Camu-Camu Reduces Obesity and Improves Diabetic Profiles of Obese and Diabetic Mice : A Dose-Ranging Study

Overweight, obesity, and their comorbidities are currently considered a major public health concern. Today considerable efforts are still needed to develop efficient strategies able to attenuate the burden of these diseases. Nutritional interventions, some with plant extracts, present promising health benefits. In this study, we evaluated the action of Camu-Camu (Myrciaria dubia), an Amazonian fruit rich in polyphenols and vitamin C, on the prevention of obesity and associated disorders in mice and the abundance of Akkermansia muciniphila in both cecum and feces. Methods: We investigated the dose-response effects of Camu-Camu extract (CCE) in the context of high-fat-diet (HFD)-induced obesity. After 5 weeks of supplementation, we demonstrated that the two doses of CCE differently improved glucose and lipid homeostasis. The lowest CCE dose (62.5 mg/kg) preferentially decreased non-HDL cholesterol and free fatty acids (FFA) and increased the abundance of A. muciniphila without affecting liver metabolism, while only the highest dose of CCE (200 mg/kg) prevented excessive body weight gain, fat mass gain, and hepatic steatosis. Both doses decreased fasting hyperglycemia induced by HFD. In conclusion, the use of plant extracts, and particularly CCE, may represent an additional option in the support of weight management strategies and glucose homeostasis alteration by mechanisms likely independent from the modulation of A. muciniphila abundance.Peer reviewe

Découverte de nouvelles entérosynes ciblant le système nerveux entérique, par des approches nutritionnelles : impact sur le métabolisme glucidique

