Gut feelings: the emerging biology of gut–brain communication

Neuronal signaling

Based on the location of their cell body, the afferent neurons that innervate the gut are divided into extrinsic (spinal and vagal afferents) as well as several classes of intrinsic, primary afferents (IPANs)⁴⁴ (FIG. 1a). IPANs greatly outnumber the extrinsic connections, with an estimated 100 million IPANs versus 50,000 extrinsic afferent nerve processes in the human gut¹. Both intrinsic and extrinsic primary afferents show mechano- and chemosensitivity to both physiological and noxious mechanical stimuli⁴⁵. Luminal signals do not influence afferent nerve terminals directly, but act through intermediate cells in the lamina propria (including enteroendocrine cells)⁴⁶. Both extrinsic and intrinsic primary afferents provide input to multiple reflex loops to optimize gut function and maintain gastrointestinal homeostasis during internal perturbations (BOX 3). Subpopulations of modality-specific extrinsic primary afferents synapse with dorsal horn neurons in lamina I of the spinal dorsal horn or with cell bodies in the vagal nucleus tractus solitarius (NTS), providing the brain with a wide range of gut-related information. There are differences between the stomach and the intestine in the relative importance of intrinsic and extrinsic reflex regulation: whereas gastric function is predominantly regulated by vago–vagal reflexes, which are modulated within the dorsal vagal complex by cortical, humoral and endocrine signals, intestinal function relies primarily on intrinsic reflex regulation, mediated by IPANs and enteric motorneurons¹.

IPANs are connected with each other through excitatory synapses, forming extensive self-reinforcing net-works⁴⁷. Such networks are likely to amplify local signals that arise through direct activation of IPANs by an afferent stimulus. Some IPANs are polymodal, for example, responding to both chemical stimuli arising from entero-chromaffin cells as well as to mechanical stimuli that result from gut contractions and distensions. Whereas IPANs feed this information into a variety of local intramural reflexes that regulate and integrate gut functions such as propulsion, secretion and blood flow (but do not communicate directly with the CNS), extrinsic afferents provide afferent information to mesenteric, spinal and supraspinal reflex loops involving larger distances of the bowel and different regions of the gastrointestinal tract.

The fibres of the mechanosensitive extrinsic afferents that innervate the gastrointestinal tract end within the mesentery and longitudinal and circular muscle sheets, within the enteric ganglia^48–50, or in close proximity to interstitial cells of Cajal⁵¹. These afferent terminals are sensitive to distension, contractions or movement of the gut through activation of a variety of mechano-sensitive ion channels, including members of the transient receptor potential (TRP) family (TRPV1, TRPV2, TRPV3 and TRPV4, and TRPA1) and acid-sensing channels (ASICs)⁵². Subclasses of extrinsic afferents have been identified based on their mechanical and electro-physiological response properties, including low- and high-threshold mechanosensitive vagal and spinal afferents^53–55. A large number of such afferents do not respond to mechanical stimuli under normal conditions but develop mechanosensitivity following inflammation^56,57.

Different subpopulations of primarily vagal afferents terminate in close proximity (but without specialized synaptic connections) to enteroendocrine cells⁵⁸ Their terminals are chemosensitive, responding to neuropeptides released from enteroendocrine cells in response to luminal chemical and mechanical events (FIG. 1). Different classes of vagal afferents express receptors for both orexigenic (hunger generating) as well as anorexigenic (satiety generating) gut peptides contained in specialized enteroendocrine cells distributed throughout the gastrointestinal tract, from the oral cavity to the colon. Recent evidence suggests that the expression of these receptors on vagal afferents can be altered by the nutritional state of the animal and possibly by diet⁵⁹, and that the cholecystokinin 1 receptor (CCK1R; also known as CCKAR) has an important role in this process^60,61. The expression of receptors for orexigenic peptides was found to be increased by fasting (increasing the signal to eat), whereas that for anorexigenic peptides was decreased. These findings demonstrate the plasticity of the vagal afferent phenotype depending on the homeostatic state of the animal, analogous to the inflammation-induced phenotype switching of mechanosensitive afferents discussed above. Terminals of some vagal afferents end in close proximity to mucosal immune cells⁶² and have been shown to respond to a variety of signalling molecules that are released by mast cells and lymphocytes, including tryptase, histamine, 5-HT and various cytokines⁴⁶.

