapalli et al. (2018) identified a subgroup of Drosophila clock neurons that responds to temperature input with changes in intracellular calcium and mediates effects of temperature on circadian entrainment and sleep. Circadian clocks are found in almost all organisms and serve to coordinate behavior and physiology with daily environmental cycles. The molecular clock is comprised of transcription-translation feedback loops that have an endogenous period of 24 hr and maintain rhythms even in constant conditions. A network of clock-containing neurons in the brain serves as a central pacemaker in organisms from flies to humans. The central clock is reset daily by environmental cues, termed zeitgebers, which include light and temperature. In nature, light and temperature usually vary together and synergistically shape circadian behavior and clock neuron physiology (Yoshii et al., 2009). While the endoge-
nous period is resistant to changes in temperature over a physiological range (16 C–30 C) through a phenomenon known as temperature compensation, clocks are readily entrained by even small temperature oscillations of 2 C–3 C. Recent work from the Shafer lab (Yadlapalli et al., 2018) offers new insights into the role of specific circadian neurons in temperature entrainment. Decades of work in Drosophila have elucidated key features of the molecular circadian clock and characterized subpopulations of clock neurons and their roles in shaping rhythmic behavior. In flies, the central clock consists of a network of 150 clock-expressing neurons. The small ventral lateral neurons
(sLNvs) are the master regulators of this network and coordinate the activity of other clock neurons through the release of the neuropeptide pigment-dispersing factor (PDF) (Allada and Chung, 2010). Though LNvs are sufficient to set period and drive rest/activity rhythms in constant conditions, robust rhythms of behavior and physiology are an emergent property of the entire clock network. To explain how the clock network maintains both temperature entrainment and temperature compensation, a two-oscillator model has been proposed in which the sLNvs are temperature insensitive and maintain a fixed phase relationship with the light cycle while a second oscillator in the dorsal neurons (DN1, DN2, and
Cell Metabolism 27, May 1, 2018 ª 2018 Elsevier Inc. 951
Previews bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381. Krall, A.S., Xu, S., Graeber, T.G., Braas, D., and Christofk, H.R. (2016). Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457. Krebs, A.M., Mitschke, J., Lasierra Losada, M., Schmalhofer, O., Boerries, M., Busch, H., Boettcher, M., Mougiakakos, D., Reichardt, W., Bronsert, P., et al. (2017). The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529. Liao, J., Liu, P.P., Hou, G., Shao, J., Yang, J., Liu, K., Lu, W., Wen, S., Hu, Y., and Huang, P. (2017). Regulation of stem-like cancer cells by glutamine through b-catenin pathway mediated by redox signaling. Mol. Cancer 16, 51. Liu, S., Cong, Y., Wang, D., Sun, Y., Deng, L., Liu, Y., Martin-Trevino, R., Shang, L., McDermott, S.P.,
Landis, M.D., et al. (2013). Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78–91.
Thompson, C.B., and Zhang, J. (2018). As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438.e5.
Mani, S.A., Guo, W., Liao, M.J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F., Zhang, C.C., Shipitsin, M., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715.
Stankic, M., Pavlovic, S., Chin, Y., Brogi, E., Padua, D., Norton, L., Massague´, J., and Benezra, R. (2013). TGF-b-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 5, 1228– 1242.
Ocan˜a, O.H., Co´rcoles, R., Fabra, A., MorenoBueno, G., Acloque, H., Vega, S., Barrallo-Gimeno, A., Cano, A., and Nieto, M.A. (2012). Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724. Pavlova, N.N., and Thompson, C.B. (2016). The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47. Pavlova, N.N., Hui, S., Ghergurovich, J.M., Fan, J., Intlekofer, A.M., White, R.M., Rabinowitz, J.D.,
Vander Heiden, M.G., and DeBerardinis, R.J. (2017). Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669. Zhang, J., Fan, J., Venneti, S., Cross, J.R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E.H., Judkins, A.R., et al. (2014). Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218.
