Fredrik Bäckhed

University of Gothenburg, Goeteborg, Västra Götaland, Sweden

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Publications (22)207.41 Total impact

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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.
    EMBO Reports 12/2014; · 7.19 Impact Factor
  • 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.
    Mucosal Immunology 08/2014; · 7.54 Impact Factor
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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.
    Cell metabolism 07/2014; · 17.35 Impact Factor
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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.
    PLoS ONE 01/2014; 9(1):e85254. · 3.53 Impact Factor
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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.
    PNAS. 01/2014; 1:1407597111-.
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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.
    Endocrinology 07/2013; · 4.72 Impact Factor
  • Fredrik Bäckhed
    Nature medicine 05/2013; 19(5):533-4. · 27.14 Impact Factor
  • 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.
    Nature Reviews Microbiology 02/2013; · 22.49 Impact Factor
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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.
    Cell metabolism 02/2013; 17(2):225-35. · 17.35 Impact Factor
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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.
    Gut Microbes 01/2013; 4(2).
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    ABSTRACT: Indigenous microbiota are an essential component in the modern concept of human health, but the composition and functional characteristics of a healthy microbiome remain to be precisely defined. Patterns of microbial colonization associated with disease states have been documented, but the health-associated microbial patterns and their functional characteristics are less clear. A healthy microbiome, considered in the context of body habitat or body site, could be described in terms of ecologic stability (i.e., ability to resist community structure change under stress or to rapidly return to baseline following a stress-related change), by an idealized (presumably health-associated) composition or by a desirable functional profile (including metabolic and trophic provisions to the host). Elucidation of the properties of healthy microbiota would provide a target for dietary interventions and/or microbial modifications aimed at sustaining health in generally healthy populations and improving the health of individuals exhibiting disrupted microbiota and associated diseases.
    Cell host & microbe 11/2012; 12(5):611-22. · 13.02 Impact Factor
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    Fredrik Bäckhed
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    ABSTRACT: The human gut is home to vast numbers of bacteria (gut microbiota), which outnumber the cells in the human body by an order of magnitude. The gut microbiota has coevolved with humans and can be considered an organ of similar size as the liver, containing more than 1,000 cell types (bacterial species) and encoding 150-fold more genes than are present in the human genome. Accordingly, the gut microbiota may have profound effects on various host responses, either directly or indirectly, by modifying food components or endogenously produced molecules into signaling molecules. Recent findings suggest that an altered gut microbial composition is associated with inflammatory bowel disease and obesity, indicating that the gut microbiota should be considered a contributing factor in several common diseases.
    Nutrition Reviews 08/2012; 70 Suppl 1:S14-7. · 4.60 Impact Factor
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    ABSTRACT: Rotavirus is a major cause of diarrhea worldwide and exhibits a pronounced small intestinal epithelial cell (IEC) tropism. Both human infants and neonatal mice are highly susceptible, whereas adult individuals remain asymptomatic and shed only low numbers of viral particles. Here we investigated age-dependent mechanisms of the intestinal epithelial innate immune response to rotavirus infection in an oral mouse infection model. Expression of the innate immune receptor for viral dsRNA, Toll-like receptor (Tlr) 3 was low in the epithelium of suckling mice but strongly increased during the postnatal period inversely correlating with rotavirus susceptibility, viral shedding and histological damage. Adult mice deficient in Tlr3 (Tlr3(-/-)) or the adaptor molecule Trif (Trif(Lps2/Lps2)) exerted significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild-type animals. In contrast, neonatal mice deficient in Tlr3 or Trif did not display impaired cell stimulation or enhanced rotavirus susceptibility. Using chimeric mice, a major contribution of the non-hematopoietic cell compartment in the Trif-mediated antiviral host response was detected in adult animals. Finally, a significant age-dependent increase of TLR3 expression was also detected in human small intestinal biopsies. Thus, upregulation of epithelial TLR3 expression during infancy might contribute to the age-dependent susceptibility to rotavirus infection.
