Publications by authors named "Fredrik Bäckhed"

176 Publications

Structural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production.

Nat Commun 2021 03 1;12(1):1347. Epub 2021 Mar 1.

Experimental Medical Science, Medical Structural Biology, BMC C13, Lund University, Lund, Sweden.

The human microbiome can produce metabolites that modulate insulin signaling. Type 2 diabetes patients have increased circulating concentrations of the microbially produced histidine metabolite, imidazole propionate (ImP) and administration of ImP in mice resulted in impaired glucose tolerance. Interestingly, the fecal microbiota of the patients had increased capacity to produce ImP, which is mediated by the bacterial enzyme urocanate reductase (UrdA). Here, we describe the X-ray structures of the ligand-binding domains of UrdA in four different states, representing the structural transitions along the catalytic reaction pathway of this unexplored enzyme linked to disease in humans. The structures in combination with functional data provide key insights into the mechanism of action of UrdA that open new possibilities for drug development strategies targeting type 2 diabetes.
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http://dx.doi.org/10.1038/s41467-021-21548-yDOI Listing
March 2021

Longitudinal plasma protein profiling of newly diagnosed type 2 diabetes.

EBioMedicine 2021 Jan 3;63:103147. Epub 2020 Dec 3.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status.

Methods: To elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes.

Findings: Early stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM.

Interpretation: The results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments.

Funding: This work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
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http://dx.doi.org/10.1016/j.ebiom.2020.103147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718461PMC
January 2021

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology.

Nat Commun 2020 11 18;11(1):5881. Epub 2020 Nov 18.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45, Gothenburg, Sweden.

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
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http://dx.doi.org/10.1038/s41467-020-19589-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676231PMC
November 2020

Gut microbial metabolites as multi-kingdom intermediates.

Nat Rev Microbiol 2021 02 23;19(2):77-94. Epub 2020 Sep 23.

Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

The gut microbiota contributes to host physiology through the production of a myriad of metabolites. These metabolites exert their effects within the host as signalling molecules and substrates for metabolic reactions. Although the study of host-microbiota interactions remains challenging due to the high degree of crosstalk both within and between kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. Metabolites, as the functional output of combined host and microorganism interactions, provide a snapshot in time of an extraordinarily complex multi-organism system. Although substantial work remains towards understanding host-microbiota interactions and the underlying mechanisms, we review the current state of knowledge for each of the major classes of microbial metabolites with emphasis on clinical and translational research implications. We provide an overview of methodologies available for measurement of microbial metabolites, and in addition to discussion of key challenges, we provide a potential framework for integration of discovery-based metabolite studies with mechanistic work. Finally, we highlight examples in the literature where this approach has led to substantial progress in understanding host-microbiota interactions.
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http://dx.doi.org/10.1038/s41579-020-0438-4DOI Listing
February 2021

Integration of molecular profiles in a longitudinal wellness profiling cohort.

Nat Commun 2020 09 8;11(1):4487. Epub 2020 Sep 8.

Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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http://dx.doi.org/10.1038/s41467-020-18148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479148PMC
September 2020

Obesity-associated microbiota contributes to mucus layer defects in genetically obese mice.

J Biol Chem 2020 11 8;295(46):15712-15726. Epub 2020 Sep 8.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

The intestinal mucus layer is a physical barrier separating the tremendous number of gut bacteria from the host epithelium. Defects in the mucus layer have been linked to metabolic diseases, but previous studies predominantly investigated mucus function during high-caloric/low-fiber dietary interventions, thus making it difficult to separate effects mediated directly through diet quality from potential obesity-dependent effects. As such, we decided to examine mucus function in mouse models with metabolic disease to distinguish these factors. Here we show that, in contrast to their lean littermates, genetically obese (ob/ob) mice have a defective inner colonic mucus layer that is characterized by increased penetrability and a reduced mucus growth rate. Exploiting the coprophagic behavior of mice, we next co-housed ob/ob and lean mice to investigate if the gut microbiota contributed to these phenotypes. Co-housing rescued the defect of the mucus growth rate, whereas mucus penetrability displayed an intermediate phenotype in both mouse groups. Of note, non-obese diabetic mice with high blood glucose levels displayed a healthy colonic mucus barrier, indicating that the mucus defect is obesity- rather than glucose-mediated. Thus, our data suggest that the gut microbiota community of obesity-prone mice may regulate obesity-associated defects in the colonic mucosal barrier, even in the presence of dietary fiber.
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http://dx.doi.org/10.1074/jbc.RA120.015771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667970PMC
November 2020

Effects of a Vegetarian Diet on Cardiometabolic Risk Factors, Gut Microbiota, and Plasma Metabolome in Subjects With Ischemic Heart Disease: A Randomized, Crossover Study.

