Research Center in Human Nutrition - Rhône-Alpes

European public funding

Sponsorship: Hospices Civils de Lyon

Purpose: The aim of this pilot study was to analyze concomitantly the kinetics of production of 13C-labeled gut-derived metabolites from 13C-labeled wheat bran in three biological matrices (breath, plasma, stools), in order to assess differential fermentation profiles among subjects.

Methods: Six healthy women in their thirties, with normal weight status and above-average daily fiber intake but below national dietary recommendations, consumed a controlled breakfast containing 13C-labeled wheat bran biscuits. H2, CH4 and 13CO2, 13CH4 24 h-concentrations in breath were measured, respectively, by gas chromatography (GC) and GC-isotope ratio mass spectrometry (GC-IRMS). Plasma and fecal concentrations of 13C-short-chain fatty acids (linear SCFAs: acetate, propionate, butyrate, valerate; branched SCFAs: isobutyrate, isovalerate) were quantified using GC-combustion-IRMS. Gut microbiota composition was assessed by16S rRNA gene sequencing analysis.

Results: H2 and CH4 24 h-kinetics distinguished two groups in terms of fermentation-related gas excretion: high-CH4 producers vs low-CH4 producers (fasting concentrations: 45.3 ± 13.6 ppm vs 6.5 ± 3.6 ppm). Expired 13CH4 was enhanced and prolonged in high-CH4 producers compared to low-CH4 producers. The proportion of plasma and stool 13C-butyrate tended to be higher in low-CH4 producers, and inversely for 13C-acetate. Plasma branched SCFAs revealed different kinetics of apparition compared to linear SCFAs.

Conclusion: This pilot study allowed to consider novel procedures for the development of biomarkers revealing dietary fiber-gut microbiota interactions. The non-invasive assessment of exhaled gas following 13C-labeled fibers ingestion enabled to decipher distinct fermentation profiles: high-CH4 producers vs low-CH4 producers. The isotope labeling permits a specific in vivo characterisation of the dietary fiber impact consumption on microbiota metabolite production.

Scientific valorisation :

Publishing: Meiller, L., Sauvinet, V., Breyton, AE. et al. Metabolic signature of 13C-labeled wheat bran consumption related to gut fermentation in humans: a pilot study. Eur J Nutr 62, 2633–2648 (2023). doi : 10.1007/s00394-023-03161-5

Congress: results presentation during journée francophones de la nutrition in 2019 (oral communication) and in 2020 (poster)

Public funding

Sponsorship: Insel hospital (Bern)

Purpose: Post-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals.

Methods: In this case–control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia.

Results: The rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period. During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group. Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group. Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups.

Conclusion: The glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia.

Scientific valorisation :

Publishing: Tripyla, A., Herzig, D., Reverter-Branchat, G. et al. Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals. Diabetologia 66, 741–753 (2023). https://doi.org/10.1007/s00125-022-05861-9

Congress: results presentation in American Diabetes Association in 2022 (oral communication).

Private funding (industrial)

Sponsorship : Bridor

Purpose: The aim of the study was to assess the impact on gut microbiota composition and functions as well as on cardiometabolic profile of two months ingestion of bread enriched with a pre-selected fiber blend compared with standard bread in subjects at cardiometabolic risk.

Methods: About forty subjects (18-70 years old) at cardiometabolic risk were included in a randomized, cross-over, twice 8-week study, and consumed daily 150 g of standard bread or enriched with a 7-dietary fiber mixture. Before and after intervention, stool samples were collected for gut microbiota analysis, and cardiometabolic profile was assessed.

Results: Multi-fiber bread consumption have not altered microbiota diversity but has significantly modified microbiota composition. Compared to control bread, multi-fiber bread decreased total cholesterol, LDL-cholesterol, and improved insulin sensibility estimated by HOMA. The effects of the intervention were greatest in people with the highest waist circumferences.

Conclusion: Consumption of bread enriched with selected fibers altered the composition and abundance of the intestinal microbiota and improved certain metabolic parameters. Thus, we can hypothesize that increasing fiber quantity and diversity could be relevant for preventing cardiometabolic risks.

