Fredrik Bäckhed

University of Gothenburg, Goeteborg, Västra Götaland, Sweden

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Publications (34)284.6 Total impact

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    ABSTRACT: The intestinal commensal microbiota is essential for many host physiological processes, but its impact on infectious diseases is poorly understood. Here we investigate the influence of the gut microbiota during oral Salmonella infection. We report a higher bacterial burden in mesenteric lymph nodes (MLN) of intragastrically infected germ-free (GF) mice compared to conventionally-raised (CONV-R) animals, despite similar inflammatory phagocyte recruitment. Salmonella penetration into the lamina propria of the small intestine and splenic bacterial burden were not altered in the absence of the microbiota. Intragastrically infected GF mice also displayed a higher frequency of IFN-γ-producing NK, NKT, CD4+ and CD8+ T cells in the MLN despite IL-12 levels similar to infected CONV-R mice. However, infecting mice intraperitoneally abrogated the difference in MLN bacterial load and IFN-γ-producing cells observed in intragastrically-infected animals. Moreover, mice treated with antibiotics (ABX) and intragastrically infected with Salmonella had a greater bacterial burden and frequency of IFN-γ-producing cells in the MLN. In ABX mice the number of Salmonella correlated with the frequency of IFN-γ-producing lymphocytes in the MLN, while no such correlation was observed in the MLN of infected GF mice. Overall, the data show that the lack of the microbiota influences pathogen colonization of the MLN, and the increased IFN-γ in the MLN of infected GF mice is not only due to the absence of commensals at the time of infection but the lack of immune signals provided by the microbiota from birth.
    Full-text · Article · Dec 2015 · Frontiers in Cellular and Infection Microbiology
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    ABSTRACT: The intestinal mucus layer provides a barrier limiting bacterial contact with the underlying epithelium. Mucus structure is shaped by intestinal location and the microbiota. To understand how commensals modulate gut mucus, we examined mucus properties under germ-free (GF) conditions and during microbial colonization. Although the colon mucus organization of GF mice was similar to that of conventionally raised (Convr) mice, the GF inner mucus layer was penetrable to bacteria-sized beads. During colonization, in which GF mice were gavaged with Convr microbiota, the small intestine mucus required 5 weeks to be normally detached and colonic inner mucus 6 weeks to become impenetrable. The composition of the small intestinal microbiota during colonization was similar to Convr donors until 3 weeks, when Bacteroides increased, Firmicutes decreased, and segmented filamentous bacteria became undetectable. These findings highlight the dynamics of mucus layer development and indicate that studies of mature microbe-mucus interactions should be conducted weeks after colonization.
    No preview · Article · Nov 2015 · Cell host & microbe
  • Hanns-Ulrich Marschall · Fredrik Bäckhed

