Neuroimmunophysiology of the gastrointestinal tract.

Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.

Control of colonic motility using electrical stimulation to modulate enteric neural activity.

Electrical stimulation of the enteric nervous system (ENS) is an attractive approach to modify gastrointestinal transit. Colonic motor complexes (CMCs) occur with a periodic rhythm, but the ability to elicit a premature CMC depends, at least in part, upon the intrinsic refractory properties of the ENS, which are presently unknown. The objectives of this study were to record myoelectric complexes (MCs, the electrical correlates of CMCs) in the smooth muscle and 1) determine the refractory periods of MCs, 2) inform and evaluate closed-loop stimulation to repetitively evoke MCs, and 3) identify stimulation methods to suppress MC propagation. We dissected the colon from male and female C57BL/6 mice, preserving the integrity of intrinsic circuitry while removing the extrinsic nerves, and measured properties of spontaneous and evoked MCs in vitro. Hexamethonium abolished spontaneous and evoked MCs, confirming the necessary involvement of the ENS for electrically evoked MCs. Electrical stimulation reduced the mean interval between evoked and spontaneous CMCs (24.6 ± 3.5 vs. 70.6 ± 15.7 s, P = 0.0002, n = 7). The absolute refractory period was 4.3 s (95% confidence interval (CI) = 2.8-5.7 s, R2 = 0.7315, n = 8). Electrical stimulation applied during fluid distention-evoked MCs led to an arrest of MC propagation, and following stimulation, MC propagation resumed at an increased velocity (n = 9). The timing parameters of electrical stimulation increased the rate of evoked MCs and the duration of entrainment of MCs, and the refractory period provides insight into timing considerations for designing neuromodulation strategies to treat colonic dysmotility.NEW & NOTEWORTHY Maintained physiological distension of the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs). MCs evoked repeatedly by closed-loop electrical stimulation entrain MCs more frequently than spontaneously occurring MCs. Electrical stimulation delivered at the onset of a contraction temporarily suppresses the propagation of MC contractions. Controlled electrical stimulation can either evoke MCs or temporarily delay MCs in the isolated mouse colon, depending on timing relative to ongoing activity.

Influence of Acetylcholine Esterase Inhibitors and Memantine, Clinically Approved for Alzheimer's Dementia Treatment, on Intestinal Properties of the Mouse.

Four drugs are currently approved for the treatment of Alzheimer's disease (AD) by the FDA. Three of these drugs-donepezil, rivastigmine, and galantamine-belong to the class of acetylcholine esterase inhibitors. Memantine, a NMDA receptor antagonist, represents the fourth and a combination of donepezil and memantine the fifth treatment option. Recently, the gut and its habitants, its microbiome, came into focus of AD research and added another important factor to therapeutic considerations. While the first data provide evidence that AD patients might carry an altered microbiome, the influence of administered drugs on gut properties and commensals have been largely ignored so far. However, the occurrence of digestive side effects with these drugs and the knowledge that cholinergic transmission is crucial for several gut functions enforces the question if, and how, this medication influences the gastrointestinal system and its microbial stocking. Here, we investigated aspects such as microbial viability, colonic propulsion, and properties of enteric neurons, affected by assumed intestinal concentration of the four drugs using the mouse as a model organism. All ex vivo administered drugs revealed no direct effect on fecal bacteria viability and only a high dosage of memantine resulted in reduced biofilm formation of E. coli. Memantine was additionally the only compound that elevated calcium influx in enteric neurons, while all acetylcholine esterase inhibitors significantly reduced esterase activity in colonic tissue specimen and prolonged propulsion time. Both, acetylcholine esterase inhibitors and memantine, had no effect on general viability and neurite outgrowth of enteric neurons. In sum, our findings indicate that all AD symptomatic drugs have the potential to affect distinct intestinal functions and with this-directly or indirectly-microbial commensals.

Hypnosis and Cognitive Behavioral Therapies for the Management of Gastrointestinal Disorders.