Endocrine and paracrine signaling

Although enteroendocrine cells make up less than 1% of all gut epithelial cells, they constitute the largest endocrine organ of the body. Based on their content, over 20 different types of enteroendocrine cells have been described^63,64. Enteroendocrine cells provide the first level of integration for all chemical and certain mechanical stimuli that are related to intraluminal gut contents. Their output is involved both in the regulation of digestive functions through ENS circuits and in the regulation of CNS processes through endocrine and paracrine signalling to vagal afferents. The relative importance of paracrine (for example, vagal) versus endocrine signalling to the hypothalamus and other brain regions in the regulation of food intake remains to be determined. Some enteroendocrine cells (so-called open cells) respond to luminal contents through multiple receptors (FIG. 1b). Mechanisms of enteroendocrine and enterochromaffin cell activation include depolarization by activation of mechanosensitive cation channels located on microvilli in response to the shearing forces of moving intestinal contents⁶⁴, activation by fatty acids through an acyl chain length-specific Ca²⁺-dependent mechanism⁶⁵, presumably a G protein-coupled receptor (GPCR)⁶⁶, activation by vagal efferents³⁵ as well as depolarization through G protein-coupled taste receptors⁶⁷. In addition, enter-oendocrine cells respond to the presence and activity of intraluminal microbial organisms through pattern recognition receptors (including TLRs), (reviewed in ^{REFS 12,68}). One example for this multimodal sensitivity is illustrated by the observation of increased release of cholecystokinin from enteroendocrine cells in response to intestinal pathogens^69,70. There has been a recent surge of interest in the sensors that detect sweet and bitter sensations and amino acids in the gut, which were originally described as taste receptors in the tongue⁶⁷. The taste receptor type 1 (T1R) family comprises three members that heterodimerize to form sweet taste receptors (T1R2 and T1R3) and amino acid receptors (T1R1 and T1R3), and the T2R family includes GPCRs that are involved in bitter taste reception. As in the tongue, taste receptor signalling involves a specific Gα subunit, α-gustducin, a taste-specific signalling protein with a prominent role in bitter taste⁷¹. Each of the channels described above triggers different signal transduction mechanisms, resulting in intracellular calcium increases and peptide release, or TLR-mediated activation of NF-κb, activator protein 1 (AP1; also known as transcription factor AP1) and interferon regulatory factors (IRFs); which leads to cytokine release¹². Crosstalk among these signalling channels might enable signals from pathogenic and commensal microorganisms to alter the response of certain enteroendocrine cells to mechanical and/or chemical stimulation⁵⁹.

A particularly well-studied type of enteroendocrine cell is the 5-HT-containing enterochromaffin cell of the small and large intestine⁶⁴. 95% of the organism's 5-HT is located in the gut, primarily in enterochromaffins. It is released on the basolateral side of these cells in response to shearing forces that are produced by moving luminal contents⁶⁴ that activate mechanosensitive cation channels located on microvilli on the apical side of enterochromaffin cells. Although mechanically released 5-HT is essential for triggering normal peristalsis and secretomotor reflexes, it is unknown if signalling to the CNS occurs during such physiological sensing and if tonic, vagally medidated 5-HT signalling to the brain is involved in modulating affective brain circuits.

Immune-related signaling

70–80% of the body's immune cells are contained within the gut-associated lymphoid tissue, reflecting the unique challenge for this part of the immune system to maintain a homeostatic balance between tolerance and immunity in the intestine. A single layer of columnar intestinal epithelial cells (IECs) forms the barrier between the host and one of the largest and most complex microbial habitats. The fact that mucosal immune cells remain immunologically hyporesponsive to commensal bacteria but also maintain their responsiveness to pathogenic organisms, suggests that under physiological conditions, the intestinal immune system recognizes commensal bacteria and elicits basal or tonic signals in the absence of full activation of the innate and adaptive immune response⁷². The physical constraints that the undisturbed epithelial layer imparts on sampling the luminal space are overcome by specialized lymphoid structures (including small intestinal Peyer's patches) that are embedded in the lamina propria throughout the intestine⁷². Two epithelial transduction mechanisms have been identified: specialized microfold cells that can sample antigens and microorganisms, and deliver them through transcytosis to antigen processing cells within Peyer's patches, and lamina propria dendritic cells, which extend their dendrites between epithelial tight junctions, to sample the luminal environment. Similarly to enteroendocrine cells, both EICs and dendritic cells express a wide range of pattern recognition receptors, including TLRs⁷³, emphasizing the central role of the gut in interactions with microorganisms and in discriminating between pathogens and commensals. Subsets of vagal afferent nerve terminals are in close proximity to mucosal immune cells and contain receptors for signalling molecules released from these cells, including mast cell products (proteases, histamine, serotonin and corticotropin releasing factor (CRF))⁶² and cytokines that are released from macrophages. Immune cell products can indirectly influence the functional properties of enteroendocrine cells, as illustrated by the increased cholecystokinin secretion in a mouse model of gut inflammation owing to the release of interleukin-4 (IL-4) and IL-13 from CD4⁺ T cells⁷⁰. Similarly, changes in the properties of the enterochromaffin cell-based 5-HT signalling system in the context of gut inflammation have been described⁷⁴.