    No preview · Article · Aug 2015 · Hepatology
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    Full-text · Dataset · Jul 2015
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    Full-text · Dataset · Jul 2015
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    ABSTRACT: Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.
    Full-text · Article · Jul 2015 · Nature Communications
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    ABSTRACT: Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance and insulin sensitivity is essential to identify new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis, based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis and increased insulin sensitivity. Stk25-/- mice were protected from diet-induced liver steatosis, accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25-/- skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts, and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. Our findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for treatment of type 2 diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Full-text · Article · Apr 2015 · Diabetes
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    ABSTRACT: The worldwide prevalence of obesity and type 2 diabetes mellitus (T2DM) continues to rise at an alarming pace. Recently the potential role of the gut microbiome in these metabolic disorders has been identified. Obesity is associated with changes in the composition of the intestinal microbiota, and the obese microbiome seems to be more efficient in harvesting energy from the diet. Lean male donor fecal microbiota transplantation (FMT) in males with metabolic syndrome resulted in a significant improvement in insulin sensitivity in conjunction with an increased intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains. Such differences in gut microbiota composition might function as early diagnostic markers for the development of T2DM in high-risk patients. Products of intestinal microbes such as butyrate may induce beneficial metabolic effects through enhancement of mitochondrial activity, prevention of metabolic endotoxemia, and activation of intestinal gluconeogenesis via different routes of gene expression and hormone regulation. Future research should focus on whether bacterial products (like butyrate) have the same effects as the intestinal bacteria that produce it, in order to ultimately pave the way for more successful interventions for obesity and T2DM. The rapid development of the currently available techniques, including use of fecal transplantations, has already shown promising results, so there is hope for novel therapies based on the microbiota in the future. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Jan 2015 · Diabetes Care
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    ABSTRACT: Two C57BL/6 mice colonies maintained in two rooms of the same specific pathogen-free (SPF) facility were found to have different gut microbiota and a mucus phenotype that was specific for each colony. The thickness and growth of the colon mucus were similar in the two colonies. However, one colony had mucus that was impenetrable to bacteria or beads the size of bacteria—which is comparable to what we observed in free-living wild mice—whereas the other colony had an inner mucus layer penetrable to bacteria and beads. The different properties of the mucus depended on the microbiota, as they were transmissible by transfer of caecal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, whereas mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus, our study shows that bacteria and their community structure affect mucus barrier properties in ways that can have implications for health and disease. It also highlights that genetically identical animals housed in the same facility can have rather distinct microbiotas and barrier structures.
    Full-text · Article · Dec 2014 · EMBO Reports
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    F Sommer · F Bäckhed
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    ABSTRACT: The epithelium is a first line of defense against microorganisms in the gut. Reactive oxygen species (ROS) have an important role in controlling the normal gut microbiota and pathogenic bacteria. Dual oxidase 2 (DUOX2) is an important source of hydrogen peroxide in the small and large intestine, and the gut microbiota induces Duox2 expression. Here, we investigated the microbial regulation of Duox2 expression. We found that Duox2 was expressed by intestinal epithelial cells mainly in the tip of the epithelium. Duox2 expression was strongly induced by the presence of a normal microbiota in mice, but not when germ-free mice were colonized with various commensal bacteria. Duox2 expression was more rapidly induced by the gut microbiota in the colon than in the ileum. Furthermore, we showed that regulation of Duox2 expression in the ileum involved TIR-domain-containing adaptor protein including interferon-β (TRIF) and canonical nuclear factor-κB p50/p65 signaling, whereas regulation of Duox2 expression in the colon involved MyD88 and the p38 pathway. Collectively, these data indicate that the gut microbiota uses two distinct signaling pathways to induce Duox2 expression in the ileum and colon epithelium.Mucosal Immunology advance online publication, 27 August 2014; doi:10.1038/mi.2014.74.
    Full-text · Article · Aug 2014 · Mucosal Immunology
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    ABSTRACT: The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a two-layered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin {beta}-deficient mice was now found to be attached. Meprin {beta} is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin {beta} was added to the attached mucus of meprin {beta}-deficient mice, the mucus was detached from the epithelium. Similar to meprin {beta}-deficient mice, germ-free mice have attached mucus as they did not shed the membrane-anchored meprin {beta} into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin {beta} to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin {beta} cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin {beta} in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.
    Full-text · Article · Aug 2014 · Proceedings of the National Academy of Sciences
  • Muhammad Tanweer Khan · Max Nieuwdorp · Fredrik Bäckhed
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    ABSTRACT: The gut microbiota has emerged as an integral factor that impacts host metabolism and has been suggested to play a vital role in metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. In humans, cross-sectional studies have identified microbiota profiles associated with metabolic diseases, whereas causation mainly has been demonstrated in animal models. Recent studies involving microbiota-based interventions in humans, or transfer of disease-associated microbiota into germ-free mice, underscore that an altered microbiota may directly modulate host metabolism in humans. However, it will be essential to determine whether an altered gut microbiota precedes development of insulin resistance and diabetes and to identify the underlying molecular mechanisms. Increased mechanistic insights of how the microbiota modulates metabolic disease in humans may pave the way for identification of innovative microbiota-based diagnostics and/or therapeutics.
    No preview · Article · Jul 2014 · Cell metabolism