PURPOSE OF REVIEW: To review the nature, current evidence of efficacy, recent developments, and future prospects for cognitive behavioral therapy (CBT) and gut-directed hypnotherapy, the two best established psychological interventions for managing gastrointestinal (GI) disorders. RECENT FINDINGS: New large randomized controlled trials are showing that cost-effective therapy delivery formats (telephone-based, Internet-based, fewer therapist sessions, or group therapy) are effective for treating GI disorders. CBT and hypnotherapy can produce substantial improvement in the digestive tract symptoms, psychological well-being, and quality of life of GI patients. However, they have long been hampered by limited scalability and significant cost, and only been sufficiently tested for a few GI health problems. Through adoption of more cost-effective therapy formats and teletherapy, and by expanding the scope of efficacy testing to additional GI treatment targets, these interventions have the potential to become widely available options for improving clinical outcomes for patients with hard-to-treat GI disorders.

Regulating the Enteric Nervous System against Obesity in Mice by Electroacupuncture.

BACKGROUND AND OBJECTIVES: The enteric nervous system (ENS) dominates the onset of obesity and has been shown to regulate nutrient absorption and energy metabolism. METHODS AND STUDY DESIGN: This study was performed to investigate the role of electroacupuncture in regulating ENS function in obese mice. Obese mice were obtained by high-fat diet. 16S rRNA pyrosequencing, Western blotting, quantitative PCR, and neurotransmitter analysis were used for this purpose. RESULTS: Body weight, Lee index, serum lipid, leptin, and adiponectin levels, and other basic indices were significantly ameliorated after electroacupuncture intervention. The pathological ENS scores, serum neurotransmitter levels, and intestinal transit rate were markedly changed in obese mice. Moreover, electroacupuncture promoted the diversity of gut microbiota. No significant differences were observed 21 and 28 days after electroacupuncture. CONCLUSIONS: These results suggested ENS may be a new treatment approach to obesity.

Alterations in Galanin-Like Immunoreactivity in the Enteric Nervous System of the Porcine Stomach Following Acrylamide Supplementation.

In recent years, a significant increase in the consumption of products containing large amounts of acrylamide (e.g., chips, fries, coffee), especially among young people has been noted. The present study was created to establish the impact of acrylamide supplementation, in tolerable daily intake (TDI) dose and a dose ten times higher than TDI, on the population of galanin-like immunoreactive (GAL-LI) stomach neurons in pigs. Additionally, in the present study, the possible functional co-operation of GAL with other neuroactive substances and their role in acrylamide intoxication was investigated. Using double-labelling immunohistochemistry, alterations in the expression of GAL were examined in the porcine stomach enteric neurons after low and high doses of acrylamide supplementation. Generally, upregulation in GAL-LI immunoreactivity in both myenteric and submucous plexuses was noted in all stomach fragments studied. Additionally, the proportion of GAL-expressing cell bodies simultaneously immunoreactive to vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS) and cocaine- and amphetamine- regulated transcript peptide (CART) also increased. The results suggest neurotrophic or/and neuroprotective properties of GAL and possible co-operation of GAL with VIP, nNOS, CART in the recovery processes in the stomach enteric nervous system (ENS) neurons following acrylamide intoxication.

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease.

The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.

Electro-acupuncture at ST37 and ST25 induce different effects on colonic motility via the enteric nervous system by affecting excitatory and inhibitory neurons.

