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Towards novel therapeutics for disorders of the brain-gut axis: Interfacing food and medicine
Abstracts of Pharma Nutrition 2013 / PharmaNutrition 2 (2014) 75–119
microbiota, driving TH 1, TH 2, TH 17, TH 22 and T regulatory responses; these microbial interactions with the innate and adaptive immune system modulate host immunity in both health and disease. Various conditions including infection, aging, alcohol use, circadian rhythm disruption, and poor dietary quality may alter microbiota metabolites (SCFA) and immune function and lead to disrupted barrier function. The resultant bacterial products in circulation can drive systemic inflammatory responses; the outcomes of this response may contribute to metabolic, cardiovascular, and neurocognitive diseases. By modifying nutritional factors in the gastrointestinal tract, one can beneficially affect the host microbiota and modify disease outcomes. These dietary factors include fermentable fibers (prebiotics), probiotics, and synbiotics that have been shown to have positive effects on both the human intestinal epithelium and systemic health through modulation of microbiota, production of SCFA (butyrate), and modification of gut immunity. http://dx.doi.org/10.1016/j.phanu.2013.11.008 [INV7] Tea polyphenols: Bane or bonanza? Interaction with phospholipids and proteins T. Nakayama ∗ , T. Ishii University of Shizuoka, Japan Tea polyphenols, catechins in green tea and theaflavins in black tea, have been reported to show various biological effects in vitro and in vivo. Most reported effects are good for our health, bonanza. Some are, however, toxic to our body, bane. This depends on various factors: age, race, eating habit, and dose. Biological effects of pharmaceuticals and food factors could be based on their chemical properties. The representative chemical properties of catechins are their relatively high affinities for various biological substances, such as phospholipids and proteins. Green tea mainly contains four catechins, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg). Among these catechins, EGCg is most abundant in green tea and its biological effects are extensively examined. High doses of EGCg are usually toxic. We found that affinities of EGCg and ECg, gallate-type catechins, for phospholipid membranes and proteins always higher than those of EGC and EC, nongallate-type catechins. Interactions of the gallatetype catechins with phospholipid membrane are nonspecific and those with proteins are relatively specific. Recently it has been reported that bitterness and astringency of the gallate-type catechins are stronger than those of nongallate-type catechins. This suggests the close connection among beneficial effects, toxicity and taste, providing a suitable example of “Good medicine taste bitter.” It is well known that EGCg shows both antioxidant and prooxidant effects based on its strong reducing property. If it reacts with free radicals in our body, it works as an antioxidant. On the other hand, if it reduces an oxygen molecule to form hydrogen peroxide, it works as a prooxidant. The factors such as pH, concentrations of oxygen molecules and catechins, and the presence or absence of transition metal ions are determinant in which direction, i.e. as an antioxidant or a prooxidant, the catechins react for. http://dx.doi.org/10.1016/j.phanu.2013.11.009
77
[INV8] Towards novel therapeutics for disorders of the brain-gut axis: Interfacing food and medicine J.F. Cryan University College Cork, Ireland There is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Our research has focused on how the microbiome communicates with the central nervous system (CNS) and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotic agents which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus the concept of a microbiome-gut brain axis is emerging which suggests that modulation of the gut microbiome may be a tractable strategy for developing novel therapeutics for complex CNS disorders where there is a huge unmet medical need. Furthermore the brain-gut-microbiota axis participates in stress-related gastrointestinal disorders including irritable bowel syndrome (IBS). We have shown that patients with IBS have specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis, immune function, tryptophan metabolism and microbiota. Similar changes are also observed in animal models of the disorder. The molecular mechanisms of brain-gut microbiota dysfunction have not been elucidated but are of marked commercial interest for therapeutic exploitation for stress-related disorders and obesity by both the food and pharmaceutical industries. However, advances in the development of pharmabiotic-based strategies for stressrelated disorders and obesity is thwarted by the dearth of scientific understanding into their potential mechanism of action coupled with an increasingly challenging regulatory environment. In this presentation we will discuss the potential of modulation of the brain-gut-microbiota axis as having important pathophysiological consequences and provides an important target for preventive or therapeutic intervention with major commercial potential at the interface of food and medicine. http://dx.doi.org/10.1016/j.phanu.2013.11.010 [INV9] Specialised nutrition in neurology: A new horizon P.J. Kamphuis 1,2 1 2
Danone Research, The Netherlands Utrecht University, The Netherlands
Synaptic loss has been recognized to be the strongest structural correlate with memory impairment in Alzheimer’s disease (AD) and is apparent early in the disease process. Synapses and neurites consist of neuronal membranes largely composed of phosphatides. Phosphatide synthesis depends on the presence of the dietary precursors DHA, UMP and choline. Additionally, B-vitamins, phospholipids and antioxidants are co-factors in the synthesis pathway of neuronal membranes, e.g. by elevating precursor plasma levels. The role of nutrition in AD has been underscored by several studies demonstrating increased AD risk when adhering specific dietary patterns, and by the lowered plasma nutrient status in AD. DHA, UMP and choline synergistically increased brain phosphatide, synaptic protein, and dendritic spine formation in animals. Supplementation with combinations of DHA, EPA, UMP, choline, phospholipids, vitamins B, C and E, and selenium showed increased