The gut-brain axis is one of the first systems of communication altered during type 2 diabetes. Data from our team demonstrate that the chemo-sensing of enteric glucose generates an afferent signal, modifying the hypothalamic activity and so the glucose utilization. We then show that this regulatory loop is altered in obese/diabetic mice, concomitantly with intestinal changes (microbiota, incretin release) and hypothalamic nitric oxide (NO) release. We developed a new concept since changes in the mechanical activity of intestinal smooth muscle cells, under the influence of enteric nervous system (ENS) neurons, can have a major impact on glycemia. We also found that intestinal hyper-contractility 1) is associated with an increased glucose uptake, and 2) generates an afferent signal that informs the brain to block glucose entry into muscle. Modification of ENS/smooth muscle cells activity has repercussions on glycaemia by acting through a "local" effect on glucose absorption (an increased contraction under fed condition is positively correlated with glucose uptake leading to hyperglycaemia) and a "central" effect on glucose utilization in muscle through a hypothalamic relay. A deregulation of these local and central effects contribute to the development of hyperglycemia and insulin resistance observed during T2D. Obese/diabetic mice and humans have impaired ENS activity associated with intestinal hyper-contractility. Targeting the pair "ENS-smooth muscle" therefore represents a new therapeutic approach to treat T2DM. This is why, the key to this innovative strategy is to identify intestinal molecules capable of modulating ENS neurons, called enterosynes. The objective of my thesis was: 1) to identify the role of the intestinal microbiota (using prebiotics) in the control of duodenal motility and to determine its mode of action (= type of enterosynes involved); 2) to study the impact of glucose on intestinal motility in normal and diabetic mice. This allowed us to know if we could consider glucose as an enterosyne; and 3) to determine the impact of breast milk on intestinal motility, and its effect on carbohydrate metabolism. Our work has shown that the use of prebiotics could improve the metabolic status of diabetic mice by signalling pathways involving a lipid (=12-HETE) and a peptide (=enkephalin) providing 2 new potential therapeutic targets. In addition, glucose, through its action on stimulating contractions, seems to play a key role in the development of type 2 diabetes. Finally, we have discovered that treatments of breast milk under high pressure make it possible to maintain the content of bioactive peptides, which improves glucose tolerance by slowing duodenal contractions. Thus, our results encourage the use of nutritional approaches which are particularly interesting to identify new enterosynes for therapeutic purposes.L'axe intestin-cerveau est l'un des premiers systèmes de communication altéré au cours d'un diabète de type 2. Des données de notre équipe démontrent que la chémo-détection du glucose entérique, génère un signal afférent, qui en modifiant l'activité hypothalamique, contrôle l'utilisation du glucose. Nous avons également montré que cette boucle de régulation est altérée chez les souris obèses/diabétiques, de façon concomitante avec des modifications intestinales (microbiote, libération d'incrétines) et une libération d'oxyde nitrique (NO) hypothalamique. De plus, nous avons développé un nouveau concept basé sur le fait que des modifications de l'activité mécanique des cellules musculaires lisses intestinales, sous l'influence des neurones du système nerveux entérique (SNE), peuvent avoir un impact majeur sur la glycémie. En effet, nous avons découvert que l'hyper-contractilité intestinale 1) est associée à une augmentation de l'absorption de glucose, et 2) génère un signal afférent qui informe le cerveau afin de bloquer l'entrée de glucose dans le muscle. C'est pourquoi, une modification de l'activité du couple SNE-cellules musculaires lisses a des répercussions sur la glycémie en agissant via un effet "local" sur l'absorption du glucose (une augmentation des contractions en condition nourries est positivement corrélée avec l'absorption du glucose conduisant à l'hyperglycémie) et un effet "central" sur l'utilisation du glucose dans le muscle via un relai hypothalamique. Une dérégulation de ces effets locaux et centraux participe au développement de l'hyperglycémie et la résistance à l'insuline observée au cours du DT2. Les souris et hommes obèses/diabétiques ont une altération de l'activité du SNE associée à une hyper-contractilité intestinale. Cibler ce couple "SNE-muscles lisses" représente donc une nouvelle approche thérapeutique pour traiter le DT2. C'est pourquoi, la clef de cette stratégie innovante est d'identifier des molécules intestinales capables de moduler les neurones du SNE, appelée entérosynes. L'objectif de ma thèse a été : 1) d'identifier le rôle du microbiote intestinale (en utilisant des prébiotiques) dans le contrôle de la motilité duodénale et de déterminer son mode d'action (= type d'entérosynes impliquées); 2) d'étudier l'impact du glucose sur la motricité intestinale chez la souris normale et chez la souris diabétique. Ceci nous a permis de savoir si nous pouvions considérer le glucose comme une entérosyne ; et 3) de déterminer l'impact du lait maternel sur la motilité intestinale, et son effet sur le métabolisme glucidique. Nos travaux ont montré que l'utilisation de prébiotiques pouvait améliorer le statut métabolique de souris diabétiques par des voies de signalisation impliquant un lipide (=le 12-HETE) et un peptide (=enképhaline) apportant 2 nouvelles cibles thérapeutiques potentielles. De plus, le glucose, par son action de stimulation des contractions, semble jouer un rôle primordial dans le développement du diabète de type 2. Enfin, nous avons découvert que les traitements du lait maternel sous haute pression permettent de maintenir le contenu en peptides bioactifs, ce qui améliore la tolérance au glucose en ralentissant les contractions duodénales. Ainsi, nos résultats montrent que les approches nutritionnelles sont particulièrement importantes pour identifier de nouvelles entérosynes à visée thérapeutique

Discovery of new enterosynes targeting the enteric nervous system, through nutritional approaches : impact on glucose metabolism