Meta-representation of gut-related feeling states

A growing literature on the topic of different sensory modalities supports the concept that actual viscerosensory (and somatosensory) stimulation, as well as expected or imagined sensory experiences, engage different regions of the INS. For example, although actual distension of the gut in healthy subjects is associated with activation of the mid INS and aINS, consistent with the reported findings about insular viscerosensory representation⁸², the expectation of visceral pain has been shown to be associated with activation of the aINS only⁹⁵, consistent with the role of the aINS in the processing of interoceptive memories. Similar findings had previously been reported for expected somatic pain⁹⁶.

Activations of aINS (and ACC) have also been reported when subjects experienced disgust, or viewed images of others experiencing disgust⁹⁷, in the absence of a vagally mediated signal from the gastrointestinal tract signalling nausea. This suggests that homeostatic reflexes at the level of the aINS and ACC can be triggered in the absence of interoceptive input, presumably based on the recall of interoceptive memories while viewing an interoceptive feeling expressed by another individual or by expecting or imaging a particular feeling state.

The mechanisms and functional neuroanatomy underlying the formation of interoceptive memories of complex gut-related homeostatic states with affective and motivational dimensions (such as pain, nausea, hunger and satiation) are incompletely understood but are likely to include the encoding of such memories during development, possibly beginning with the earliest experience of pain (hunger and abdominal discomfort) and pleasure related to food intake of the newborn. Gut to brain signalling in the newborn underlies early undifferentiated emotions and stereotypic behavioural responses (suckling, vomiting, defecation and crying). It represents the primary mechanism that regulates positive and negative feeling states, providing the child with the first value-based map of the world, founded on positive and negative experiences related to food intake, satiation and associated gut responses. For example, the response to sweet taste receptor stimulation of the tongue in the newborn is a stereotypically organized reflex response also seen in decerebrate rats⁹⁸ and in anencephalic infants⁹⁹. The concept of a body-based value map is closely related to the ‘somatic marker’ hypothesis or to the concept of interoceptive memories (BOX 2). For example, the close relationship between sucrose ingestion and the resulting activation of sweet taste receptors on the tongue and central release of opioids (important mediators of homeostasis and well being), has been shown both in rodents¹⁰⁰ and in children¹⁰¹. This basic gut-based neurochemical encoding of feeling states is often maintained in the adult but complemented by learned meta-representation of such sensations (FIG. 3). For example, the close relationship of the gastric-based ghrelin signalling system, which plays a prominent part in the generation of the homeostatic emotion of hunger, and the associated craving for food, with the dopamine-based reward system is maintained throughout development, as peripherally released ghrelin can stimulate central dopamine release through vagal and endocrine mecha-nisms¹⁰². These initially gut-based responses to appetitive and aversive stimuli may also form the basis for interoceptive brain-based memories of basic emotional states (FIG. 3) that are relevant for complex social emotions, including predictions about the future and intuitive decision making. The fact that predictions and prediction errors are associated with activations of sub-regions of the aINS^103,104, and that patients with lesion of the OFC, a brain region closely connected to the aINS, are greatly compromised in their ability to make adaptive decisions about the future¹⁰⁵, provides indirect evidence for such a hypothesis. It has been speculated that a system of specialized cells (von Economo (VEN) cells) that are located in the aINS and share certain receptors and peptides that are rare in other brain regions but abundant in the ENS (including bombesin-like peptides and 5-HT receptor 2B (5HT2B)), may be related in evolutionary terms to gut–brain signals¹⁰⁶. The proposed close relationship between brain and gut systems is supported by evolutionary, developmental and neurobiological evidence. For example, there is a close relationship between pleasant gut-related emotions (associated with food intake) and social interactions in societies and cultures of human and non-human primates, as well as in lay language. Conversely, there is a close relationship between negative gut-related feeling states (including nausea and abdominal discomfort) and social withdrawal.