Scientific valorisation:

Publishing: Ranaivo H, Thirion F, Béra-Maillet C, Guilly S, Simon C, Sothier M, Van Den Berghe L, Feugier-Favier N, Lambert-Porcheron S, Dussous I, Roger L, Roume H, Galleron N, Pons N, Le Chatelier E, Ehrlich SD, Laville M, Doré J, Nazare JA. Increasing the diversity of dietary fibers in a daily-consumed bread modifies gut microbiota and metabolic profile in subjects at cardiometabolic risk. Gut Microbes. 2022 Jan-Dec;14(1):2044722. doi: 10.1080/19490976.2022.2044722.

Aubin A, Hornero-Ramirez H, Ranaivo H, Simon C, Van Den Berghe L, Favier NF, Dussous I, Roger L, Laville M, Béra-Maillet C, Doré J, Caussy C, Nazare JA. Assessing metabolic flexibility response to a multifibre diet: a randomised-controlled trial. J Hum Nutr Diet. 2024 Oct;37(5):1186-1196. doi: 10.1111/jhn.13350. Epub 2024 Aug 13. PMID: 39138876.

Public funding

Sponsorship: Hospices Civils de Lyon

Purpose: Various types of dietary polyphenols, bioactive compounds derived from plants, have been shown to have protective metabolic effects in rodents. They could also help to improve lipid profiles and thus reduce cardiometabolic risk in humans. The aim of the project was therefore to determine whether dietary supplementation with polyphenols extracted from grapes could limit the deleterious metabolic effects of lipid- and sucrose-rich overnutrition in healthy humans, on hepatic and lipoprotein metabolism.

Methods: A randomized placebo-controlled double-blind paralleled trials on 42 men with BMI comprised between 23 and 27 kg/m2 were designed to test 2 g/day of a grape polyphenol extract during 39 days of high calorie-high frutose overfeeding (+50% of daily caloric need during 31 days) with food as snacks. Before and after intervention, anthropometrics, cardiometabolic profile, inflammatory parameters, stool sample for gut microbiota analysis, body and liver composition, insulin sensitivity (clamps) and postprandial lipid metabolism using a test meal containing 13C-labelled triglycerides to monitor the fate of ingested lipids postprandially were assessed.

Results: After 1 month of overfeeding, bodyweight, fat mass and liver fat increased. While whole body insulin sensitivity did not change, homeostasis model assessment of insulin resistance (HOMA-IR) and the hepatic insulin resistance index (HIR) increased during overfeeding. Moreover, overfeeding has induced change in 163 genes expression in placebo group versus 352 genes in group with polyphenol supplementation. Genes were principally involved in lipids metabolism and adipose tissue remodelling. Immunhistochemistry and gene expression data confirmed the reduction in angiogenesis in the group with polyphenol supplementation.

Conclusion: This first clinical trial evaluating the effects of grape polyphenol supplementation did not counteract the moderated metabolic alterations and anthropometric parameters induced by 1-month of overfeeding. Moreover, this supplementation did not prevent the modulation of genes related to lipid metabolism induced by overfeeding, but did have an impact on angiogenesis mechanisms.

Scientific valorisation:

Publishing: Segrestin B, Delage P, Nemeth A, Seyssel K, Disse E, Nazare J-A, Lambert-Porcheron S, Meiller L, Sauvinet V, Chanon S, Simon C, Ratiney H, Beuf O, Pralong F, Naba-al-Huda Y, Boizot A, Gachet M Burton-Pimentel K-J, Vidal H, Meugnier E, Vionnet N et Laville M. Polyphenol Supplementation did not affect insulin sensitivity and fat deposition during one-month overfeeding in randomized placebo-controlled trials in men and in women Front. Nutr. Volume 9 – 2022 | https://doi.org/10.3389/fnut.2022.854255

Delage P, Ségrestin B, Seyssel K, Chanon S, Vieille-Marchiset A, Durand A, Nemeth A, Métairon S, Charpagne A, Descombes P, Hager J, Laville M, Vidal H, Meugnier E. Adipose tissue angiogenesis genes are down-regulated by grape polyphenols supplementation during a human overfeeding trial. J Nutr Biochem. 2023 Jul;117:109334. doi: 10.1016/j.jnutbio.2023.109334. Epub 2023 Mar 24. PMID: 36965784.