L'axe intestin-cerveau est l'un des premiers systèmes de communication altéré au cours d'un diabète de type 2. Des données de notre équipe démontrent que la chémo-détection du glucose entérique, génère un signal afférent, qui en modifiant l'activité hypothalamique, contrôle l'utilisation du glucose. Nous avons également montré que cette boucle de régulation est altérée chez les souris obèses/diabétiques, de façon concomitante avec des modifications intestinales (microbiote, libération d'incrétines) et une libération d'oxyde nitrique (NO) hypothalamique. De plus, nous avons développé un nouveau concept basé sur le fait que des modifications de l'activité mécanique des cellules musculaires lisses intestinales, sous l'influence des neurones du système nerveux entérique (SNE), peuvent avoir un impact majeur sur la glycémie. En effet, nous avons découvert que l'hyper-contractilité intestinale 1) est associée à une augmentation de l'absorption de glucose, et 2) génère un signal afférent qui informe le cerveau afin de bloquer l'entrée de glucose dans le muscle. C'est pourquoi, une modification de l'activité du couple SNE-cellules musculaires lisses a des répercussions sur la glycémie en agissant via un effet "local" sur l'absorption du glucose (une augmentation des contractions en condition nourries est positivement corrélée avec l'absorption du glucose conduisant à l'hyperglycémie) et un effet "central" sur l'utilisation du glucose dans le muscle via un relai hypothalamique. Une dérégulation de ces effets locaux et centraux participe au développement de l'hyperglycémie et la résistance à l'insuline observée au cours du DT2. Les souris et hommes obèses/diabétiques ont une altération de l'activité du SNE associée à une hyper-contractilité intestinale. Cibler ce couple "SNE-muscles lisses" représente donc une nouvelle approche thérapeutique pour traiter le DT2. C'est pourquoi, la clef de cette stratégie innovante est d'identifier des molécules intestinales capables de moduler les neurones du SNE, appelée entérosynes. L'objectif de ma thèse a été : 1) d'identifier le rôle du microbiote intestinale (en utilisant des prébiotiques) dans le contrôle de la motilité duodénale et de déterminer son mode d'action (= type d'entérosynes impliquées); 2) d'étudier l'impact du glucose sur la motricité intestinale chez la souris normale et chez la souris diabétique. Ceci nous a permis de savoir si nous pouvions considérer le glucose comme une entérosyne ; et 3) de déterminer l'impact du lait maternel sur la motilité intestinale, et son effet sur le métabolisme glucidique. Nos travaux ont montré que l'utilisation de prébiotiques pouvait améliorer le statut métabolique de souris diabétiques par des voies de signalisation impliquant un lipide (=le 12-HETE) et un peptide (=enképhaline) apportant 2 nouvelles cibles thérapeutiques potentielles. De plus, le glucose, par son action de stimulation des contractions, semble jouer un rôle primordial dans le développement du diabète de type 2. Enfin, nous avons découvert que les traitements du lait maternel sous haute pression permettent de maintenir le contenu en peptides bioactifs, ce qui améliore la tolérance au glucose en ralentissant les contractions duodénales. Ainsi, nos résultats montrent que les approches nutritionnelles sont particulièrement importantes pour identifier de nouvelles entérosynes à visée thérapeutique.The gut-brain axis is one of the first systems of communication altered during type 2 diabetes. Data from our team demonstrate that the chemo-sensing of enteric glucose generates an afferent signal, modifying the hypothalamic activity and so the glucose utilization. We then show that this regulatory loop is altered in obese/diabetic mice, concomitantly with intestinal changes (microbiota, incretin release) and hypothalamic nitric oxide (NO) release. We developed a new concept since changes in the mechanical activity of intestinal smooth muscle cells, under the influence of enteric nervous system (ENS) neurons, can have a major impact on glycemia. We also found that intestinal hyper-contractility 1) is associated with an increased glucose uptake, and 2) generates an afferent signal that informs the brain to block glucose entry into muscle. Modification of ENS/smooth muscle cells activity has repercussions on glycaemia by acting through a "local" effect on glucose absorption (an increased contraction under fed condition is positively correlated with glucose uptake leading to hyperglycaemia) and a "central" effect on glucose utilization in muscle through a hypothalamic relay. A deregulation of these local and central effects contribute to the development of hyperglycemia and insulin resistance observed during T2D. Obese/diabetic mice and humans have impaired ENS activity associated with intestinal hyper-contractility. Targeting the pair "ENS-smooth muscle" therefore represents a new therapeutic approach to treat T2DM. This is why, the key to this innovative strategy is to identify intestinal molecules capable of modulating ENS neurons, called enterosynes. The objective of my thesis was: 1) to identify the role of the intestinal microbiota (using prebiotics) in the control of duodenal motility and to determine its mode of action (= type of enterosynes involved); 2) to study the impact of glucose on intestinal motility in normal and diabetic mice. This allowed us to know if we could consider glucose as an enterosyne; and 3) to determine the impact of breast milk on intestinal motility, and its effect on carbohydrate metabolism. Our work has shown that the use of prebiotics could improve the metabolic status of diabetic mice by signalling pathways involving a lipid (=12-HETE) and a peptide (=enkephalin) providing 2 new potential therapeutic targets. In addition, glucose, through its action on stimulating contractions, seems to play a key role in the development of type 2 diabetes. Finally, we have discovered that treatments of breast milk under high pressure make it possible to maintain the content of bioactive peptides, which improves glucose tolerance by slowing duodenal contractions. Thus, our results encourage the use of nutritional approaches which are particularly interesting to identify new enterosynes for therapeutic purposes

