Browsing by Subject "Diet"

Nearly all animals live in environments with fluctuations in nutrient availability. The ability to sense and respond to these changes is essential for survival. Nutrition impacts physiology immediately, but can also have long-lasting effects across generations. The nematode Caenorhabditis elegans is particularly well-adapted to thrive in conditions of variable food availability. Here we find that starvation responses in C. elegans are largely independent of the larval stage at which worms experience starvation. Starvation in worms results in shrinkage, delayed growth upon recovery, and ultimately death. In order to adapt to starvation, metabolism is dramatically altered. At a gross level, this can be seen in a reduction of mitochondrial genomes and a more fragmented network of mitochondria.

Insulin-like signaling is a key cell signaling pathway controlling nutrient responses. We interrogate the role of insulin-like signaling in regulation of the acute starvation response. We show that daf-16/FoxO restructures carbohydrate metabolism by driving carbon flux through the glyoxylate shunt and gluconeogenesis and into synthesis of trehalose, a disaccharide of glucose. Trehalose is a well-known stress protectant, capable of preserving membrane organization and protein structure during abiotic stress. Metabolomic, genetic, and pharmacological analyses confirm increased trehalose synthesis and further show that trehalose not only supports survival as a stress protectant, but also serves as a glycolytic input. Further, we provide evidence that metabolic cycling between trehalose and glucose is necessary for this dual function of trehalose. This work demonstrates that daf-16/FoxO promotes starvation resistance by shifting carbon metabolism to drive trehalose synthesis, which in turn supports survival by providing an energy source and acting as a stress protectant.

In addition to acute changes in response to the nutrient environment, effects can persist intergenerationally. Maternal effects of environmental conditions produce intergenerational phenotypic plasticity. Adaptive value of these effects depends on appropriate anticipation of environmental conditions in the next generation, and mismatch between conditions may contribute to disease. However, regulation of intergenerational plasticity is poorly understood. Dietary restriction (DR) delays aging but maternal effects have not been investigated. We demonstrate maternal effects of DR in the roundworm C. elegans. Worms cultured in DR produce fewer but larger progeny. Nutrient availability is assessed in late larvae and young adults, rather than affecting a set point in young larvae, and maternal age independently affects progeny size. Reduced signaling through the insulin-like receptor daf-2/InsR in the maternal soma causes constitutively large progeny, and its effector daf-16/FoxO is required for this effect. nhr-49/Hnf4, pha-4/FoxA, and skn-1/Nrf also regulate progeny-size plasticity. Genetic analysis suggests that insulin-like signaling controls progeny size in part through regulation of nhr-49/Hnf4, and that pha-4/FoxA and skn-1/Nrf function in parallel to insulin-like signaling and nhr-49/Hnf4. Furthermore, progeny of DR worms are buffered from adverse consequences of early-larval starvation, growing faster and producing more off- spring than progeny of worms fed ad libitum. These results suggest a fitness advantage when mothers and their progeny experience nutrient stress, compared to an environmental mismatch where only progeny are stressed. This work reveals maternal provisioning as an organismal response to DR, demonstrates potentially adaptive intergenerational phenotypic plasticity, and identifies conserved pathways mediating these effects.