Congress: Oral communication during JFN, 2021

Poster presentation during SFD, 2022 and International Conference on Polyphenols and Health- Londres (GB) (best poster price for clinical trials category)

European public finding

Sponsorship: Hospices Civils de Lyon

Purpose: Chitin-glucan (CG), an insoluble dietary fiber, has been shown to improve cardiometabolic disorders associated with obesity in mice. When consumed, these fibers can serve as a substrate for microbiota to produce gut-derived metabolites such as short-chain fatty acids, which in turn can play a role in improving glycaemic and lipid parameters. This study aimed at investigate the impacts of CG on the cardiometabolic profile and gut microbiota composition and functions in 15 subjects at cardiometabolic risk.

Methods: A double blind, randomized, crossover exploratory study with twice 3-week sequences of dietary supplements (4.5g of CG daily versus 4.5g of maltodextrin as control) and a 4-week wash-out period in 15 subjects at cardiometabolic risk. Before and after both interventions, fasting and postprandial metabolic parameters using a test meal, named FlexMeal (rich in glucose and lipids), exhaled gases (hydrogen and methane), gut microbiota composition, fecal concentrations of bile acids, long- and short-chain fatty acids, zonulin, calprotectin, and lipopolysaccharide binding protein (LBP) were analysed and compared.

Results: Compared to control, CG supplementation in subjects at cardiometabolic risk modified gut microbiota composition, in particular the abundance of certain species. CG supplementation increased exhaled H2 following an enriched-fiber breakfast ingestion, suggesting that CG induce more fermentation after a rich fiber diet. These changes were accompanied by significant improvements in glucose profiles only in high H2 producers (according to the lactulose test) and in postprandial lipids (reduction in incremental curve air and triglyceride peak following a FlexMeal).

Conclusion: This study demonstrated benefices of 3-week CG supplementation for health of cardiometabolic risk subjects. Our results also suggested breath H2 production as a non-invasive parameter of interest for predicting the effectiveness of dietary fiber intervention.

Scientific valorisation:

Publishing: Ranaivo H, Zhang Z, Alligier M, Van Den Berghe L, Sothier M, Lambert-Porcheron S, Feugier N, Cuerq C, Machon C, Neyrinck AM, Seethaler B, Rodriguez J, Roumain M, Muccioli GG, Maquet V, Laville M, Bischoff SC, Walter J, Delzenne NM, Nazare JA. Chitin-glucan supplementation improved postprandial metabolism and altered gut microbiota in subjects at cardiometabolic risk in a randomized trial. Sci Rep. 2022 May 25;12(1):8830. doi: 10.1038/s41598-022-12920-z.

Private funding (industrial)

Sponsorship: Mondelez

Purpose: Carbohydrates, especially starch plays a crucial role in the management of glycaemia because carbohydrates represents the main source of daily caloric consumption and they have an impact on glycaemia. Starch can be categorized in several types, including slowly digestible starch which causes slower release and absorption of glucose in blood, results in a significant reduction of the glycaemic variations. Short-term fluctuations in blood glucose concentrations may be detectable using Continuous Glucose Monitoring System (CGMS) and they have been correlated with cardiovascular complications of diabetes. The aim of this study was to determine whether modulating carbohydrates digestibility of the whole diet, by increasing the Slowly Digestible Starch (SDS) content in T2D patients, could reduce glycemic variability and postprandial hyperglycemia, as measured by CGMS, in comparison to a conventional diet containing a low SDS content. The aim is to be able to provide simple dietary and culinary advice to these patients in order to improve their glycaemic variability and profile.

Before proposing a large-scale clinical trial, we set up a pilot study. Whose main objective was to assess the ability of CGMS to discriminate differences in glycaemic profiles over the day according to whether people are following a diet rich in slowly digestible starch or, on the contrary, low in starch in the short term in type 2 diabetic patients.

Methods: For this randomized double blind, cross-over pilot study, 8 subjects with T2D consumed a controlled diet for one week, containing starchy products high or low in SDS. The order between the two diets was randomly assigned to each volunteer, and the two diets periods were separated by a two-week wash-out period. A CGMS was fitted at the start of each week of intervention, recording glycaemia over the week and providing a blood glucose profile.

Results: In the pilot study, we observed favourable and significant changes in glycaemic profile (reduction of glycaemic variability and postprandial excursions) thanks to CGMS and following one week of a diet rich in slowly digestible starch compared with poor diet. Further investigations are needed to confirm this effect on a larger scale and avec the long term, and to better understand the impact of this intervention on the biomarkers and comorbidities of T2D.