J Am Heart Assoc 2020 09 6;9(18):e016518. Epub 2020 Sep 6.

Department of Cardiology, Faculty of Health Örebro University Hospital Örebro Sweden.

Background A vegetarian diet (VD) may reduce future cardiovascular risk in patients with ischemic heart disease. Methods and Results A randomized crossover study was conducted in subjects with ischemic heart disease, assigned to 4-week intervention periods of isocaloric VD and meat diet (MD) with individually designed diet plans, separated by a 4-week washout period. The primary outcome was difference in oxidized low-density lipoprotein cholesterol (LDL-C) between diets. Secondary outcomes were differences in cardiometabolic risk factors, quality of life, gut microbiota, fecal short-chain and branched-chain fatty acids, and plasma metabolome. Of 150 eligible patients, 31 (21%) agreed to participate, and 27 (87%) participants completed the study. Mean oxidized LDL-C (-2.73 U/L), total cholesterol (-5.03 mg/dL), LDL-C (-3.87 mg/dL), and body weight (-0.67 kg) were significantly lower with the VD than with the MD. Differences between VD and MD were observed in the relative abundance of several microbe genera within the families Ruminococcaceae, Lachnospiraceae, and Akkermansiaceae. Plasma metabolites, including l-carnitine, acylcarnitine metabolites, and phospholipids, differed in subjects consuming VD and MD. The effect on oxidized LDL-C in response to the VD was associated with a baseline gut microbiota composition dominated by several genera of Ruminococcaceae. Conclusions The VD in conjunction with optimal medical therapy reduced levels of oxidized LDL-C, improved cardiometabolic risk factors, and altered the relative abundance of gut microbes and plasma metabolites in patients with ischemic heart disease. Our results suggest that composition of the gut microbiota at baseline may be related to the reduction of oxidized LDL-C observed with the VD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02942628.
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http://dx.doi.org/10.1161/JAHA.120.016518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726986PMC
September 2020

Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study.

Eur Heart J 2020 Nov;41(44):4259-4267

Department of Internal Medicine, section Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

Aims : Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups.

Methods And Results : We included 4672 subjects (mean age 49.8 ± 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP.

Conclusions : Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP.
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http://dx.doi.org/10.1093/eurheartj/ehaa704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724641PMC
November 2020

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation.

Cell Metab 2020 Oct 11;32(4):643-653.e4. Epub 2020 Aug 11.

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden. Electronic address:

Metformin is the first-line therapy for type 2 diabetes, but there are large inter-individual variations in responses to this drug. Its mechanism of action is not fully understood, but activation of AMP-activated protein kinase (AMPK) and changes in the gut microbiota appear to be important. The inhibitory role of microbial metabolites on metformin action has not previously been investigated. Here, we show that concentrations of the microbial metabolite imidazole propionate are higher in subjects with type 2 diabetes taking metformin who have high blood glucose. We also show that metformin-induced glucose lowering is not observed in mice pretreated with imidazole propionate. Furthermore, we demonstrate that imidazole propionate inhibits AMPK activity by inducing inhibitory AMPK phosphorylation, which is dependent on imidazole propionate-induced basal Akt activation. Finally, we identify imidazole propionate-activated p38γ as a novel kinase for Akt and demonstrate that p38γ kinase activity mediates the inhibitory action of imidazole propionate on metformin.
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http://dx.doi.org/10.1016/j.cmet.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546034PMC
October 2020

The Gut Microbiota in Prediabetes and Diabetes: A Population-Based Cross-Sectional Study.

Cell Metab 2020 Sep 10;32(3):379-390.e3. Epub 2020 Jul 10.

