Gut Brain Axis, Hormonal and Feeding Disorders

Hormone, Peripheral administration of toxic bacterial products and cytokines have been used to model the immunological, physiological, and behavioral responses to infection, including the anorexia of disease. The vagus nerve is the major neuroanatomic linkage between gut sites exposed to peripheral endotoxins and cytokines and the central nervous system regions that mediate the control of food intake, and thus has been a major research focus of the neurobiological approach to understanding cytokine-induced anorexia. Molecular biological and neurophysiologic evidence demonstrates that peripheral anorectic doses of cytokines and endotoxins elicit significant increases in neural activation at multiple peripheral and central levels of the gut-brain axis and in some cases may modify the neural processing of meal-related gastrointestinal signals that contribute to the negative feedback control of ingestion. The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis. Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy. The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism. During cachexia, the organism is maintained in a constant negative energy balance. This can rarely be explained by the actual energy and substrate demands by tumors in patients with cancer. Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions. Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system). Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. The data show that the cachexia-anorexia syndrome is multifactorial, and understanding the interactions between peripheral and brain mechanisms is pivotal to characterizing the underlying integrative pathophysiology of this disorder.

The need to understand the regulation of appetite and energy balance has never been greater. The emergence of obesity as a global public health problem has imparted impetus to efforts directed at characterizing the complex neuroendocrine interactions that govern feeding. Similarly, eating disorders are responsible for very significant morbidity, mortality, and socioeconomic dysfunction. A recent review of outcomes in anorexia nervosa (AN) painted a gloomy picture, reporting a crude mortality rate of 5% and a recovery rate of less than 50%, figures that have changed little over the course of the last century. More effective therapeutic approaches are needed, and it is in this context that work to define better the pathogenesis of AN has been making progress. With some timely data on peptide YY (PYY) in AN, Misra et al. supplement our existing knowledge of the changes in the gut hormone milieu that accompany changes in body weight.

The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis. Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy. The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism. During cachexia, the organism is maintained in a constant negative energy balance.

Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions. Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system).

Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis.

Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy.

The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism.

During cachexia, the organism is maintained in a constant negative energy balance. This can rarely be explained by the actual energy and substrate demands by tumors in patients with cancer. Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions.

Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system).

Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. Thus, the data show that the cachexia-anorexia syndrome is multifactorial, and understanding the interactions between peripheral and brain mechanisms is pivotal to characterizing the underlying integrative pathophysiology of this disorder.

Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity.

Behavioral studies of the anorectic effects of peripheral cytokines and endotoxins have shown that neither vagal nor splanchnic visceral afferent fibers supplying the gut are necessary for the reduction of food intake in these models. These data do not rule out the potential contribution of supradiaphragmatic vagal afferents or a modulatory role for immune-stimulated gut vagal afferent signals in the expression of cytokine and endotoxin-induced anorexia in the intact organism.

PYY, so named because it has a tyrosine residue at either end, is a 36-amino-acid peptide released postprandially by the L-cells of the gastrointestinal tract into the circulation in proportion to the calories ingested. It is also present in the central nervous system (CNS), and a role for PYY in the regulation of food intake was initially predicated on the basis of observations that PYY injected directly into the CNS, either into the ventricular system or into the paraventricular nucleus of the hypothalamus, mediated an increase in food intake .

A number of lines of evidence argued for a place for PYY, acting as a neurotransmitter, in the pathogenesis of eating disorders. In particular, similarities were noted between the hyperphagia induced by CNS injection of PYY and the pattern of ingestive behavior associated with bulimia nervosa, and several studies demonstrated differences in cerebrospinal fluid levels of PYY in abstaining bulimics when compared with controls, anorexics, or their own cerebrospinal fluid shortly after binge eating and vomiting.

Neuropeptide Y (NPY) is structurally related to PYY, and they bind to the same receptor family. NPY is present in the CNS in much larger quantities than PYY and, importantly, it is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project onto key appetite-regulatory areas, including the paraventricular nucleus (6). The orexigenic properties of NPY are well recognized, and the possibility therefore remains that the hyperphagia mediated by CNS-injected PYY is a pharmacological, rather than a physiological, effect, arising from the action of exogenous PYY at receptors that would physiologically be occupied by NPY.