Hold the Door: Role of the Gut Barrier in Diabetes Anthony Martin1 and Suzanne Devkota1,2,* 1Inflammatory
Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.04.017 2Department
While metabolic tissues such as adipose, liver, muscle, and pancreas have been extensively studied in dysmetabolism, the contribution of the gut remains poorly understood. In a recent Science article, Thaiss et al. (2018) unravel mechanisms underlying intestinal permeability observed in obesity and link barrier dysfunction and risk for infection with hyperglycemia. The list of features that characterize ‘‘metabolic syndrome’’ or pre-diabetes continues to evolve in line with the growing appreciation for cardiometabolic risk phenotypes. While hallmark features include insulin resistance, high blood pressure, and dyslipidemia (Miranda et al., 2005), a recent study by Thaiss et al. (2018) suggests that increased intestinal permeability and systemic exposure to bacterial antigen should be used to further define metabolic syndrome. Compromised small or large intestinal barrier function involves the weakening of tight junction and adhesion proteins between intestinal epithelial cells, resulting in increased diffusion of bacterial components into the blood, lymph, and extra-intestinal tissues (Winer et al., 2016; Randolph et al., 2016). Loss of barrier integrity has been proposed as a driver
of chronic low-grade inflammation seen in obesity (Cani et al., 2007), but an additional, underappreciated consequence involves an increased risk for pathogenic infections (Kaspersen et al., 2015). The exact culprit(s) or biochemical basis for gut permeability continues to be investigated, but the strongest candidates include diet, gut microbiota-derived metabolites, or a combination of the two (Desai et al., 2016; Zhao et al., 2018). Thaiss et al. hypothesized that some central feature of dysmetabolism is responsible for persistent intestinal permeability. Through use of several wellestablished rodent models of obesity and diabetes, the study dissects potential roles for leptin, gut microbiota, and obesity itself as possible mediators of intestinal permeability. However, the authors ultimately conclude that dysregulated intracellular
glucose metabolism in intestinal epithelial cells, mediated by the insulin-independent glucose transporter GLUT2, drives barrier dysfunction (Figure 1). To identify which metabolic abnormalities drive gut permeability, the authors first explored the role of the satiety hormone leptin. They found that obese leptin receptor (LepR) knockout (db/db) or leptin-deficient (ob/ob) mice exhibit diminished barrier function and increased intestinal permeability in comparison to wild-type littermates. When orally challenged with Citrobacter rodentium, an established model mimicking human Escherichia coli enteric infection, db/db and ob/ob mice displayed an inability to clear the intestinally colonized pathogen. Whole-body disruption of leptin signaling appeared to enhance C. rodentium invasion, so the authors wanted to
Cell Metabolism 27, May 1, 2018 ª 2018 Elsevier Inc. 949
Cell Metabolism
Previews Tight Junction Glucose GLUT2 Transporter C. rodentium Bacterial Product
Systemic Circulation
Elevated Blood Glucose
Blood Vessel Insulin GLUT2 Ablation
XX
Basal
↑ Glucose Influx ↑ Glucose Metabolism ↑ Intestinal Permeability Glucose Metabolism
2-DG
Intestinal Epithelial Cell
Apical
↓ Barrier Function ↑ C. rodentium Colonization Intestine
Figure 1. Hyperglycemia Disrupts Intestinal Epithelial Cell Barrier Integrity Persistent vascular transport of glucose into intestinal epithelial cells via the insulin-independent GLUT2 transporter mediates aberrant intracellular glucose metabolism. This results in increased intestinal permeability, permissive translocation of bacterial products into systemic circulation, and sustained colonization of Citrobacter rodentium infection in the intestine. However, administration of insulin, genetic ablation of GLUT2, or inhibition of glucose metabolism with 2-deoxyglucose (2-DG) can reverse the consequential loss in barrier integrity and dissemination of bacterial products to systemic tissues.