The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, 41345 Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Science University of Copenhagen, Copenhagen, Denmark. Electronic address:

The link between the gut microbiota and type 2 diabetes (T2D) warrants further investigation because of known confounding effects from antidiabetic treatment. Here, we profiled the gut microbiota in a discovery (n = 1,011) and validation (n = 484) cohort comprising Swedish subjects naive for diabetes treatment and grouped by glycemic status. We observed that overall gut microbiota composition was altered in groups with impaired glucose tolerance, combined glucose intolerance and T2D, but not in those with impaired fasting glucose. In addition, the abundance of several butyrate producers and functional potential for butyrate production were decreased both in prediabetes and T2D groups. Multivariate analyses and machine learning microbiome models indicated that insulin resistance was strongly associated with microbial variations. Therefore, our study indicates that the gut microbiota represents an important modifiable factor to consider when developing precision medicine approaches for the prevention and/or delay of T2D.
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http://dx.doi.org/10.1016/j.cmet.2020.06.011DOI Listing
September 2020

Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.

Nature 2020 05 6;581(7808):310-315. Epub 2020 May 6.

Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium.

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease. Reported changes in stool consistency and inflammation status during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.
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http://dx.doi.org/10.1038/s41586-020-2269-xDOI Listing
May 2020

Hepatic expression of lipopolysaccharide-binding protein (Lbp) is induced by the gut microbiota through Myd88 and impairs glucose tolerance in mice independent of obesity.

Mol Metab 2020 07 16;37:100997. Epub 2020 Apr 16.

The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345, Gothenburg, Sweden. Electronic address:

Objective: Gut-derived inflammatory factors can impair glucose homeostasis, but the underlying mechanisms are not fully understood. In this study, we investigated how hepatic gene expression is regulated by gut colonization status through myeloid differentiation primary response 88 (MYD88) and how one of the regulated genes, lipopolysaccharide-binding protein (Lbp), affects insulin signaling and systemic glucose homeostasis.

Methods: Liver transcriptomics analysis was conducted on four groups of mice fed a chow diet: conventionally raised (CONV-R) wild-type, germ-free (GF) wild-type, CONV-R Myd88 KO, and GF Myd88 KO. Primary hepatocytes were exposed to combinations of lipopolysaccharide (LPS), LBP, and the LBP-blocking peptide LBPK95A, and the effect on insulin signaling was determined. To assess how LBP affects glucose metabolism in vivo, two mouse models were applied: treatment with LBPK95A and hepatic knockdown of Lbp using CRISPR-CAS9.

Results: We showed that the colonization status regulates gene expression in the liver and that a subset of these genes, including Lbp, is regulated through MYD88. Furthermore, we demonstrated that LBP impairs insulin signaling in hepatocytes in the presence of low levels of LPS and that the effect of LBP is abolished by LBPK95A. We showed that both systemic pharmacological blocking of LBP by LBPK95A and CRISPR-CAS9-mediated downregulation of hepatic Lbp improve glucose homeostasis.

Conclusions: Our results demonstrate that the gut microbiota regulates hepatic expression of Lbp through MYD88-dependent signaling. LBP potentiates LPS inhibition of insulin signaling in vitro and impairs systemic glucose homeostasis in vivo.
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http://dx.doi.org/10.1016/j.molmet.2020.100997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229497PMC
July 2020

From Association to Causality: the Role of the Gut Microbiota and Its Functional Products on Host Metabolism.

Mol Cell 2020 05 31;78(4):584-596. Epub 2020 Mar 31.

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden. Electronic address:

Many genomic studies have revealed associations between the gut microbiota composition and host metabolism. These observations led to the idea that a causal relationship could exist between the microbiota and metabolic diseases, a concept supported by studies showing compositional changes in the microbial community in metabolic diseases and transmissibility of host phenotype via microbiota transfer. Accumulating data suggest that the microbiota may affect host metabolic phenotypes through the production of metabolites. These bioactive microbial metabolites, sensitive fingerprints of microbial function, can act as inter-kingdom signaling messengers via penetration into host blood circulation and tissues. These fingerprints may be used for diagnostic purposes, and increased understanding of strain specificity in producing microbial metabolites can identify bacterial strains or specific metabolites that can be used for therapeutic purposes. Here, we will review data supporting the causal role of the gut microbiota in metabolism and discuss mechanisms and potential clinical implications.
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http://dx.doi.org/10.1016/j.molcel.2020.03.005DOI Listing
May 2020

L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling.

Diabetes 2020 04 10;69(4):614-623. Epub 2020 Feb 10.