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Figure 3

Gut signalling systems, gut sensations and meta-representations of such sensations

Gastrointestinal interoceptive signals to the brain play a key part in the maintenance of homeostasis under resting conditions. Whereas signalling under homeostatic conditions is generally associated with pleasant sensations (satiety), signalling under non-homeostatic conditions is typically associated with aversive sensations (pain and nausea). Perception of these signals as gut sensations is associated with activation of the anterior insula (aINS) and the orbitofrontal cortex (OFC), where gustatory, olfactory and viscerosensory signals are integrated and where they are modulated by affective and cognitive input. The generation of such gut sensations can lead to the formation of interoceptive memories of the multidimensional experience associated with the sensation (such as the feeling of nausea associated with a disgusting experience or a particular taste with a pleasant social experience). The interoceptive memory is encoded within a distributed network involving the aINS, OFC, the amygdala (AMYG) and hippocampus (HIPP). Often, environmental stimuli that are unrelated to the gut, such as an image, sound or smell, may trigger the recall of these feeling states as meta-representations of the original gut-triggered sensation. The experience of such memories can result in the engagement of similar brain regions (aINS, anterior cingulate cortex (ACC), OFC and amygdala) in the absence of gut signalling. This recall may be the basis for feelings such as disgust, craving or emotional pain, in the absence of any interoceptive input from the gut, and may occur when watching another person in pain, when hearing about a disgusting experience or when viewing images of rich foods. Recall of such memories without conscious awareness may bias behavioural responses¹⁴⁹, and such behavioural biases may be a reflection of an internal value map based on ‘gut feelings’. 5-HT, 5-hydroxytryptamine (serotonin); CKK, cholecystokinin; CRF, corticotropin releasing factor; NPY, neuropeptide Y; PY, peptide YY; SP, substance P.

The close relationship between gut signalling systems, basic feeling states and meta-representations of these feeling states in basic emotions and behaviours is not limited to nutrient-related signals. Gut-based signalling systems that are related to an insult of gut homeostasis (by chemicals, toxins and inflammation) can easily fit into this general model. This includes the 5HT–5HT₃ receptor–vagal signalling system related to toxin-induced nausea¹⁰⁷, the cytokine–vagal signalling system¹⁰⁸ that is engaged in the generation of fatigue and sickness behaviour, and the CRF signalling system that is related to the threat of mucosal homeostasis by gut inflammation¹⁰⁹. The concept of a primordial stress response system that is related to immune activation, which is co-opted into a generalized stress response system for both interoceptive and exteroceptive stressors has previously been suggested¹¹⁰. Given the magnitude and complexity of gut-based signalling systems, compared to those of other organs, brain–gut interactions have to be considered an important, but largely ignored, component of the neuroscience of emotions.

Alterations in signalling systems

Extensive evidence supports the involvement of different peripheral signalling systems in perturbations of gut to brain signalling. For example, when intestinal enterochromaffin cells are activated by potentially noxious stimuli, such as food-related or bacterial toxins (or certain chemotherapeutic drugs), increased 5-HT release activates 5-HT₃ receptors on myenteric IPANs as well as on vagal afferents, resulting not only in exaggerated intestinal motor and secretory reflexes but also in the activation of brain regions receiving vagal input. Activation of this enterochromaf-fin cell–vagal afferent pathway by harmful substances, including certain pathogens, is associated with the subjective sensations of discomfort and nausea, and may be accompanied by vomiting. Together, the peripheral and central responses initiate a complex adaptive response aimed at expelling the offending agent.

Another well-characterized example of a brain–gut signalling system that is engaged during perturbation of homeostasis is the CRF signalling system. Central release of CRF during experimental stress, or central injection of this peptide in unstressed animals produces a distinct, stereotypic pattern of stress-induced gastrointestinal motor and secretory responses that are associated with anxiety-like behaviours²³. As the stress-induced gut response can be prevented by either peripheral or central CRF1 receptor antagonism, both peripheral and central CRF–CRF receptor 1 (CRFR1) signalling systems seem to be involved. The slowing or reversal of gastric motility and the acceleration of distal bowel motility and secretion result in the reduced exposure of the gastrointestinal tract to luminal factors, reducing the metabolic demand generated by gut-related motor, secretory and absorptive function, and shifting blood flow to the cardiovascular and skeletomotor system for the fight and flight response.