microbiota, driving TH 1, TH 2, TH 17, TH 22 and T regulatory responses; these microbial interactions with the innate and adaptive immune system modulate host immunity in both health and disease. Various conditions including infection, aging, alcohol use, circadian rhythm disruption, and poor dietary quality may alter microbiota metabolites (SCFA) and immune function and lead to disrupted barrier function. The resultant bacterial products in circulation can drive systemic inflammatory responses; the outcomes of this response may contribute to metabolic, cardiovascular, and neurocognitive diseases. By modifying nutritional factors in the gastrointestinal tract, one can beneficially affect the host microbiota and modify disease outcomes. These dietary factors include fermentable fibers (prebiotics), probiotics, and synbiotics that have been shown to have positive effects on both the human intestinal epithelium and systemic health through modulation of microbiota, production of SCFA (butyrate), and modification of gut immunity. http://dx.doi.org/10.1016/j.phanu.2013.11.008 [INV7] Tea polyphenols: Bane or bonanza? Interaction with phospholipids and proteins T. Nakayama ∗ , T. Ishii University of Shizuoka, Japan Tea polyphenols, catechins in green tea and theaflavins in black tea, have been reported to show various biological effects in vitro and in vivo. Most reported effects are good for our health, bonanza. Some are, however, toxic to our body, bane. This depends on various factors: age, race, eating habit, and dose. Biological effects of pharmaceuticals and food factors could be based on their chemical properties. The representative chemical properties of catechins are their relatively high affinities for various biological substances, such as phospholipids and proteins. Green tea mainly contains four catechins, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg). Among these catechins, EGCg is most abundant in green tea and its biological effects are extensively examined. High doses of EGCg are usually toxic. We found that affinities of EGCg and ECg, gallate-type catechins, for phospholipid membranes and proteins always higher than those of EGC and EC, nongallate-type catechins. Interactions of the gallatetype catechins with phospholipid membrane are nonspecific and those with proteins are relatively specific. Recently it has been reported that bitterness and astringency of the gallate-type catechins are stronger than those of nongallate-type catechins. This suggests the close connection among beneficial effects, toxicity and taste, providing a suitable example of “Good medicine taste bitter.” It is well known that EGCg shows both antioxidant and prooxidant effects based on its strong reducing property. If it reacts with free radicals in our body, it works as an antioxidant. On the other hand, if it reduces an oxygen molecule to form hydrogen peroxide, it works as a prooxidant. The factors such as pH, concentrations of oxygen molecules and catechins, and the presence or absence of transition metal ions are determinant in which direction, i.e. as an antioxidant or a prooxidant, the catechins react for. http://dx.doi.org/10.1016/j.phanu.2013.11.009
77
[INV8] Towards novel therapeutics for disorders of the brain-gut axis: Interfacing food and medicine J.F. Cryan University College Cork, Ireland There is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Our research has focused on how the microbiome communicates with the central nervous system (CNS) and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotic agents which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus the concept of a microbiome-gut brain axis is emerging which suggests that modulation of the gut microbiome may be a tractable strategy for developing novel therapeutics for complex CNS disorders where there is a huge unmet medical need. Furthermore the brain-gut-microbiota axis participates in stress-related gastrointestinal disorders including irritable bowel syndrome (IBS). We have shown that patients with IBS have specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis, immune function, tryptophan metabolism and microbiota. Similar changes are also observed in animal models of the disorder. The molecular mechanisms of brain-gut microbiota dysfunction have not been elucidated but are of marked commercial interest for therapeutic exploitation for stress-related disorders and obesity by both the food and pharmaceutical industries. However, advances in the development of pharmabiotic-based strategies for stressrelated disorders and obesity is thwarted by the dearth of scientific understanding into their potential mechanism of action coupled with an increasingly challenging regulatory environment. In this presentation we will discuss the potential of modulation of the brain-gut-microbiota axis as having important pathophysiological consequences and provides an important target for preventive or therapeutic intervention with major commercial potential at the interface of food and medicine. http://dx.doi.org/10.1016/j.phanu.2013.11.010 [INV9] Specialised nutrition in neurology: A new horizon P.J. Kamphuis 1,2 1 2
Danone Research, The Netherlands Utrecht University, The Netherlands
Synaptic loss has been recognized to be the strongest structural correlate with memory impairment in Alzheimer’s disease (AD) and is apparent early in the disease process. Synapses and neurites consist of neuronal membranes largely composed of phosphatides. Phosphatide synthesis depends on the presence of the dietary precursors DHA, UMP and choline. Additionally, B-vitamins, phospholipids and antioxidants are co-factors in the synthesis pathway of neuronal membranes, e.g. by elevating precursor plasma levels. The role of nutrition in AD has been underscored by several studies demonstrating increased AD risk when adhering specific dietary patterns, and by the lowered plasma nutrient status in AD. DHA, UMP and choline synergistically increased brain phosphatide, synaptic protein, and dendritic spine formation in animals. Supplementation with combinations of DHA, EPA, UMP, choline, phospholipids, vitamins B, C and E, and selenium showed increased