In the circulation, the major form of PYY is the N-terminal-truncated PYY3–36, which demonstrates relative specificity for the receptor subtype Y2. This receptor is highly expressed on NPY neurons in the ARC, where it putatively acts as an inhibitory autoreceptor, providing a means for NPY to regulate its own release. PYY3–36 injected systemically into a number of animal species, including humans, inhibits food intake, in contrast to the actions of CNS-injected peptide. This effect occurs at plasma levels of PYY3–36 similar to those seen physiologically after a meal and is lost in Y2 receptor knockout mice. Furthermore, peripherally injected PYY3–36 induces expression of c-fos in the ARC, and injection directly into the ARC inhibits food intake, again contrasting with the effects of less-targeted intracerebroventricular administration . Notwithstanding a failure of some groups to reproduce the anorexigenic effect of peripherally injected PYY3–36 in rodents, the weight of evidence now available strongly favors a satiety-promoting role for PYY.

The quest for novel therapies for diseases characterized by disordered energy homeostasis leads naturally to an examination of the possibility that abnormal gut hormone signaling may play a role in the pathogenesis of these conditions. Elevated levels of several gut hormones after gastric bypass surgery have been proposed as a possible mechanism by which postoperative reduction in appetite and loss of weight is achieved. Similarly, PYY levels have been found to be lower in obese individuals than in lean controls but to rise after weight loss. The findings reported in this issue by Misra et al. both of significantly elevated fasting plasma PYY levels in subjects with AN, and of a reciprocal change in PYY levels with weight change, are concordant with these previous observations.

The tantalizing thought that AN may arise out of a tendency toward elevated levels of gut satiety signals must be tempered, however, by a number of caveats. First of all, any model that defines the pathogenesis of AN in terms of dysregulation of the gut-brain axis must also explain the epidemiological characteristics of the condition in terms of sex, age, social class, and geographical distribution. Furthermore, levels of other gut peptides have been found to be altered in patients with AN, resulting in a mixture of both orexigenic and anorexigenic signals. The integration of these opposing drives into a net effect on food intake will be crucial to any understanding of the contribution of peripheral signals to the development of AN. The influence of gut hormones on food intake is a function not only of basal circulating peptide levels but also of the dynamic response to a meal. In this regard, the data presented here, as the authors acknowledge, is somewhat at odds with a previous, smaller study in which the secretion profile of PYY in response to a liquid mixed meal was found to be no different in subjects with AN compared with controls

AN is a multisystem disorder, and some studies report intriguing results demonstrating a correlation between log fasting PYY levels and a number of markers of bone turnover. This follows on from recent interest in the influence of Y2 receptor activity on bone turnover. Again, although the existence of a correlation does not necessarily imply a causal relationship, if prevailing PYY activity does affect bone turnover, the implications would extend beyond AN. Any therapy for obesity, for instance, based on PYY or Y2 receptor agonism would have to be carefully evaluated for its effects on bone density in a population already at increased risk of osteoporosis.

The data reported by Misra et al. further illuminate our understanding of the interrelationship between body weight and circulating levels of PYY and are suggestive of a gut-bone interaction that introduces challenges for future therapeutic manipulation of the gut-brain axis. But will PYY antagonism be a useful treatment for AN? That depends on the nature of the association that has been revealed. The epidemiology of AN makes it unlikely that the primary cause of the disease is disordered gut hormone signaling. On the other hand, the elevation in PYY levels might result simply from an increase in speed of delivery of nutrients to the distal gut caused by chronic anxiety-related intestinal hurry—analogous to the discomfort many readers may have experienced when anticipating a stressful event. Against this explanation is the relative paucity of patterns of food intake characteristic of AN and also the observation that postmeal dynamic PYY levels in AN sufferers are similar to those in both normal weight and obese individuals.

Recent advances in knowledge of the gut-brain axis leave room for a third, more intriguing, explanation, namely that the psychopathology of AN results in direct up-regulation of neuroendocrine signaling from the distal gut. Further investigation of this possibility, perhaps using techniques including functional imaging and electrophysiological studies, may shed light on the mechanisms and pathways by which higher centers participate in the control of satiety. In the meantime, a realization that AN sufferers are exposed to abnormally elevated levels of a satiety-promoting gut hormone provides ample justification for an empirical trial of treatments aimed at ameliorating the imbalance between signal and body energy stores.

References

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