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of and transcription factors and L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1-dependent and serotonin-mediated mechanism.
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http://dx.doi.org/10.2337/db19-0764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224989PMC
April 2020

Protein Turnover in Epithelial Cells and Mucus along the Gastrointestinal Tract Is Coordinated by the Spatial Location and Microbiota.

Cell Rep 2020 01 28;30(4):1077-1087.e3. Epub 2020 Jan 28.

Department of Medical Biochemistry, University of Gothenburg, 405 30 Gothenburg, Sweden. Electronic address:

The gastrointestinal tract is covered by a single layer of epithelial cells that, together with the mucus layers, protect the underlying tissue from microbial invasion. The epithelium has one of the highest turnover rates in the body. Using stable isotope labeling, high-resolution mass spectrometry, and computational analysis, we report a comprehensive dataset of the turnover of more than 3,000 and the expression of more than 5,000 intestinal epithelial cell proteins, analyzed under conventional and germ-free conditions across five different segments in mouse intestine. The median protein half-life is shorter in the small intestine than in the colon. Differences in protein turnover rates along the intestinal tract can be explained by distinct physiological and immune-related functions between the small and large intestine. An absence of microbiota results in an approximately 1 day longer protein half-life in germ-free animals.
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http://dx.doi.org/10.1016/j.celrep.2019.12.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996021PMC
January 2020

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

J Biol Chem 2020 01 10;295(4):969-980. Epub 2019 Dec 10.

Institute for Clinical Diabetology, German Diabetes Center, D-40225 Düsseldorf, Germany

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4) NOD mice. In 70-90-day-old normoglycemic (prediabetic) female NOD TLR4 and NOD TLR4 mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured and Compared with NOD TLR4 mice, NOD TLR4 animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance-related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.
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http://dx.doi.org/10.1074/jbc.RA119.010816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983849PMC
January 2020

Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health.

Gut 2020 07 14;69(7):1229-1238. Epub 2019 Oct 14.

The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Objective: The gut microbiota has been implicated in the aetiology of obesity and associated comorbidities. Patients with Prader-Willi syndrome (PWS) are obese but partly protected against insulin resistance. We hypothesised that the gut microbiota of PWS patients differs from that of non-genetically obese controls and correlate to metabolic health. Therefore, here we used PWS as a model to study the role of gut microbiota in the prevention of metabolic complications linked to obesity.

Design: We conducted a case-control study with 17 adult PWS patients and 17 obese subjects matched for body fat mass index, gender and age. The subjects were metabolically characterised and faecal microbiota was profiled by 16S ribosomal RNA gene sequencing. The patients' parents were used as a non-obese control group. Stool samples from two PWS patients and two obese controls were used for faecal microbiota transplantations in germ-free mice to examine the impact of the microbiota on glucose metabolism.

Results: The composition of the faecal microbiota in patients with PWS differed from that of obese controls, and was characterised by higher phylogenetic diversity and increased abundance of several taxa such as , and Archaea, and decreased abundance of . Microbial taxa prevalent in the PWS microbiota were associated with markers of insulin sensitivity. Improved insulin resistance of PWS was partly transmitted by faecal microbiota transplantations into germ-free mice.

Conclusion: The gut microbiota of PWS patients is similar to that of their non-obese parents and might play a role for the protection of PWS patients from metabolic complications.
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http://dx.doi.org/10.1136/gutjnl-2019-319322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306984PMC
July 2020

Obeticholic acid may increase the risk of gallstone formation in susceptible patients.

J Hepatol 2019 11 27;71(5):986-991. Epub 2019 Jun 27.

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address:

Background & Aims: The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has been developed for the treatment of liver diseases. We aimed to determine whether OCA treatment increases the risk of gallstone formation.

Methods: Twenty patients awaiting laparoscopic cholecystectomy were randomized to treatment with OCA (25 mg/day) or placebo for 3 weeks until the day before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7α-hydroxy-4-cholesten-3-one), and fibroblast growth factor 19 (FGF19) were measured before and after treatment. During surgery, biopsies from the liver and the whole bile-filled gallbladder were collected for analyses of gene expression, biliary lipids and FGF19.