Conclusion: Following the results of the pilot study, a randomized, single blind, two-arm parallel-controlled clinical trial was carried out on 51 patients who consumed either a slowly digestible starch-rich diet or a slowly digestible starch-low control diet for 12 weeks, depending on their arm. CGMS were used to assess numerous parameters of glycemic variability. Metabolic, cardiovascular and inflammatory parameters were also collected before and at the end of the trial, both fasting and postprandially following a Flexmeal (a meal very rich in sugars and lipids). The results of the trial are currently being analyzed and will be published shortly.

Scientific valorisation:

Publishing: Breyton A-E, Goux A, Lambert-Porcheron S, Meynier A, Sothier M, VanDen Berghe L, Brack O, Disse E, Laville M, Vinoy S, Nazare J-A. Starch digestibility modulation significantly improves glycemic variability in type2 diabetic subjects : A pilot study. J.numecd. 2021 Jan 4;31 (1). doi: 10.1016/j.numecd.2020.08.010

Breyton A-E, Lambert-Porcheron S, Laville M, Vinoy S, Nazare J-A. CGMS and glycemic variability, relevance in Clinical Research to Evaluate Intervention in T2D, a Literature Review. Frontier in Endocrinology. 2021; 12. doi : 10.3389/fendo.2021.666008

Goux A, Breyton A-E, Meynier A, Lambert-Porcheron S, Sothier M, Van Den Berghe L, et al. Design and Validation of a Diet Rich in Slowly Digestible Starch for Type 2 Diabetic Patients for Significant Improvement in Glycemic Profile. Nutrients 2020;12:2404. https://doi.org/10.3390/nu12082404.

Public funding

Sponsorship: Hospices Civils de Lyon (HCL)

Purpose: Strong interactions betwee certain components of diet and the gut have recently been identified as a key determinant of their immune-modulatory effects, thus constituting a preferred intervention tool to modulate low-grade inflammation and cardiometabolic risk associated. The SINFONI project proposes an innovative approach by combaning different bioactive dietary concept to modulate chronic inflammation and cardiometabolic risk.

Methods: We designed a cereal-based product enriched with polyphenols (with procyanidines from canneberg), fibers, omega-3 and slowly digestible starch. A crossover trial involving 30 subjects with metabolic risk, where participants consumed during 2 months this enriched cereal-based product compared to 2 months consumption of a standard cereal-based product. Following the intervention, there was a week of supplementation with fructose. Inflammatory profile and markers of cardio metabolic risk were assessed both in the fasted and postprandial states after high-carbohydrate and high-fat meal. Microbiota composition and plasma metabolome were also assessed.

Results: Validation of a dietary matrix containing selected bioactive elements within a cereal-based product with a favourable impact on glycemic and insulinemic responses was a first result of the SINFONI project. The clinical trial highlighted that compared to control, two-months of enriched cereal-based product consumption reduced intestinal inflammation (calprotectine) without alteration of systemic inflammation. We also noted a tendency to reduce endotoxemia, an increase in the abundance of 5 beneficial species of gut microbiota and a decrease in the concentration of serum branched-chain amino acids. Cardiometabolic markers remained unchanged, with the exception of a trand towards reduced adipo-IR.

Conclusion: Ours results highlighted that a 2-month dietary intervention combining multiple bioactive compound could improve intestinal health and inflammatory and cardiometabolic markers.

Scientific valorisation:

Publishing: Horner-Ramirez H, Morisette A, Marcotte B, and all. (2024) Multifunctional dietary approach reduces intestinal inflammation in relation with changes in gut microbiota composition in subjects at cardiometabolic risk: the SINFONI project. Gut Microbes, in press

Hornero-Ramirez H, Aubin A, Michalski MC, Vinoy S, Caussy C and Nazare JA (2024) Multifunctional dietary interventions, low-grade inflammation and cardiometabolic profile: a scoping review. Front. Immunol. 15:1304686. doi: 10.3389/fimmu.2024.1304686

Demangeat, A.; Hornero-Ramirez, H.; Meynier, A.; Sanoner, P.; Atkinson, F.S.; Nazare, J.-A.; Vinoy, S. Complementary Nutritional Improvements of Cereal-Based Products to Reduce Postprandial Glycemic Response. Nutrients 2023, 15, 4401. https://doi.org/10.3390/nu15204401