    PLoS Pathogens 05/2012; 8(5):e1002670. · 8.14 Impact Factor
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    ABSTRACT: Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.
    Nature 04/2012; 484(7395):524-8. · 38.60 Impact Factor
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    ABSTRACT: The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4(+) T cells and CD11b(+) /GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(6):1357-67. · 6.04 Impact Factor
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    ABSTRACT: Glycans on mucosal surfaces have an important role in host-microbe interactions. The locus encoding the blood-group-related glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) is subject to strong selective forces in natural house-mouse populations that contain a common allelic variant that confers loss of B4galnt2 gene expression in the gastrointestinal (GI) tract. We reasoned that altered glycan-dependent intestinal host-microbe interactions may underlie these signatures of selection. To determine whether B4galnt2 influences the intestinal microbial ecology, we profiled the microbiota of wild-type and B4galnt2-deficient siblings throughout the GI tract using 16S rRNA gene pyrosequencing. This revealed both distinct communities at different anatomic sites and significant changes in composition with respect to genotype, indicating a previously unappreciated role of B4galnt2 in host-microbial homeostasis. Among the numerous B4galnt2-dependent differences identified in the abundance of specific bacterial taxa, we unexpectedly detected a difference in the pathogenic genus, Helicobacter, suggesting Helicobacter spp. also interact with B4galnt2 glycans. In contrast to other glycosyltransferases, we found that the host intestinal B4galnt2 expression is not dependent on presence of the microbiota. Given the long-term maintenance of alleles influencing B4galnt2 expression by natural selection and the GI phenotypes presented here, we suggest that variation in B4galnt2 GI expression may alter susceptibility to GI diseases such as infectious gastroenteritis.
    The ISME Journal 01/2012; 6(7):1345-55. · 8.95 Impact Factor
  • Atherosclerosis Supplements 06/2011; 12(1):65-65. · 4.33 Impact Factor
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    R Caesar, F Fåk, F Bäckhed
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    ABSTRACT: Recent studies have revealed a close relationship between inflammatory and metabolic pathways, and inflammation is now recognized to have a major role in obesity and metabolic diseases such as insulin resistance and atherosclerosis. The human body is home to a large number of distinct microbial communities, with the densest population in the distal gut (the gut microbiota). Bacteria have long been known to activate inflammatory pathways, and recent data demonstrate that the gut microbiota may affect lipid metabolism and function as an environmental factor that influences the development of obesity and related diseases. Here, we review how the gut microbiota may affect metabolic diseases by activating the innate immune system.
    Journal of Internal Medicine 10/2010; 268(4):320-8. · 6.46 Impact Factor
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    F Bäckhed
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    ABSTRACT: Mammals are metagenomic, in that they are composed not only of their own genome but also those of all of their associated microbes (microbiome). Individual variations in the microbiome influence host health and may be implicated in disease aetiology. Therefore, it is not surprising that decreased microbial diversity is associated with both obesity and inflammatory bowel disease. Studies in germ-free mice have demonstrated that the gut microbiota is required for development of diet-induced obesity as well as inflammatory diseases. However, the underlying molecular mechanism(s) for how the gut microbiota causes metabolic diseases is only beginning to be clarified. Furthermore, emerging data suggest that the gut microbiota may predispose or protect against other important diseases such as cardiovascular disease and diabetes.
    Clinical & Experimental Immunology 04/2010; 160(1):80-4. · 3.41 Impact Factor
  • Fredrik Bäckhed
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    ABSTRACT: Identification of the gut microbiota as an environmental factor that modulates obesity and metabolic diseases has provided the medical and functional food industry with new targets to treat metabolic diseases. However, only limited knowledge about the mechanisms by which the gut microbiota contributes to these lifestyle diseases are known. The gut microbiota is involved in energy harvest from the diet, modulation of endocrine signalling, and promoting metabolic inflammation. This review will discuss how the gut microbiota is altered in obesity, some of the mechanisms by which it promotes disease development, and how pre- and probiotics may be used to improve metabolic diseases.
    International Dairy Journal. 01/2010;

Publication Stats

660 Citations
207.41 Total Impact Points

Institutions

  • 2009–2014
    • 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