In Vivo Assessment of Antioxidant Potential of Human Milk Treated by Holder Pasteurization or High Hydrostatic Pressure Processing: A Preliminary Study on Intestinal and Hepatic Markers in Adult Mice

Preterm infants are highly susceptible to oxidative stress due to an imbalance between endogenous oxidant and antioxidant systems. In addition, these newborns are frequently fed with donor milk (DM) treated by Holder pasteurization (HoP) at 62.5 °C for 30 min, which is known to alter numerous heat-sensitive factors, including some antioxidants. High hydrostatic pressure (HHP) processing was recently proposed as an innovative method for the treatment of DM. The present study aimed to measure the redox balance of HoP- and HHP-DM and to study, in vivo, the effects of HoP- and HHP-DM on the gut and liver. H2O2, vitamin A and vitamin E (α- and γ-tocopherols) concentrations, as well as the total antioxidant capacity (TAC), were measured in raw-, HoP- and HHP-DM. The gene expression level of antioxidant systems and inflammatory response were quantified in the ileum and liver of adult mice after 7 days of oral administration of HoP- or HHP-DM. HoP reduced the γ-tocopherol level, whereas HHP treatment preserved all vitamins close to the raw milk level. The milk H2O2 content was reduced by HHP but not by HoP. The total antioxidant capacity of DM was reduced after HHP processing measured by PAOT-Liquid® technology but was unaffected after measurement by ORAC assay. In mice, HHP-DM administration induced a stimulation of antioxidant defenses and reduced some inflammatory markers in both the ileum and liver compared to HoP-DM treatment. Our preliminary study suggests that the HHP processing of DM may better protect preterm infants from gut and liver pathologies compared to HoP, which is currently used in most human milk banks

Découverte de nouvelles entérosynes ciblant le système nerveux entérique, par des approches nutritionnelles : impact sur le métabolisme glucidique

