Food Matters Live, Nov 21-23 rd, London Exploring the link between gut microbiota and metabolic health Ellen Blaak Professor in Physiology of fat metabolism, Department of Human Biology NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Medical Centre + The Netherlands
Overview Modulation of microbiota and metabolic health: feces transplantation and antibiotics Role of SCFA and metabolic health: Colonic SCFA administration Intervention with prebiotics-dietary fibers Department of Human Biology
Microbiota, obesity and type 2 diabetes mellitus Worldwide, obesity is reaching epidemic proportions The obesity pandemic is not fully explained by most common gene-environment interactions Gut microbiota provide additional gene products that may affect host metabolism, gut physiology, body weight control and insulin sensitivity through several mechanisms Obesity and Type 2 diabetes mellitus are associated with differential composition of gut microbiota and/or gut microbiome Interventions to manipulate gut-microbiota may favorably affect metabolism and reduce diabesity risk Department of Human Biology
Obesity pandemic of 21 st century Department
Obesity: an important risk factor for chronic metabolic diseases OBESITY Cardiovascular disease Type 2 diabetes Liver steatosis Cancer Department of Human Biology
Feces transplantation from mice to mice Department of Human Biology
From mice to mice: Gut Flora contributes to the high-fat induced metabolic diseases in mice (Bäckhed et al, 2004, 2007) Germ-free mice are protected from development of insulin resistance and glucose intolerance Department of Human Biology
From man to mice: Gut microbiota from twins discordant for obesity modulate metabolism in mice V K Ridaura et al. Science 2013;341:1241214 Department of Human Biology
From man to man: feces transplantation and human metabolism Department of Human Biology
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Transferring microbiota between conventional and germ free rodents, humans and rodents and humans and humans have shown the role of intestinal microbiota in the development of obesity and insulin resistance Department of Human Biology
Department of Human Biology
Antibiotics intervention Treatment Placebo Amoxicillin Vancomycin 1500 mg/day 7 days 40-70y IFG/IGT HOMA-IR>2.2 n=56 Timing wk 1 pre wk 2 2d wash out wk 3 post wk 8 followup Department of Human Biology Reijnders et al, Cell metabolism, 2016
Distinct changes in microbiota composition Microbiota composition Vanco: Increased gram negative Proteobacteria less grampositive bacteria decreased diversity After 8 weeks similarity with baseline still lower, diversity slightly lower Amox: no diversity and/or composition differences Department of Human Biology Reijnders et al, Cell metabolism, 2016
No effect on insulin sensitivity Two-step hyperinsulinemic-euglycemic clamp Endogenous Glucose Production Rate of Disappearance No effect on whole body insulin resistance Suppression of Free Fatty Acids 8 wk after stopping the active intervention % Department of Human Biology Reijnders et al, Cell metabolism, 2016
Department of Human Biology Reijnders et al, Cell metabolism, 2016
Perspectives Modulation of adult microbiota by 7-day antibiotics does not affect host metabolism Host metabolism remained unchanged at 8-week follow-up, despite deviant microbiota Contradicts many rodents studies! More frequent antibiotic use, long term diet effects? Department of Human Biology
Function of micrbiota: site of fermentation transverse colon: combination of saccharolytic and proteolytic fermentation proximal colon: primarily saccharolytic fermentation distal colon: primarily proteolytic fermentation Department of Human Biology
Major SCFA Acetate Propionate Butyrate Department of Human Biology
Functionality of microbiota: SCFA Canfora, E. E. et al. (2015) Short-chain fatty acids in control of body weight and insulin sensitivity Nature Reviews Endocrinology doi:10.1038/nrendo.2015.128 Department of Human Biology
Colonic acetate infusion and metabolic profile Hypothesis:Colonic administration of SCFA has beneficial effects on human substrate and energy metabolism Question: Where to administer? Distal / Proximal? Department of Human Biology
Aim: Distal and proximal colonic acetate infusion and metabolic profile To investigate differential effects of proximal and distal colonic infusions with sodium acetate on human fat oxidation, energy expenditure and circulating metabolic markers Study design Double blind, placebo controlled, randomized crossover study Six healthy overweight males (BMI 25 34.9 kg/m 2 ) Aged 20 50 years; Weight stable for at least 3 months (± 2 kg) No use of antibiotics, pre- or probiotics Intervention 1. Sodium acetate 100mmol/L (12mmol in 120mL water) 2. Sodium acetate 180mmol/L (21.6mmol in 120mL water) 3. Placebo (0.9% NaCl) in 120mL Department of Human Biology Van der Beek et al, Clin Sci 2017
