Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity
Abstract Background Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-06-01
|
| Series: | Microbiome |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40168-022-01264-5 |
| _version_ | 1811334629744967680 |
|---|---|
| author | Julia Münzker Nadine Haase Andreas Till Robert Sucher Sven-Bastiaan Haange Linda Nemetschke Thorsten Gnad Elisabeth Jäger Jiesi Chen Sjaak J. Riede Rima Chakaroun Lucas Massier Peter Kovacs Mario Ost Ulrike Rolle-Kampczyk Nico Jehmlich Juliane Weiner John T. Heiker Nora Klöting Gudrun Seeger Markus Morawski Verena Keitel Alexander Pfeifer Martin von Bergen Joerg Heeren Ute Krügel Wiebke K. Fenske |
| author_facet | Julia Münzker Nadine Haase Andreas Till Robert Sucher Sven-Bastiaan Haange Linda Nemetschke Thorsten Gnad Elisabeth Jäger Jiesi Chen Sjaak J. Riede Rima Chakaroun Lucas Massier Peter Kovacs Mario Ost Ulrike Rolle-Kampczyk Nico Jehmlich Juliane Weiner John T. Heiker Nora Klöting Gudrun Seeger Markus Morawski Verena Keitel Alexander Pfeifer Martin von Bergen Joerg Heeren Ute Krügel Wiebke K. Fenske |
| author_sort | Julia Münzker |
| collection | DOAJ |
| description | Abstract Background Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear. Methods To evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery. Results In this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis. Conclusion Our results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome. Video Abstract Graphical abstract Bariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue. |
| first_indexed | 2024-04-13T17:11:53Z |
| format | Article |
| id | doaj.art-6a766a44ecdc4c6c87577142da2ab281 |
| institution | Directory Open Access Journal |
| issn | 2049-2618 |
| language | English |
| last_indexed | 2024-04-13T17:11:53Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj.art-6a766a44ecdc4c6c87577142da2ab2812022-12-22T02:38:16ZengBMCMicrobiome2049-26182022-06-0110112010.1186/s40168-022-01264-5Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesityJulia Münzker0Nadine Haase1Andreas Till2Robert Sucher3Sven-Bastiaan Haange4Linda Nemetschke5Thorsten Gnad6Elisabeth Jäger7Jiesi Chen8Sjaak J. Riede9Rima Chakaroun10Lucas Massier11Peter Kovacs12Mario Ost13Ulrike Rolle-Kampczyk14Nico Jehmlich15Juliane Weiner16John T. Heiker17Nora Klöting18Gudrun Seeger19Markus Morawski20Verena Keitel21Alexander Pfeifer22Martin von Bergen23Joerg Heeren24Ute Krügel25Wiebke K. Fenske26Medical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigDepartment of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Medical Center BonnDepartment of Visceral-, Transplant-, Thoracic- and Vascular Surgery, University of LeipzigDepartment of Molecular Systems Biology, Helmholtz Centre for Environmental Research Leipzig–UFZMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigInstitute of Pharmacology and Toxicology, University Hospital, University of BonnMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigDepartment of Neuropathology, University of LeipzigDepartment of Molecular Systems Biology, Helmholtz Centre for Environmental Research Leipzig–UFZDepartment of Molecular Systems Biology, Helmholtz Centre for Environmental Research Leipzig–UFZMedical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of LeipzigHelmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital LeipzigHelmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital LeipzigPaul Flechsig Institute of Brain Research, Faculty of Medicine, University of LeipzigPaul Flechsig Institute of Brain Research, Faculty of Medicine, University of LeipzigClinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-UniversityInstitute of Pharmacology and Toxicology, University Hospital, University of BonnDepartment of Molecular Systems Biology, Helmholtz Centre for Environmental Research Leipzig–UFZDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-EppendorfRudolf Boehm Institute of Pharmacology and Toxicology, University of LeipzigDepartment of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Medical Center BonnAbstract Background Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear. Methods To evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery. Results In this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis. Conclusion Our results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome. Video Abstract Graphical abstract Bariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue.https://doi.org/10.1186/s40168-022-01264-5Gastric bypassGut microbiotaFXRTGR5Bile acidsTaurine metabolism |
| spellingShingle | Julia Münzker Nadine Haase Andreas Till Robert Sucher Sven-Bastiaan Haange Linda Nemetschke Thorsten Gnad Elisabeth Jäger Jiesi Chen Sjaak J. Riede Rima Chakaroun Lucas Massier Peter Kovacs Mario Ost Ulrike Rolle-Kampczyk Nico Jehmlich Juliane Weiner John T. Heiker Nora Klöting Gudrun Seeger Markus Morawski Verena Keitel Alexander Pfeifer Martin von Bergen Joerg Heeren Ute Krügel Wiebke K. Fenske Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity Microbiome Gastric bypass Gut microbiota FXR TGR5 Bile acids Taurine metabolism |
| title | Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity |
| title_full | Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity |
| title_fullStr | Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity |
| title_full_unstemmed | Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity |
| title_short | Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity |
| title_sort | functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal fxr tgr5 crosstalk in diet induced obesity |
| topic | Gastric bypass Gut microbiota FXR TGR5 Bile acids Taurine metabolism |
| url | https://doi.org/10.1186/s40168-022-01264-5 |
| work_keys_str_mv | AT juliamunzker functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT nadinehaase functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT andreastill functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT robertsucher functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT svenbastiaanhaange functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT lindanemetschke functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT thorstengnad functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT elisabethjager functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT jiesichen functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT sjaakjriede functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT rimachakaroun functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT lucasmassier functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT peterkovacs functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT marioost functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT ulrikerollekampczyk functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT nicojehmlich functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT julianeweiner functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT johntheiker functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT norakloting functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT gudrunseeger functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT markusmorawski functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT verenakeitel functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT alexanderpfeifer functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT martinvonbergen functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT joergheeren functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT utekrugel functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity AT wiebkekfenske functionalchangesofthegastricbypassmicrobiotareactivatethermogenicadiposetissueandsystemicglucosecontrolviaintestinalfxrtgr5crosstalkindietinducedobesity |