The gut-brain axis is one of the first systems of communication altered during type 2 diabetes. Data from our team demonstrate that the chemo-sensing of enteric glucose generates an afferent signal, modifying the hypothalamic activity and so the glucose utilization. We then show that this regulatory loop is altered in obese/diabetic mice, concomitantly with intestinal changes (microbiota, incretin release) and hypothalamic nitric oxide (NO) release. We developed a new concept since changes in the mechanical activity of intestinal smooth muscle cells, under the influence of enteric nervous system (ENS) neurons, can have a major impact on glycemia. We also found that intestinal hyper-contractility 1) is associated with an increased glucose uptake, and 2) generates an afferent signal that informs the brain to block glucose entry into muscle. Modification of ENS/smooth muscle cells activity has repercussions on glycaemia by acting through a "local" effect on glucose absorption (an increased contraction under fed condition is positively correlated with glucose uptake leading to hyperglycaemia) and a "central" effect on glucose utilization in muscle through a hypothalamic relay. A deregulation of these local and central effects contribute to the development of hyperglycemia and insulin resistance observed during T2D. Obese/diabetic mice and humans have impaired ENS activity associated with intestinal hyper-contractility. Targeting the pair "ENS-smooth muscle" therefore represents a new therapeutic approach to treat T2DM. This is why, the key to this innovative strategy is to identify intestinal molecules capable of modulating ENS neurons, called enterosynes. The objective of my thesis was: 1) to identify the role of the intestinal microbiota (using prebiotics) in the control of duodenal motility and to determine its mode of action (= type of enterosynes involved); 2) to study the impact of glucose on intestinal motility in normal and diabetic mice. This allowed us to know if we could consider glucose as an enterosyne; and 3) to determine the impact of breast milk on intestinal motility, and its effect on carbohydrate metabolism. Our work has shown that the use of prebiotics could improve the metabolic status of diabetic mice by signalling pathways involving a lipid (=12-HETE) and a peptide (=enkephalin) providing 2 new potential therapeutic targets. In addition, glucose, through its action on stimulating contractions, seems to play a key role in the development of type 2 diabetes. Finally, we have discovered that treatments of breast milk under high pressure make it possible to maintain the content of bioactive peptides, which improves glucose tolerance by slowing duodenal contractions. Thus, our results encourage the use of nutritional approaches which are particularly interesting to identify new enterosynes for therapeutic purposes.L'axe intestin-cerveau est l'un des premiers systèmes de communication altéré au cours d'un diabète de type 2. Des données de notre équipe démontrent que la chémo-détection du glucose entérique, génère un signal afférent, qui en modifiant l'activité hypothalamique, contrôle l'utilisation du glucose. Nous avons également montré que cette boucle de régulation est altérée chez les souris obèses/diabétiques, de façon concomitante avec des modifications intestinales (microbiote, libération d'incrétines) et une libération d'oxyde nitrique (NO) hypothalamique. De plus, nous avons développé un nouveau concept basé sur le fait que des modifications de l'activité mécanique des cellules musculaires lisses intestinales, sous l'influence des neurones du système nerveux entérique (SNE), peuvent avoir un impact majeur sur la glycémie. En effet, nous avons découvert que l'hyper-contractilité intestinale 1) est associée à une augmentation de l'absorption de glucose, et 2) génère un signal afférent qui informe le cerveau afin de bloquer l'entrée de glucose dans le muscle. C'est pourquoi, une modification de l'activité du couple SNE-cellules musculaires lisses a des répercussions sur la glycémie en agissant via un effet "local" sur l'absorption du glucose (une augmentation des contractions en condition nourries est positivement corrélée avec l'absorption du glucose conduisant à l'hyperglycémie) et un effet "central" sur l'utilisation du glucose dans le muscle via un relai hypothalamique. Une dérégulation de ces effets locaux et centraux participe au développement de l'hyperglycémie et la résistance à l'insuline observée au cours du DT2. Les souris et hommes obèses/diabétiques ont une altération de l'activité du SNE associée à une hyper-contractilité intestinale. Cibler ce couple "SNE-muscles lisses" représente donc une nouvelle approche thérapeutique pour traiter le DT2. C'est pourquoi, la clef de cette stratégie innovante est d'identifier des molécules intestinales capables de moduler les neurones du SNE, appelée entérosynes. L'objectif de ma thèse a été : 1) d'identifier le rôle du microbiote intestinale (en utilisant des prébiotiques) dans le contrôle de la motilité duodénale et de déterminer son mode d'action (= type d'entérosynes impliquées); 2) d'étudier l'impact du glucose sur la motricité intestinale chez la souris normale et chez la souris diabétique. Ceci nous a permis de savoir si nous pouvions considérer le glucose comme une entérosyne ; et 3) de déterminer l'impact du lait maternel sur la motilité intestinale, et son effet sur le métabolisme glucidique. Nos travaux ont montré que l'utilisation de prébiotiques pouvait améliorer le statut métabolique de souris diabétiques par des voies de signalisation impliquant un lipide (=le 12-HETE) et un peptide (=enképhaline) apportant 2 nouvelles cibles thérapeutiques potentielles. De plus, le glucose, par son action de stimulation des contractions, semble jouer un rôle primordial dans le développement du diabète de type 2. Enfin, nous avons découvert que les traitements du lait maternel sous haute pression permettent de maintenir le contenu en peptides bioactifs, ce qui améliore la tolérance au glucose en ralentissant les contractions duodénales. Ainsi, nos résultats montrent que les approches nutritionnelles sont particulièrement importantes pour identifier de nouvelles entérosynes à visée thérapeutique

Targeting the Enteric Nervous System to Treat Metabolic Disorders? "Enterosynes" as Therapeutic Gut Factors.