  • No preview · Article · Jun 2014 · Journal of Cystic Fibrosis
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    ABSTRACT: A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt (-/-) mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt (-/-) mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt(-/-) mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture.
    Full-text · Article · Jan 2014 · PLoS ONE
  • Fredrik Bäckhed
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    ABSTRACT: The human gut is colonized by trillions of bacteria that complement our own human genes with 150-fold more microbial genes. Acting at the intersection between diet and host biology the gut microbiota can be considered a metabolic organ that affects host physiology. Here we explore evidence that supports the hypothesis that there is a dynamic interrelationship between our diet and gut microbiota that plays an important role in nutrition as well as modulating energy balance. Furthermore, the gut microbiota is altered in obesity and germ-free mice have reduced adiposity and are protected against diet-induced obesity. Accordingly, the gut microbiota may be considered an important environmental factor that contributes to obesity and metabolic diseases.
    No preview · Article · Jan 2014
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    ABSTRACT: The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood.To investigate if the gut microbiota affects hypothalamic and brainstem body fat regulating circuits, we compared gene expression of food intake regulating neuropeptides between germ-free and conventionally raised mice.We found that conventionally raised mice had decreased expression of the anti-obesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in brainstem. Moreover, in both the hypothalamus and the brainstem, conventional mice had decreased expression of the anti-obesity neuropeptide brain-derived neurotrophic factor (Bdnf). Conventionally raised mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the anti-obesity peptides pro-opiomelanocortin (Pomc) and cocain and amphetamine regulated transcript (Cart) in the hypothalamus. The changes in neuropeptide expression could be secondary to elevated fat mass in conventionally raised mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in conventional mice compared with germ free mice. The hypothalamic expression of leptin resistance associated suppressor of cytokine signaling 3 (Socs-3) was increased in conventionally raised mice.In conclusion, the gut microbiota reduces the expression of two genes coding for body fat suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat inducing gut microbiota is associated with hypothalamic signs of Socs-3 mediated leptin resistance, which may be linked to failed compensatory body fat reduction.
    No preview · Article · Jul 2013 · Endocrinology
  • Fredrik Bäckhed

    No preview · Article · May 2013 · Nature medicine
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    Felix Sommer · Fredrik Bäckhed
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    ABSTRACT: Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host-microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.
    Full-text · Article · Feb 2013 · Nature Reviews Microbiology
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    ABSTRACT: Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
    Full-text · Article · Feb 2013 · Cell metabolism
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    ABSTRACT: The intimate interplay between the gut microbiota and the host may contribute to health and disease in the host. Experiments using conventionalized and conventionally raised animal models have illustrated the role of the intestinal microbiota in shaping and maintaining the host immune system. However, it is still unclear whether colonization at birth or at adulthood induces different host responses. Here, we perform comparative transcriptome analyses to elucidate the impact of the gut microbiota on the development and maintenance of the immune system in adult conventionalized (after 16 and 30 d of colonization) and conventionally raised mice, which were obtained in two independent laboratories. Transcriptional profiles of jejunum, ileum and colon were compared between germfree, conventionally raised mice and conventionalized mice. Germfree mice from the two different facilities clustered together, establishing the validity of the comparative analysis. Nevertheless, significant spatial differences were detected along the gut; jejunum and colon exhibited a transient response (conventionalized mice) that eventually returned to a homeostatic level (conventionally raised). In contrast, the ileal response to microbiota was similar in conventionalized and conventionally raised mice. Overall, this comparative analysis supports the hypothesis that co-development of the gut microbiota and its host initiates at early stage of development and indicates that despite the achieved homeostasis, immune development is substantially different in mice conventionalized in adulthood. These findings imply that colonization during development is required to meet the window of opportunity where the gut microbiota can imprint the host's mucosal immune-homeostasis in a way that cannot be achieved at later stages in life.
    Full-text · Article · Jan 2013 · Gut Microbes

Publication Stats

2k Citations
284.60 Total Impact Points

Institutions

  • 2009-2015
    • University of Gothenburg
      • • Department of Molecular and Clinical Medicine
      • • Sahlgrenska Center for Cardiovascular and Metabolic Research (CMR)
      • • The Wallenberg Laboratory for Cardiovascular and Metabolic Research
      Goeteborg, Västra Götaland, Sweden
  • 2008
    • Laboratory for Molecular Infection Medicine Sweden
      Umeå, Västerbotten, Sweden