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The cholinergic system is intricately linked with hippocampal memory. As well, choline is anti-inflammatory in the brain and periphery (Terrando et al., 2011; Rivera et al., 1998). However, few have analyzed the anti-inflammatory properties of choline as an alternate means by which cholinergic manipulations affect hippocampal memory throughout the lifespan. The first aim of this dissertation work sought to determine if dietary choline supplementation protects against the deleterious effects of air pollution in the developing brain. Pregnant mice were given a high-choline diet (approximately 4.5x the choline chloride in the control diet) or a synthetic control diet. As well, dams were exposed to a series of diesel particulate (DEP) or saline vehicle sessions throughout pregnancy. Mice were sacrificed and tissues were collected on embryonic day 18. The activation state of microglia, identified by quantifying morphology using Iba1+ immunohistochemical staining, was examined in the dentate gyrus of the hippocampus (DG), the paraventricular nucleus (PVN) of the hypothalamus, the basolateral amygdala (AMY), and the parietal cortex (PCX). As expected, we found that DEP led to increased microglial activation in the fetal DG in males. Choline supplementation partially prevented this increase in activation. Interestingly, these effects were region-specific: the opposite pattern is seen in the PVN, and no significant diesel effect was seen in the AMY and PCX. These findings suggest that prenatal choline supplementation throughout pregnancy may protect the fetal hippocampus against the neuroinflammation associated with air pollution. To analyze whether the acute effects of dietary choline seen prenatally also occur in adulthood, adult dietary choline supplementation alongside the tibial fracture model of post-operative cognitive dysfunction (POCD) was used. POCD occurs when increased neuroinflammation due to peripheral surgery leads to impairments in cognition. Differences were found in almost hippocampal-dependent behavior, astrocytic activation, and cell proliferation. Differences were time point-specific. In the hippocampus, astrocytic activation, cell proliferation, and hilar granule cells all increased 1 day after surgery, and these increases were blunted by dietary choline. An increase in hippocampal young neurons was found 2 weeks after surgery. However, both were blunted by choline supplementation. At both time points assessed, tibial fracture impaired novel object recognition performance, and dietary choline rescued these impairments. As well, dietary choline supplementation did not mitigate the increase in anxiety-related behavior – specifically implicating hippocampal actions of the nutrient. Because the hippocampal-dependent memory impairment and rescue is not time point-specific, but the neural effects of tibial fracture are each specific to a certain timepoint, the mechanisms of behavior are likely different at each time point. Building upon aim 2, aim 3 explores if perinatal choline supplementation can act via “programming” of the neuroimmune system in development to prevent POCD in adulthood. Perinatal choline supplementation prevented POCD and neuroinflammation due to peripheral surgery, but did not protect against increases in young neurons or hilar neurons. Perinatal choline nutrition, in addition to its already-known neuroprotection, is additionally protective against POCD and its associated neuroinflammation in adulthood. Taken together, this body of work concludes that dietary choline supplementation at various administration dates is protective in neuroinflammatory models in behavior and brain.

The human gut microbiome is increasingly recognized as having a causal or contributing role in a wide variety of diseases. While mechanisms by which the microbiome contributes to or triggers disease processes are myriad, short-chain fatty acid (SCFA) production has been found to be a powerful regulator of inflammation and gastrointestinal (GI) function, and may be central to the link between host and microbiota. Supplementing the diet with microbially accessible carbohydrates, termed prebiotics, is one mechanism by which SCFA production can be augmented or altered. While prebiotic therapies to increase SCFA in the gut have shown some promise in treating or preventing disease, treatment potential is limited by substantial inter-individual variation in responses to prebiotics. Determining the cause for this variation is necessary to develop treatment approaches that maximize patient responsiveness. Ultimately, tools to predict an individual’s response to a prebiotic and to guide treatment options must be developed. Here, I seek to understand the drivers of inter-individual and intra-individual variation in prebiotic response and to develop strategies to predict this response. In Chapter One, I introduce the human gut microbiome and its roles in maintaining host health and contributing to disease processes. I also present the existing evidence for substantial variation in SCFA productive response to prebiotic supplementation and highlight the need for a more nuanced understanding of the drivers of such variation. In Chapter Two, I explore the contributions of host factors and prebiotic choice to variation in SCFA production. This chapter introduces a novel in vitro fiber fermentation system, which is used throughout this thesis, and shows our methods validation of such. We find not only that host identity and prebiotic choice both impact SCFA production, but that the interaction of these terms is a significant contributor, introducing the possibility of the need for personalization. We then identify multiple host factors, including microbiota community composition and baseline SCFA metabolic state of stool, that explain some portion of inter-individual variation in prebiotic response. In Chapter Three, this relationship is further explored during the first in vivo triple-crossover prebiotic supplementation study. We supply 28 healthy adults with three different prebiotic supplements in a balanced and uniform crossover design, measuring SCFA as the primary outcome. This study makes the major contribution of quantifying the relative contribution of individual identity and prebiotic choice to butyrogenic response, and identifying individual as the vastly stronger predictor. We also identify habitual diet and baseline fecal SCFA concentrations as potential predictors of prebiotic efficacy. As a secondary analysis, we apply co-inertia analysis to draw associations between dietary choices and fecal SCFA metabolism. Together, these works highlight the need for personalization of prebiotic therapy and introduce potential biomarkers of responsiveness. In Chapter Four, we apply the concept of prebiotic therapy to graft-versus-host disease (GVHD) and show efficacy in a murine model. Importantly, we show that efficacy of prebiotics in this model of GVHD is dependent on the starting state of the microbiota, as observed through community composition analysis and functional in vitro fiber fermentation.

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