The gut-brain axis is of crucial importance for controlling glucose homeostasis. Alteration of this axis promotes the type 2 diabetes (T2D) phenotype (hyperglycaemia, insulin resistance). Recently, a new concept has emerged to demonstrate the crucial role of the enteric nervous system in the control of glycaemia via the hypothalamus. In diabetic patients and mice, modification of enteric neurons activity in the proximal part of the intestine generates a duodenal hyper-contractility that generates an aberrant message from the gut to the brain. In turn, the hypothalamus sends an aberrant efferent message that provokes a state of insulin resistance, which is characteristic of a T2D state. Targeting the enteric nervous system of the duodenum is now recognized as an innovative strategy for treatment of diabetes. By acting in the intestine, bioactive gut molecules that we called "enterosynes" can modulate the function of a specific type of neurons of the enteric nervous system to decrease the contraction of intestinal smooth muscle cells. Here, we focus on the origins of enterosynes (hormones, neurotransmitters, nutrients, microbiota, and immune factors), which could be considered therapeutic factors, and we describe their modes of action on enteric neurons. This unsuspected action of enterosynes is proposed for the treatment of T2D, but it could be applied for other therapeutic solutions that implicate communication between the gut and brain

Interactions between the microbiota and enteric nervous system during gut-brain disorders

For the last 20 years, researchers have focused their intention on the impact of gut microbiota in healthy and pathological conditions. This year (2021), more than 25,000 articles can be retrieved from PubMed with the keywords “gut microbiota and physiology”, showing the constant progress and impact of gut microbes in scientific life. As a result, numerous therapeutic perspectives have been proposed to modulate the gut microbiota composition and/or bioactive factors released from microbes to restore our body functions. Currently, the gut is considered a primary site for the development of pathologies that modify brain functions such as neurodegenerative (Parkinson’s, Alzheimer’s, etc.) and metabolic (type 2 diabetes, obesity, etc.) disorders. Deciphering the mode of interaction between microbiota and the brain is a real original option to prevent (and maybe treat in the future) the establishment of gut-brain pathologies. The objective of this review is to describe recent scientific elements that explore the communication between gut microbiota and the brain by focusing our interest on the enteric nervous system (ENS) as an intermediate partner. The ENS, which is known as the “second brain”, could be under the direct or indirect influence of the gut microbiota and its released factors (short-chain fatty acids, neurotransmitters, gaseous factors, etc.). Thus, in addition to their actions on tissue (adipose tissue, liver, brain, etc.), microbes can have an impact on local ENS activity. This potential modification of ENS function has global repercussions in the whole body via the gut-brain axis and represents a new therapeutic strategy

High Hydrostatic Pressure Processing of Human Milk Increases Apelin and GLP-1 Contents to Modulate Gut Contraction and Glucose Metabolism in Mice Compared to Holder Pasteurization

International audienceBackground: High hydrostatic pressure (HHP) processing is a non-thermal method proposed as an alternative to Holder pasteurization (HoP) for the sterilization of human breast milk (BM). HHP preserves numerous milk bioactive factors that are degraded by HoP, but no data are available for milk apelin and glucagon-like peptide 1 (GLP-1), two hormones implicated in the control of glucose metabolism directly and via the gut-brain axis. This study aims to determine the effects of HoP and HHP processing on apelin and GLP-1 concentrations in BM and to test the effect of oral treatments with HoP-and HHP-BM on intestinal contractions and glucose metabolism in adult mice. Methods: Mice were treated by daily oral gavages with HoP-or HHP-BM during one week before intestinal contractions, and glucose tolerance was assessed. mRNA expression of enteric neuronal enzymes known to control intestinal contraction was measured. Results: HoP-BM displayed a reduced concentration of apelin and GLP-1, whereas HHP processing preserved these hormones close to their initial levels in raw milk. Chronic HHP-BM administration to mice increased ileal mRNA nNos expression level leading to a decrease in gut contraction associated with improved glucose tolerance. Conclusion: In comparison to HoP, HPP processing of BM preserves both apelin and GLP-1 and improves glucose tolerance by acting on gut contractions. This study reinforces previous findings demonstrating that HHP processing provides BM with a higher biological value than BM treated by HoP