Results: In serum, OCA increased FGF19 (from 95.0 ± 8.5 to 234.4 ± 35.6 ng/L) and decreased C4 (from 31.4 ± 22.8 to 2.8 ± 4.0 nmol/L) and endogenous BAs (from 1,312.2 ± 236.2 to 517.7 ± 178.9 nmol/L; all p <0.05). At surgery, BAs in gallbladder bile were lower in patients that received OCA than in controls (OCA, 77.9 ± 53.6 mmol/L; placebo, 196.4 ± 99.3 mmol/L; p <0.01), resulting in a higher cholesterol saturation index (OCA, 2.8 ± 1.1; placebo, 1.8 ± 0.8; p <0.05). In addition, hydrophobic OCA conjugates accounted for 13.6 ± 5.0% of gallbladder BAs after OCA treatment, resulting in a higher hydrophobicity index (OCA, 0.43 ± 0.09; placebo, 0.34 ± 0.07, p <0.05). Gallbladder FGF19 levels were 3-fold higher in OCA patients than in controls (OCA, 40.3 ± 16.5 ng/L; placebo, 13.5 ± 13.1 ng/ml; p <0.005). Gene expression analysis indicated that FGF19 mainly originated from the gallbladder epithelium.

Conclusions: Our results show for the first time an enrichment of FGF19 in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF19 might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk of gallstone development.

Lay Summary: Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary levels of fibroblast growth factor 19, our findings suggest that pharmacological activation of the farnesoid X receptor increases the risk of gallstone formation. Clinical trial number: NCT01625026.
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http://dx.doi.org/10.1016/j.jhep.2019.06.011DOI Listing
November 2019

Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time.

Gut 2020 03 30;69(3):502-512. Epub 2019 May 30.

Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Objective: Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.

Design: Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (H-glucose and H-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.

Results: We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.

Conclusion: Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.

Trial Registration Number: NTR4327.
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http://dx.doi.org/10.1136/gutjnl-2019-318320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034343PMC
March 2020

Intestinal Microbiota in Cardiovascular Health and Disease: JACC State-of-the-Art Review.

J Am Coll Cardiol 2019 04;73(16):2089-2105

Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Despite major strides in reducing cardiovascular disease (CVD) burden with modification of classic CVD risk factors, significant residual risks remain. Recent discoveries that linked intestinal microbiota and CVD have broadened our understanding of how dietary nutrients may affect cardiovascular health and disease. Although next-generation sequencing techniques can identify gut microbial community participants and provide insights into microbial composition shifts in response to physiological responses and dietary exposures, provisions of prebiotics or probiotics have yet to show therapeutic benefit for CVD. Our evolving understanding of intestinal microbiota-derived physiological modulators (e.g., short-chain fatty acids) and pathogenic mediators (e.g., trimethylamine N-oxide) of host disease susceptibility have created novel potential therapeutic opportunities for improved cardiovascular health. This review discusses the roles of human intestinal microbiota in normal physiology, their associations with CVD susceptibilities, and the potential of modulating intestinal microbiota composition and metabolism as a novel therapeutic target for CVD.
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http://dx.doi.org/10.1016/j.jacc.2019.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518422PMC
April 2019

Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS.

Cell Metab 2019 06 11;29(6):1400-1409.e5. Epub 2019 Apr 11.

The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity.
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http://dx.doi.org/10.1016/j.cmet.2019.03.010DOI Listing
June 2019

Shining light on microbial signaling to distant organs.

Authors:
Fredrik Bäckhed

Proc Natl Acad Sci U S A 2019 04 29;116(16):7617-7619. Epub 2019 Mar 29.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;

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http://dx.doi.org/10.1073/pnas.1902664116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475377PMC
April 2019

Simplified Intestinal Microbiota to Study Microbe-Diet-Host Interactions in a Mouse Model.

Cell Rep 2019 03;26(13):3772-3783.e6

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, 41345, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 2200, Denmark. Electronic address:

The gut microbiota can modulate human metabolism through interactions with macronutrients. However, microbiota-diet-host interactions are difficult to study because bacteria interact in complex food webs in concert with the host, and many of the bacteria are not yet characterized. To reduce the complexity, we colonize mice with a simplified intestinal microbiota (SIM) composed of ten sequenced strains isolated from the human gut with complementing pathways to metabolize dietary fibers. We feed the SIM mice one of three diets (chow [fiber rich], high-fat/high-sucrose, or zero-fat/high-sucrose diets [both low in fiber]) and investigate (1) how dietary fiber, saturated fat, and sucrose affect the abundance and transcriptome of the SIM community, (2) the effect of microbe-diet interactions on circulating metabolites, and (3) how microbiota-diet interactions affect host metabolism. Our SIM model can be used in future studies to help clarify how microbiota-diet interactions contribute to metabolic diseases.
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http://dx.doi.org/10.1016/j.celrep.2019.02.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444000PMC
March 2019

Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding.