identify the tissue-specific mediator of LepR-driven protection against infection. However, knocking out LepR in intestinal epithelial cells, hepatocytes, or specific regions of the hypothalamus did not enhance infection. Furthermore, to determine whether the permeability effects were due to obesity, the authors pair-fed db/db and ob/ob mice to match wildtype consumption and found that in the absence of obesity, barrier permeability and infection persisted. Additionally, non-obese, wild-type mice treated with a leptin antagonist also demonstrated persistent barrier dysfunction and C. rodentium infection. Thus, while providing evidence for the association of leptin deficiency and obesity with barrier dysfunction, the authors concluded there was no causative link. However, there was a consistent observation across all of the mouse models that put into focus an alternative mecha950 Cell Metabolism 27, May 1, 2018
nism driving the permeability phenotype. All mice displaying increased permeability and persistent infection were hyperglycemic regardless of leptin or obesity status. Therefore, a feasible approach to test the role of hyperglycemia on barrier function was to ablate insulin-producing beta cells to drive hyperglycemic blood glucose levels. Streptozotocin (STZ), a commonly used beta cell toxin, was administered to induce hyperglycemia in wild-type mice. Interestingly, elevation of blood glucose alone could recapitulate barrier dysfunction and susceptibility to C. rodentium infection. RNA sequencing of intestinal epithelial cells isolated from STZ-treated mice demonstrated a robust transcriptional shift toward abrogation of pathways involved in normal barrier function. Remarkably, reintroduction of insulin to STZ-treated mice protected against hyperglycemia and restored the tight junctions. This resulted in decreased
microbial byproducts in the blood and greater clearance of C. rodentium from the intestine. The developing body of evidence presented thus far suggested that risk for enteric infection due to intestinal barrier dysfunction might be resolved by disrupting epithelial uptake of glucose or intracellular glucose metabolism. Indeed, 2-deoxyglucose-mediated pharmacologic inhibition of glycolysis in isolated epithelial cells from hyperglycemic mice restored barrier integrity. Moreover, conditional genetic ablation of GLUT2 in intestinal epithelial cells rescued STZtreated mice from the deleterious consequences of impaired barrier function. Blood glucose remained elevated in the absence of GLUT2 in STZ-treated mice, implying the requirement for the intracellular transport of glucose into intestinal epithelial cells to render the barrier dysfunction phenotype. Surprisingly, the authors concluded there was no link between the gut microbiota and altered barrier function under hyperglycemic conditions. While microbiota community shifts were observed in STZtreated mice compared to wild-type, and treatment with insulin attenuated these shifts, fecal microbiota transfer (FMT) of the hyperglycemic microbiota into germfree mice did not result in transfer of the hyperglycemic phenotype or greater susceptibility to C. rodentium infection. Unfortunately, transference of phenotypes upon FMT is more often the exception than the rule and should not be used to rule out the role of the microbiota. However, in the current study the various manipulations of glucose uptake and metabolism appeared to consistently alter barrier integrity while the gut microbiota changes were variable with no apparent signatures. Upon extensive characterization of dysmetabolism and intestinal permeability in rodents, the authors wanted to determine if similar patterns are observed in humans. The authors recruited 27 healthy subjects to look for a correlation between TLR4 ligands in the blood and 45 clinical parameters collected on each individual ranging from body mass index to neutrophil counts. The highest correlation observed was with glycated hemoglobin levels (HbA1c), generally indicative of an individual’s 3-month blood glucose concentration, supporting their rodent data implicating hyperglycemia in barrier dysfunction.
Cell Metabolism
Previews This work provides compelling evidence demonstrating the link between glycemic levels and intestinal barrier function in the etiology of obesity and diabetes. The authors describe a novel mechanistic role for intracellular hyperglycemia in the intestinal epithelia, independent of the microbiome, in driving intestinal permeability. The result is subsequent dissemination of microbial antigen coupled with increased risk for enteric infection. This work contributes meaningful new insights into our multifactorial model of metabolic disease and makes a convincing case for redefining metabolic syndrome to include intestinal permeability and risk for infections. These lessons in glucose toxicity remind us of the negative impact certain dietary behaviors can confer, and the importance of glucose control in diabetic individuals. Moreover, this study
places the gut at the center of metabolic syndrome and supports the hypothesis that metabolic derangements may begin there. REFERENCES Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A.M., Fava, F., Tuohy, K.M., Chabo, C., et al. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772. Desai, M.S., Seekatz, A.M., Koropatkin, N.M., Kamada, N., Hickey, C.A., Wolter, M., Pudlo, N.A., Kitamoto, S., Terrapon, N., Muller, A., et al. (2016). A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21. Kaspersen, K.A., Pedersen, O.B., Petersen, M.S., Hjalgrim, H., Rostgaard, K., Møller, B.K., JuulSørensen, C., Kotze´, S., Dinh, K.M., Erikstrup, L.T., et al. (2015). Obesity and risk of infection: results from the Danish Blood Donor Study. Epidemiology 26, 580–589.