In Vivo Assessment of Antioxidant Potential of Human Milk Treated by Holder Pasteurization or High Hydrostatic Pressure Processing: A Preliminary Study on Intestinal and Hepatic Markers in Adult Mice

Preterm infants are highly susceptible to oxidative stress due to an imbalance between endogenous oxidant and antioxidant systems. In addition, these newborns are frequently fed with donor milk (DM) treated by Holder pasteurization (HoP) at 62.5 °C for 30 min, which is known to alter numerous heat-sensitive factors, including some antioxidants. High hydrostatic pressure (HHP) processing was recently proposed as an innovative method for the treatment of DM. The present study aimed to measure the redox balance of HoP- and HHP-DM and to study, in vivo, the effects of HoP- and HHP-DM on the gut and liver. H2O2, vitamin A and vitamin E (α- and γ-tocopherols) concentrations, as well as the total antioxidant capacity (TAC), were measured in raw-, HoP- and HHP-DM. The gene expression level of antioxidant systems and inflammatory response were quantified in the ileum and liver of adult mice after 7 days of oral administration of HoP- or HHP-DM. HoP reduced the γ-tocopherol level, whereas HHP treatment preserved all vitamins close to the raw milk level. The milk H2O2 content was reduced by HHP but not by HoP. The total antioxidant capacity of DM was reduced after HHP processing measured by PAOT-Liquid® technology but was unaffected after measurement by ORAC assay. In mice, HHP-DM administration induced a stimulation of antioxidant defenses and reduced some inflammatory markers in both the ileum and liver compared to HoP-DM treatment. Our preliminary study suggests that the HHP processing of DM may better protect preterm infants from gut and liver pathologies compared to HoP, which is currently used in most human milk banks

Glucose Stimulates Gut Motility in Fasted and Fed Conditions: Potential Involvement of a Nitric Oxide Pathway

(1) Background: Type 2 diabetes (T2D) is associated with a duodenal hypermotility in postprandial conditions that favors hyperglycemia and insulin resistance via the gut-brain axis. Enterosynes, molecules produced within the gut with effects on the enteric nervous system, have been recently discovered and pointed to as potential key modulators of the glycemia. Indeed, targeting the enteric nervous system that controls gut motility is now considered as an innovative therapeutic way in T2D to limit intestinal glucose absorption and restore the gut-brain axis to improve insulin sensitivity. So far, little is known about the role of glucose on duodenal contraction in fasted and fed states in normal and diabetic conditions. The aim of the present study was thus to investigate these effects in adult mice. (2) Methods: Gene-expression level of glucose transporters (SGLT-1 and GLUT2) were quantified in the duodenum and jejunum of normal and diabetic mice fed with an HFD. The effect of glucose at different concentrations on duodenal and jejunal motility was studied ex vivo using an isotonic sensor in fasted and fed conditions in both normal chow and HFD mice. (3) Results: Both SGLT1 and GLUT2 expressions were increased in the duodenum (47 and 300%, respectively) and jejunum (75% for GLUT2) of T2D mice. We observed that glucose stimulates intestinal motility in fasted (200%) and fed (400%) control mice via GLUT2 by decreasing enteric nitric oxide release (by 600%), a neurotransmitter that inhibits gut contractions. This effect was not observed in diabetic mice, suggesting that glucose sensing and mechanosensing are altered during T2D. (4) Conclusions: Glucose acts as an enterosyne to control intestinal motility and glucose absorption through the enteric nervous system. Our data demonstrate that GLUT2 and a reduction of NO production could both be involved in this stimulatory contracting effect