Inflammatory changes in the viscera, including the liver and the gut, can result in cytokine-mediated vagal activation of the hypothalamus and related limbic brain regions, resulting in hyperalgesia and social withdrawal referred to as ‘sickness behaviour’¹¹³. Additional non-vagal mechanisms by which peripheral cytokines can reach the CNS have been reported^114,115. Mucosal release of cytokines and other inflammatory mediators including bradykinin, histamine and proteases can also result in sensitization and activation of spinal afferent terminals, resulting in visceral hyperalgesia. Multiple effects of such inflammation or toxin-induced changes in afferent terminals have been reported, including release of neuropeptides such as substance P and calcitonin gene-related peptide from afferent nerve terminals¹¹⁶, development of mechanosensitivity of previously unresponsive afferents and development of peripheral and central sensitization, resulting in greatly increased signalling of visceral afferent information to the CNS⁵⁶.

Brain–gut interactions in chronic disease

Even though dysregulations of the brain–gut axis have been implicated in several chronic disorders, convincing evidence to support such a pathophysiological role is limited to several chronic gastrointestinal disorders (including so-called functional gastrointestinal disorders (FGIDs) and inflammatory bowel diseases (IBDs)) and to eating disorders, particularly obesity¹¹⁷ and anorexia nervosa⁸⁹.

FGIDs comprise a heterogeneous group of disorders characterized by chronically recurring pain and discomfort that is conveyed to different regions of the gastrointestinal tract. They are often associated with alterations in gastrointestinal function, and characterized by the absence of any agreed upon biological, physiological or anatomical abnormalities that would explain the symptoms¹¹⁸. In the majority of patients, increased levels of anxiety are present, and co-morbid diagnoses of anxiety and depression are seen in up to 60% of patients. Based on symptom criteria, but in the absence of any syndrome-specific pathophysiological findings, up to 40 different functional gastrointestinal syndromes have been postulated, including functional chest pain of presumed oesophageal origin, functional dyspepsia and irritable bowel syndrome (IBS)^118,119. A characteristic feature of all of these disorders is the frequent overlap of symptoms belonging to one syndrome with one or several others in the same patient, concurrently or at different life periods. One of the most common and best-studied syndromes is IBS^120,121. Despite intense clinical and preclinical research efforts during the past 20 years, no single biological abnormality has been identified that would explain the symptoms of chronically recurring pain and discomfort in all of the patients meeting current symptom-based criteria. Based on animal models and on studies performed in human patient populations, peripheral mechanisms that have been implicated include long lasting sensitization of primary afferent pathways innervating the intestine, altered microflora– epithelial–immune interactions (including alterations in mast cell regulation, increased epithelial permeability and altered gut microflora)¹²². Perceptual hypersensitivity to experimental and physiological gut signals is common among patients with IBS¹²³, but it remains unclear if this reflects an increased interoceptive signal from the gut, a central amplification mechanism related to altered cognitive and affective modulation of the perception of normal or even reduced gut signals. Based on a growing number of brain imaging studies in patients with IBS, alterations in brain responses to controlled gut distension as well as to expectation of such gut discomfort have been reported⁹. In a recent meta-analysis of 18 studies comparing brain responses to rectal distension in patients with IBS and healthy control subjects, patients with IBS showed greater activation of brain regions that are involved in the processing of visceral afferent information, in emotional arousal and in cortical modulation. Recent evidence suggests the presence of regional cortical thickness changes in corresponding brain regions^41,124. It remains to be determined whether the observed functional and structural brain changes are secondary to chronically increased gut to brain signalling and/or whether they are primary brain-based abnormalities that play a part in pain amplification and altered autonomic regulation of gut function. An important role of central dysregulation in IBS pathophysiology is suggested by the common co-morbidity with other functional gastrointestinal and non-gastrointestinal syndromes (including, but not limited to, interstitial cystitis or painful bladder syndrome, fibromyalgia and temporomandibular disorder), by the common affective co-morbidity, the prominent role of stress in symptom onset or exacerbation, the responsiveness of these syndromes to centrally targeted therapies (including tricyclic antidepressants and cognitive behavioural therapies) and the fact that the first onset of abdominal pain symptoms in children is often preceded by increased anxiety¹²⁵.