Miranda, P.J., DeFronzo, R.A., Califf, R.M., and Guyton, J.R. (2005). Metabolic syndrome: definition, pathophysiology, and mechanisms. Am. Heart J. 149, 33–45. Randolph, G.J., Bala, S., Rahier, J.-F., Johnson, M.W., Wang, P.L., Nalbantoglu, I., Dubuquoy, L., Chau, A., Pariente, B., Kartheuser, A., et al. (2016). Lymphoid aggregates remodel lymphatic collecting vessels that serve mesenteric lymph nodes in Crohn disease. Am. J. Pathol. 186, 3066–3073. Thaiss, C.A., Levy, M., Grosheva, I., Zheng, D., Soffer, E., Blacher, E., Braverman, S., Tengeler, A.C., Barak, O., Elazar, M., et al. (2018). Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359, 1376–1383. Winer, D.A., Luck, H., Tsai, S., and Winer, S. (2016). The intestinal immune system in obesity and insulin resistance. Cell Metab. 23, 413–426. Zhao, L., Zhang, F., Ding, X., Wu, G., Lam, Y.Y., Wang, X., Fu, H., Xue, X., Lu, C., Ma, J., et al. (2018). Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359, 1151–1156.
Cold Temperatures Fire up Circadian Neurons Annika F. Barber1,* and Amita Sehgal1 1Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.04.016
Circadian clocks monitor both light and temperature cycles to entrain behavior and physiology to the environment. Recently in Nature, Yadlapalli et al. (2018) identified a subgroup of Drosophila clock neurons that responds to temperature input with changes in intracellular calcium and mediates effects of temperature on circadian entrainment and sleep. Circadian clocks are found in almost all organisms and serve to coordinate behavior and physiology with daily environmental cycles. The molecular clock is comprised of transcription-translation feedback loops that have an endogenous period of 24 hr and maintain rhythms even in constant conditions. A network of clock-containing neurons in the brain serves as a central pacemaker in organisms from flies to humans. The central clock is reset daily by environmental cues, termed zeitgebers, which include light and temperature. In nature, light and temperature usually vary together and synergistically shape circadian behavior and clock neuron physiology (Yoshii et al., 2009). While the endoge-
nous period is resistant to changes in temperature over a physiological range (16 C–30 C) through a phenomenon known as temperature compensation, clocks are readily entrained by even small temperature oscillations of 2 C–3 C. Recent work from the Shafer lab (Yadlapalli et al., 2018) offers new insights into the role of specific circadian neurons in temperature entrainment. Decades of work in Drosophila have elucidated key features of the molecular circadian clock and characterized subpopulations of clock neurons and their roles in shaping rhythmic behavior. In flies, the central clock consists of a network of 150 clock-expressing neurons. The small ventral lateral neurons
(sLNvs) are the master regulators of this network and coordinate the activity of other clock neurons through the release of the neuropeptide pigment-dispersing factor (PDF) (Allada and Chung, 2010). Though LNvs are sufficient to set period and drive rest/activity rhythms in constant conditions, robust rhythms of behavior and physiology are an emergent property of the entire clock network. To explain how the clock network maintains both temperature entrainment and temperature compensation, a two-oscillator model has been proposed in which the sLNvs are temperature insensitive and maintain a fixed phase relationship with the light cycle while a second oscillator in the dorsal neurons (DN1, DN2, and
Cell Metabolism 27, May 1, 2018 ª 2018 Elsevier Inc. 951