BACKGROUND: On the basis of the importance of the enteric nervous system (ENS) in gastrointestinal motility, we hypothesized that the ENS may mediate the therapeutic efficacy of electro-acupuncture (EA) in constipation by regulating the mechanisms underlying the effects of EA on gastrointestinal function. METHODS: Model mice with constipation were generated by gastric instillation of 0-4°C normal saline. Defecation time and stool (form and wet and dry weight) were assessed. The effect of EA at ST37 or ST25 on colorectal motility and proximal colonic motility was assessed using a water-filled balloon. The expression of protein gene product 9.5 (PGP9.5), the cholinergic neuron marker acetyltransferase (ChAT) and the anticholinergic neuron marker nitric oxide synthase (nNOS) was detected by immunohistochemistry, real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. KEY RESULTS: ST37 and ST25 improved colorectal pressure; however, ST37 but not ST25 improved proximal colonic pressure. In the proximal colon, the expression of PGP9.5 returned to normal after EA at ST 37, while EA at ST25 did not have this effect. In addition, qPCR and western blot analysis showed that ST37 could downregulate the expression of nNOS and upregulate the expression of ChAT to normal levels, while ST25 could only downregulate the expression of nNOS to normal levels. CONCLUSIONS AND INFERENCES: Electro-acupuncture at specific acupoints can improve intestinal motility in constipation by altering the ENS and differentially affecting excitatory and inhibitory neurons, restoring the coordination between contraction and relaxation muscles, and working in concert with the central nervous system and peripheral neural pathways.

Apelin targets gut contraction to control glucose metabolism via the brain.

OBJECTIVE: The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. DESIGN: We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. RESULTS: In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. CONCLUSIONS: Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.

High-Dose Radiation-Induced Changes in Murine Small Intestinal Motility: Are the Changes in the Interstitial Cells of Cajal or in the Enteric Nervous System?

Murine small intestinal motility consists of phasic contraction from interstitial cells of Cajal (ICC) and migrating motor complexes (MMCs) from the enteric nervous system. The number of ICC is reduced in various gastrointestinal disorders, and this effect can be reversed once the disorder is resolved through cellular and tissue remodelling. Exposure to high-dose radiation can induce inflammation and alter intestinal motility. In this study, we investigated the changes in the small intestinal motility of 8- to 10-week-old male C3H/HeN mice after high-dose (13 Gy) irradiation. The aim of this study was to determine whether those changes are caused by changes in the ICC or enteric nervous system. After irradiation, the small intestine was dissected and stored in oxygenated Krebs-Ringer bicarbonate solution. The tension of contractions and intracellular membrane potentials were recorded at day 0, 1, 3 and 5 after irradiation and compared with those of sham-irradiated mice. Histological evaluation was performed by immunohistochemistry and apoptosis was evaluated. Quantitative real-time polymerase chain reaction (qPCR) for c-kit mRNA was also performed. Phasic contractions were not changed at day 0, 1, 3 and 5 after irradiation and did not significantly differ from those in the control mice. Slow waves were also sustained after irradiation. However, the frequency of migrating motor complexes (MMCs) was significantly higher at day 0 and 1 after exposure and the amplitude and area under the curve were significantly lower at day 3 after exposure compared with control mice. MMCs were recovered at day 5 with no difference from those of the control mice. ICC were detected after irradiation by immunohistochemistry for c-kit, and c-kit mRNA levels did not differ between sham-irradiated and irradiated mice. Histological evaluation showed that the most severe inflammation was detected at day 3 after irradiation, and apoptosis was detected only in the mucosa. Acetylcholine increased the contractility after irradiation, and tetrodotoxin decreased the number of MMCs in sham-irradiated and irradiated mice. N(w)-oxide-l-arginine (L-NA) increased the number of MMCs. MMCs were recovered after L-NA treatment at day 3 after irradiation. Sodium nitroprusside decreased the MMCs in sham-irradiated and irradiated mice. Exposure to high-dose radiation did not alter phasic contractions and slow waves in the small intestine of mice, which suggests that ICC and their functions may be sustained after high-dose irradiation. Mucosal inflammation was severe after irradiation and there were some changes in MMCs related to the enteric nervous system.

Gastrointestinal hormones and gut motility.

PURPOSE OF REVIEW: To summarize the recent findings. RECENT FINDINGS: Studies of changes in the plasma levels confirm the earlier concepts, but offer little proof of causal effect. It is increasingly realized that peptides produced in the gut have a paracrine role or an indirect effect via the gut-brain axis. Interest in prokinetic peptide agonists remains high despite the failure of two candidate drugs, but relamorelin and camicinal offer new hope. SUMMARY: We review the original studies published since January 2013 on peptides produced in the gut and with an effect on gastrointestinal motility.