Intervention protocol Department of Human Biology Van der Beek et al, Clin Sci 2017
Test day protocol! Figure 3. Test day Department of Human Biology Van der Beek et al, Clin Sci 2017
Fat oxidation (g fat 2h -1 ) Fat oxidation 3 2 iauc, distal p=0.055 * 1 break 0-1 -2 Placebo 100 mmol/l 180 mmol/l placebo 100mmol/L 180mmol/L break ANOVA * p<0.05 placebo vs 180mM Ingestion oral glucose solution Department of Human Biology Van der Beek et al, Clin Sci 2017
Distal, not proximal, colonic acetate infusion improves metabolic profile No significant effects Circulating acetate Fat oxidation PYY TNF-α Lipolysis Increasing colonic and systemic acetate beneficially affect the metabolic profile Validated distal colonic infusion as a good model to study SCFA effects on metabolism Department of Human Biology Van der Beek et al, Clin Sci 2017
Combinations of SCFA and metabolic profile To investigate acute effects of distal colonic infusions of SCFA combinations on substrate and energy metabolism Department of Human Biology Canfora et al, Scientific reports, 2017
% SCFA/NaCl in solutions Intervention protocol (1) Double blind, placebo controlled, randomized crossover study with 4 distal infusions: 100 Placebo: 40mmol NaCl 80 High sodium acetate (60:20:20): 24mmol NaAc, 8mmol NaBu, 8mmol NaPr High sodium butyrate (45:35:20): 18mmol NaAc, 14mmol NaBu, 8mmol NaPr 60 40 20 sodium chloride sodium propionate sodium butyrate sodium acetate High sodium propionate (45:20:35): 18mmol Na Ac, 8mmol NaBu, 14mmol NaPr 0 60:20:20 45:35:20 45:35:20 45:20:35 Placebo All diluted in 200mL water Department of Human Biology Canfora et al, Scientific reports, 2017
SCFA increase Fat oxidation *** *** p<0.001, ** p<0.01 Ingestion oral glucose Department of Human Biology Canfora et al, Scientific reports, 2017
iauc EE kj/t0-t120 SCFA increase Energy Expenditure * iauc energy expenditure, fasted 40 * *** # 20 0 *** p<0.001, * p<0.05, # p<0.1 Ingestion oral glucose solution placebo high acetate high propionate high butyrate Department of Human Biology Canfora et al, Scientific reports, 2017
Acetate maybe a target to prevent and treat obesityrelated co-morbidities Fat oxidation Energy Expenditure PYY IL-1β lipolysis What are the underlying mechanisms? Department of Human Biology Canfora et al, Scientific reports, 2017
Why do we hypothesize that the distal colon should be targeted? Higher density of PYY-producing L-cells in the distal colon Kuwahara (2014), Frontiers in Endocrinology Department
Increased fat oxidation and EE only after distal administration: Acetate bypass the liver circulating acetate uptake in oxidative tissues pampk fat oxidation Acetate pampk fat oxidation 1,2,3 Circulating Acetate Acetate pampk fat oxidation 1,2,4 1 Sakakibara et al., 2006; 2 Yamashita et al., 2009; 3 Kimura et al., 2013; 4 den Besten et al., 2015 Department of Human Biology
Fermentation of fibers by the gut microbiota proximal versus distal fermented distally Which fibers are best? Canfora, et al. (2017), Scientific Reports;7(1):2360 Department of Human Biology
In Summary Feces transplantation studies do show a role of microbiota in weight gain and insulin resistance, effects in humans are relatively minor Modulation of microbiota by means of antibiotics did not affect metabolic health after 7 days and in the longer term SCFA may be an important link between gut microbiota and metabolic health Distal, but not proximal, acetate infusion may improve fat oxidation and metabolic profile Rectal infusion of SCFA combinations all increase fat oxidation, energy expenditure and metabolic profile Dietary fiber intervention focussed on targeted production of SCFA may improve intervention outcome with respect to metabolic profile, but this requires further confirmation Department of Human Biology
Collaborations/Acknowledgements Gijs Goossens Johan Jocken Birgitta van der Kolk Dorien Reijnders Emanuel Canfora Rudi Stinkens Max Vogel Jasper Most Mattea Müller Kenneth Verboven Yvonne Essers Nicole Hoebers Dept Human Biology, MUMC And external Collaborations Top Institute Food and Nutrition (project GH003, microbiota, energy balance and metabolism) EU consortia: EU-Lipgene, MIRdiet, EDIPS, Diogenes Department
Future Directions.. Department