Inflammatory gastrointestinal disorders

Despite a wealth of preclinical data on the acute and persistent effects of gut inflammation on intrinsic and extrinsic gut innervation (reviewed in ^{REFS 56,74,112,126}), the role of chronic intestinal inflammation on symptoms and brain responses in human patients with inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, or gut infections are poorly understood. Surprisingly, abdominal pain or persistent visceral hyperalgesia to experimental stimuli is not a prominent feature in most patients with an uncomplicated IBD, and only a small percentage of patients with IBD or with infectious gastroenteritis, experience persistent pain once the inflammation has resolved¹²⁷. The effective engagement of peripheral¹²⁸ as well as central¹²⁹ pain inhibition systems have been proposed as plausible mechanisms for this paucity of pain symptoms in the majority of patients with IBD. Similarly to IBS, it remains to be determined whether commonly reported co-morbidity with anxiety and depression^130,131 is a consequence of the primary disease, plays a part in the chronicity of symptoms or is a vulnerability factor. Evidence from animal models supports a modulating role of the brain on gut inflammation¹³².

Eating disorders

Disturbances in ingestive behaviour are common in industrialized societies and both obesity and anorexia nervosa are major health problems in terms of morbidity, mortality and healthcare costs^133,134. Although obese subjects eat beyond their caloric needs, with food intake driven primarily by the craving for the hedonic value of food, despite the known negative health consequences¹¹⁷, individuals with anorexia nervosa have an ego-syntonic resistance to eating and an obsession with weight loss, despite a preoccupation with food and eating rituals⁸⁹.

Despite the extensive progress in the understanding of peripheral and central contributions of altered brain– gut interactions in obesity (reviewed in ^{REFS 117,135}), attempts at pharmacological treatments have been disappointing and various gastric surgical procedures are currently the most effective treatment¹³⁶. Even though the current obesity epidemic is likely to be multifactorial, a shift in the balance between hedonic and homeostatic regulation of food intake, a compromised effectiveness of cortical control mechanisms and changes in peripheral encoding mechanisms in the gut seem to play an important part. For example, diet-induced down-regulation of satiety-inducing gut to brain signaling mechanisms have been reported, including leptin and insulin resistance and alterations in the normal chole-cystokinin-dependent molecular switching mechanisms in vagal afferents during food intake from an orexigenic to an anorexigenic phenotype¹³⁷. At the same time, considerable evidence for alterations in the regulation of the hedonic aspects of food intake have been reported, consistent with the concept of food addiction¹³⁵. Brain imaging findings in humans who are obsese are consistent with an enhanced sensitivity of the reward circuitry to food cues (for example, viewing images of high caloric food) that predict reward, but a decreased sensitivity to the rewarding effects of actual food ingestion (interoceptive stimuli) in dopaminergic pathways. As several of the gut peptides are able to stimulate the central dopamine system (including ghrelin, leptin and insulin), the observed changes in the central reward circuits may in part be due to diet-related neuroplastic alterations in peripheral encoding mechanisms and the reduced responsiveness of interoceptive signalling mechanisms from the gut.

The alterations in the central regulation of food intake in anorexia nervosa have recently been reviewed⁸⁹. Despite the behavioural abnormalities, and more recently the brain abnormalities, that have been reported in patients, little is known about possible alterations in gut to brain signalling mechanisms and in particular about possible alterations in vagally mediated neu-ropeptide signalling to the brain. However, the fact that patients with anorexia nervosa showed reduced responses in homeostatic afferent brain regions (the aINS and ACC) in response to oral sucrose administration and that no correlation between activity in these regions and self-ratings of the pleasantness of the administered sucrose was observed, suggest that the influence of interoceptive signals from the gastrointestinal tract on ingestive behaviour is reduced.

Supported by grants DK048351, {"type":"entrez-nucleotide","attrs":{"text":"DK064539","term_id":"187405325","term_text":"DK064539"}}DK064539, {"type":"entrez-nucleotide","attrs":{"text":"DK082370","term_id":"187379454","term_text":"DK082370"}}DK082370 and {"type":"entrez-nucleotide","attrs":{"text":"AT002681","term_id":"6934408","term_text":"AT002681"}}AT002681 from the National Institutes of Health.