Effects of ginsenoside Re on rat jejunal contractility.

Ginsenoside Re (GRe) exerts diverse effects. Based on our observations, the present study was designed to investigate GRe-exerted bidirectional regulation (BR) on the contractility of isolated jejunal segment. Six pairs of different low and high contractile states of rat jejunal segment were established and used in the study. Stimulatory effects on the contractility of jejunal segment were exerted by GRe (10.0 µM) in all 6 low contractile states, and inhibitory effects were exerted in all 6 high contractile states, indicating that GRe exerted BR on the contractility of jejunal segment. The effects of GRe on the phosphorylation of 20 kDa myosin light chain, protein contents of myosin light chain kinase (MLCK) and MLCK mRNA expression in jejunal segment in low and high contractile states were also bidirectional. GRe-exerted BR was abolished in the presence of neurotoxin tetrodotoxin or Ca2+ channel blocker verapamil or c-Kit receptor tyrosine kinase inhibitor imatinib. Atropine blocked the stimulatory effects of GRe on jejunal contractility in low-Ca2+-induced low contractile state; phentolamine, propranolol and l-NG-nitro-arginine blocked the inhibitory effects in high-Ca2+-induced high contractile state, respectively. In summary, GRe-exerted BR depends on jejunal contractile state and requires the presence of enteric nervous system, Ca2+, and interstitial cells of Cajal; the stimulatory effects of GRe on jejunal contractility are related to cholinergic stimulation and inhibitory effects are related to adrenergic activation and nitric oxide relaxing mechanisms.

Effect of feeding colostrum versus exogenous immunoglobulin G on gastrointestinal structure and enteric nervous system in newborn pigs.

Colostrum is an indispensable source of antibodies (IgG) protecting the newborn pig against infection. We studied the effect of feeding colostrum and purified IgG on early structure and development of the gastrointestinal tract (GIT). Newborn littermate pigs were fed either colostrum, an elemental diet (ED), or an ED supplemented with purified serum IgG (ED + IgG) for 24 h or then only ED up to 72 h. Afterwards, pigs were slaughtered. Colostrum-fed pigs or ED supplemented with IgG (ED + IgG) increased thickness (P < 0.001) of stomach mucosa and muscularis (P < 0.05) compared to the ED group not receiving IgG. Feeding an ED supplemented with IgG improved morphology of the GIT towards that of colostrum-fed piglets and indicates a beneficial effect of IgG on GIT development in neonatal pigs. Immunohistochemical studies indicate that ED feeding may influence the expression of nitric oxide synthase in jejunal myenteric (but not submucous) neurons of newborn pigs.

How sacral nerve stimulation works in patients with faecal incontinence.

AIM: Sacral nerve stimulation (SNS) reduces incontinence episodes and improves the quality of life of patients treated for faecal incontinence. However, the exact mechanism of action of this technique remains unclear. The present article reviews the pertinent neuroanatomy and neurophysiology related to SNS and provides explanations for potential mechanisms of action. METHOD: A systematic review of the literature was performed for studies of the potential mechanisms of action of SNS, using MEDLINE, PubMed, Embase and the Cochrane Library. Articles dealing with the technique, adverse events and economic evaluations of SNS, as well as literature reviews, were excluded, except for reviews dealing with the mechanisms of action of SNS. The following inclusion criteria were used to select articles: (i) articles in English, (ii) randomized, double-blinded, sham-controlled studies, and (iii) cohort studies. Case-control studies or retrospective studies were cited only when randomized or cohort studies could not be found. RESULTS: We propose three hypotheses to explain the mechanism of action of SNS: (i) a somato-visceral reflex, (ii) a modulation of the perception of afferent information, and (iii) an increase in external anal sphincter activity. CONCLUSION: The mechanism of action of SNS in patients with faecal incontinence almost certainly depends on the modulation of spinal and/or supraspinal afferent inputs. Further research on humans and animals will be required to gain a better understanding of the mechanisms of action of SNS.

Enteric glia protect against Shigella flexneri invasion in intestinal epithelial cells: a role for S-nitrosoglutathione.