Mol Metab 2019 05 9;23:82-87. Epub 2019 Mar 9.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research and Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 2200, Denmark. Electronic address:

Objectives: The nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic RORα by generating mice with liver-specific RORα deletion to elucidate the role of this nuclear receptor on host metabolism.

Methods: 8 week-old mice with liver-specific RORα deletion and littermate controls were fed either chow or western-style diets (40% fat, 40% carbohydrate) for 12 weeks. Metabolic phenotyping was performed at the end of the dietary intervention.

Results: Here, we show that hepatic RORα deletion does not affect the metabolic susceptibility to either chow or western-style diet in terms of glucose metabolism and adiposity.

Conclusions: Our data indicate that liver deletion of RORα does not have a pivotal role in the regulation of hepatic glucose and lipid metabolism on chow or western-style diet.
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http://dx.doi.org/10.1016/j.molmet.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479759PMC
May 2019

The next decade of metabolism.

Nat Metab 2019 01;1(1):2-4

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.

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http://dx.doi.org/10.1038/s42255-018-0022-7DOI Listing
January 2019

Microbial fermentation of flaxseed fibers modulates the transcriptome of GPR41-expressing enteroendocrine cells and protects mice against diet-induced obesity.

Am J Physiol Endocrinol Metab 2019 03 18;316(3):E453-E463. Epub 2018 Dec 18.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg , Gothenburg , Sweden.

Dietary fibers, an integral part of the human diet, require the enzymatic activity of the gut microbiota for complete metabolism into short-chain fatty acids (SCFAs). SCFAs are important modulators of host metabolism and physiology and act in part as signaling molecules by activating G protein-coupled receptors (GPCRs), such as GPR41. Flaxseed fibers improve metabolism in rodents and mice, but their fermentation profiles, effects on enteroendocrine cells, and associated metabolic benefits are unknown. We fed GPR41-red fluorescent protein mice, an enteroendocrine reporter mouse strain, chow, high-fat diet (HFD), or HFD supplemented either with 10% nonfermentable fiber cellulose or fermentable flaxseed fibers for 12 wk to assess changes in cecal gut microbiota, enteroendocrine cell transcriptome in the ileum and colon, and physiological parameters. We observed that flaxseed fibers restructured the gut microbiota and promoted proliferation of the genera Bifidobacterium and Akkermansia compared with HFD. The shifts in cecal bacterial composition restored levels of the SCFAs butyrate similar to the chow diet, resulting in colonic but not ileal enteroendocrine cell transcriptional changes in genes related to cell cycle, mRNA, and protein transport compared with HFD. Consistent with the effects on enteroendocrine functions, flaxseed fibers also protected mice from diet-induced obesity, potentially by preventing a reduction in energy expenditure induced by an HFD. Our study shows that flaxseed fibers alter cecal microbial ecology, are fermented to SCFAs in the cecum, and modulate enteroendocrine cell transcriptome in the colon, which may contribute to their metabolically favorable phenotype.
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http://dx.doi.org/10.1152/ajpendo.00391.2018DOI Listing
March 2019

23, 22 Calling the Microbiota to Control Atherosclerosis.

Immunity 2018 11;49(5):788-790

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

While the commensal microbiota is considered an important regulator of immunity and metabolism, the mechanisms controlling the interplay between diet, cytokine signaling, and the microbiota in atherosclerosis remains unknown. In this issue of Immunity, Fatkhullina et al. (2018) demonstrate that interlukin-23-22 axis regulates diet-induced atherosclerosis by repressing pro-atherogenic microbiota.
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http://dx.doi.org/10.1016/j.immuni.2018.11.006DOI Listing
November 2018

Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1.

Cell 2018 11 25;175(4):947-961.e17. Epub 2018 Oct 25.

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1016/j.cell.2018.09.055DOI Listing
November 2018