BACKGROUND: Enteric glial cells (EGCs) are important regulators of intestinal epithelial barrier (IEB) functions. EGC-derived S-nitrosoglutathione (GSNO) has been shown to regulate IEB permeability. Whether EGCs and GSNO protect the IEB during infectious insult by pathogens such as Shigella flexneri is not known. METHODS: S flexneri effects were characterised using in vitro coculture models of Caco-2 cells and EGCs (or GSNO), ex vivo human colonic mucosa, and in vivo ligated rabbit intestinal loops. The effect of EGCs on S flexneri-induced changes in the invasion area and the inflammatory response were analysed by combining immunohistochemical, ELISA and PCR methods. Expression of small G-proteins was analysed by western blot. Expression of ZO-1 and localisation of bacteria were analysed by fluorescence microscopy. RESULTS: EGCs significantly reduced barrier lesions and inflammatory response induced by S flexneri in Caco-2 monolayers. The EGC-mediated effects were reproduced by GSNO, but not by reduced glutathione, and pharmacological inhibition of pathways involved in GSNO synthesis reduced EGC protecting effects. Furthermore, expression of Cdc42 and phospho-PAK in Caco-2 monolayers was significantly reduced in the presence of EGCs or GSNO. In addition, changes in ZO-1 expression and distribution induced by S flexneri were prevented by EGCs and GSNO. Finally, GSNO reduced S flexneri-induced lesions of the IEB in human mucosal colonic explants and in a rabbit model of shigellosis. CONCLUSION: These results highlight a major protective function of EGCs and GSNO in the IEB against S flexneri attack. Consequently, this study lays the scientific basis for using GSNO to reduce barrier susceptibility to infectious or inflammatory challenge.

Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together?

The gastrointestinal system can be considered the gateway for food entry in our body. Rather than being a passive player, it is now clear that gut strongly influence the feeding behavior and contribute to maintain energy balance with different signals. The aim of this review is to summarize the current knowledge about the role of gastrointestinal tract in the control of food intake, by focusing on the interplay existing between the enteric nervous system and gastrointestinal hormones and their ability to modulate digestive motility and sensitivity. Also the latest advances about the contribution of gut microbiota and gastrointestinal taste receptors are described. From the reported data it clearly emerges that gut hormones together with nervous signals likely contribute to the regulation of energy balance and modulate food intake through the control of digestive motility and sensations. The close linkage among gastrointestinal hormones, the gut and the central nervous systems appears very intriguing and has induced the development of a new field of research: the gastroendocrinology.

Sialic acid feeding aged rats rejuvenates stimulated salivation and colon enteric neuron chemotypes.

Old age is linked to numerous changes of body functions such as salivation, gastrointestinal motility, and permeability all linked to central and enteric nervous system decline. Thus, gut motility and barrier functions suffer. Sialic acid plays a key role in the nervous system at large and for many receptor functions specifically. Decreased sialylation in the elderly suggests an endogenous sialic acid deficit. We used a rat model of aging, to ask whether sialic acid feeding would affect (i) stimulated salivation, (ii) gut functions, and (iii) sialic acid levels and neuronal markers in brain and gut. We observed reduced levels of pilocarpine-stimulated salivation in old versus young rats and restored this function by sialic acid feeding. Brain ganglioside bound sialic acid levels were found lower in aged versus young rats, and sialic acid feeding partly restored the levels. The hypothalamic expression of cholinergic and panneuronal markers was reduced in aged rats. The expression of the nitrergic marker nNOS was increased upon sialic acid feeding in aged rats. Neither fecal output nor gut permeability was different between young and aged rats studied here, and sialic acid feeding did not alter these parameters. However, the colonic expression of specific nervous system markers nNOS and Uchl1 and the key enzyme for sialic acid synthesis GNE were differentially affected in young and aged rats by sialic acid feeding indicating that regulatory mechanisms change with age. Investigation of sialic acid supplementation as a functional nutrient in the elderly may help those who suffer from disorders of reduced salivation. Further research is needed to understand the differential effects of sialic acid feeding in young and aged rats.

Pyloric neuron morphology in the stomatogastric ganglion of the lobster, Panulirus interruptus.

The pyloric network of decapod crustaceans has been intensively studied electrophysiologically in the infraorders Astacidea, Brachyura, and Palinura. The morphology of some or all pyloric neurons has been well described in Astacidea and Brachyura, but less so in Palinura. Given the large evolutionary distance between these three groups, and the large amount of electrophysiology that has been performed in palinuroid species, it is important to fill this gap. We describe here the gross morphology of all six pyloric neuron types in a palinuroid, P. interruptus. All pyloric neurons had complicated, extended dendritic trees that filled the majority of the neuropil, with most small diameter processes present in a shell near the surface of the ganglion. Certain neuron types showed modest preferences for somata location in the ganglion, but these differences were too weak to use as identifying characteristics. Quantitative measurements of secondary branch number, maximum branch order, total process length, and neuron somata diameter were also, in general, insufficient to distinguish among the neurons, although AB and LP neuron somata diameters differed from those of the other types. One neuron type (VD) had a distinctive neurite branching pattern consisting of a small initial branch followed shortly by a bifurcation of the main neurite. The processes arising from these two branches occupied largely non-overlapping neuropil. Electrophysiological recordings showed that each major branch had its own spike initiation zone and that, although the zones fired correlated spikes, they generated spikes independently. VD neurons in the other infraorders have similar morphologies, suggesting that having two arbors is important for the function of this neuron. These data are similar to those previously obtained in Brachyura and Astacidea. It thus appears that, despite their long evolutionary separation, neuron morphology in these three infraorders has not greatly diverged.

Gut-brain axis.

PURPOSE OF REVIEW: To summarize recent studies on the regulation and the functions of the gut-brain axis. RECENT FINDINGS: Visual cues of food and food intake interact with the gut-brain axis at the level of the hypothalamus. However, the hypothalamic response to glucose intake is considerably altered in patients with type 2 diabetes mellitus, indicating involvement of the hypothalamus in the pathophysiology of this disease in humans. A large number of studies have documented the functions of gut peptides with respect to the regulation of satiety. Gut peptides are involved in the regulation of insulin secretion and sensitivity. Recent data indicate that peptide YY is a gut hormone that also modulates bone metabolism. Increasing evidence is obtained on the role of afferent gastrointestinal nerves, especially the vagal nerve, in the modulation of the functions of the gut-brain axis. SUMMARY: The gut-brain axis is involved in a multitude of physiological processes including satiety, food intake, regulation of glucose and fat metabolism, insulin secretion and sensitivity and bone metabolism. It is likely, that more aspects of this system will be found the near future.

Gut-brain axis: regulation of glucose metabolism.

Obesity and type II diabetes mellitus have reached epidemic proportions. From this perspective, knowledge about the regulation of satiety and food intake is more important than ever. The gut releases several peptides upon feeding, which affect hypothalamic pathways involved in the regulation of satiety and metabolism. Within the hypothalamus, there are complex interactions between many nuclei of which the arcuate nucleus is considered as one of the most important hypothalamic centres that regulates food intake. The neuropeptides, which are present in the hypothalamus and are involved in regulating food intake, also play a key role in regulating glucose metabolism and energy expenditure. In synchrony with the effects of those neuropeptides, gastrointestinal hormones also affect glucose metabolism and energy expenditure. In this review, the effects of the gastrointestinal hormones ghrelin, cholecystokinin, peptide YY, glucagon-like peptide, oxyntomodulin and gastric inhibitory polypeptide on glucose and energy metabolism are reviewed. These gut hormones affect glucose metabolism at different levels: by altering food intake and body weight, and thereby insulin sensitivity; by affecting gastric delay and gut motility, and thereby meal-related fluctuations in glucose levels; by affecting insulin secretion, and thereby plasma glucose levels, and by affecting tissue specific insulin sensitivity of glucose metabolism. These observations point to the notion of a major role of the gut-brain axis in the integrative physiology of whole body fuel metabolism.