Neurohormonal control of intestinal transit L Bueno, Jean Fioramonti

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L Bueno, Jean Fioramonti. Neurohormonal control of intestinal transit. Reproduction Nutrition Development, EDP Sciences, 1994, 34 (6), pp.513-525. ￿hal-00899677￿

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L Bueno J Fioramonti

INRA, Department of Pharmacology, BP 3, 31931 Toulouse, France

Summary ― This review shows that numerous neuropeptides and hormones are involved in the reg- ulation of intestinal transit. Many gastrointestinal hormones known to act on smooth muscle to influence muscle contractility also play a role in the genesis of abrupt changes associated with alimentary behaviour. In many monogastrics and ruminants, the cyclic occurrence of the migrating motor complex (MMC) is linked to peripheral hormonal factors only slightly influenced by the nature of food. is the major homone involved in triggering the gastric migrating motor complex while somatostatine and enkephalins are implicated in the propagation along the . Other hormones, like CCK8, insulin, , and neurotensin, trigger the development of an intestinal feed pattern but CCK released at the central nervous system ventromedial hypothalamus is involved in maintaining the postprandial type of activity. Gastrointestinal transit may be altered in physiopathological situations in which CRF, TRH and some cytokines (IL1 1!, TNFa) play an important role. / colon / motility / transit / hormone / neuropeptide / brain / motilin / CCK

Résumé ― Contrôle neuro-hormonal du transit intestinal. De nombreux peptides et hormones diges- tives sont impliqués dans la régulation du transit intestinal. Ils agissent soit directement sur la cellule musculaire lisse, soit possèdent des sites d’action relevant de l’innervation intrinsèque mais peuvent agir également au niveau supraspinal où ils sont responsables des adaptations motrices rapides en réponse à des stimuli externes tels que la prise alimentaire. Chez la plupart des monogastriques et chez les ruminants, l’apparition de cycles réguliers d’activité motrice que constituent les complexes moteurs migrants (CMM) est liée à des variations cycliques de la libération d’une hormone digestive : la moti- line, indépendemment de facteurs alimentaires externes. La propagation de cette activité est sous le double contrôle de la somatostatine et des enképhalines. D’autres hormones telles que la CCKB, l’in- suline, la gastrine et la neurotensine sont impliquées à plusieurs niveaux pour initier le profil d’activité postprandiale mais la CCK libérée au niveau de l’hypothalamus ventromédian intervient de façon pri- vilégiée pour maintenir ce profil pendant toute la phase digestive. Enfin, récemment, il a été montré que les altérations motrices dans des situations physiopathologiques relèvent de l’intervention de pep- tides spécifiques (CRF, TRH) ou de certaines cytokines (IL 1{3, TNFa) dont les mécanismes d’action ne sont pas totalement élucidés. appareil digestif / côlon / motricité / transit / hormones / neuropeptides / fibres / motiline / CCK l aliments INTRODUCTION neurons in vagal nerves (Abrahamsson, 1973), which enables it to accomodate food The major function of the intestine is to digest delivery by the cesophagus. The contrac- food, assimilate nutrients and expel non- tions of the corpus and the antrum are coor- digestible residues. These functions are dinated and a slow contraction of the cor- directly related to its motility which is respon- pus lasting approximately 30 s is associated sible for the intestinal delivery and transport with 3-5 more rapid contractions of the of digesta. antrum (Gill et al, 1985). After a meal, the is The fact that feeding affects gastro- digestive pattern characterized by steady intestinal motility has been known since the low-amplitude contractions (4-5 per min) in last century when Beaumont (1833) the gastric antrum with no significant motor described the changes in amplitude and fre- activity in the gastric body. quency of gastric contractions associated A cyclic pattern of gastric motility has with feeding. From 1940, improvements of been found in the dog (Itoh et al, 1977) and our knowledge of mechanical events occur- in man (Rees etal, 1982). In the rat (Bueno ring in the digestive tract were associated et al, 1982) and the rabbit (Deloof and with the development of manometric methods Rousseau, 1985) there is no cyclic organi- which permitted the recognition of the major zation of the gastric motility, and feeding patterns of gastrointestinal motility. However,r, induces an increase of both the amplitude a major step was linked to the use of elec- and frequency of the contractions. tromyographic techniques, which have allowed a clear identification of the charac- teristics of the fasted pattern, ie the migrating Small intestine motor (or myoelectric) complex (MMC) in and in other animal dogs (Szurszewski, 1969) The basic motor pattern of many animal species (Bu6no et al, 1975; Ruckebusch and species investigated consists of MMCs, first it has been Fioramonti, 1975). Recently, identified as &dquo;a caudad band of large-ampli- shown that the motor changes associated tude action potentials starting in the duode- with are related to the nature of food feeding num and traversing the small bowel&dquo; and caloric intake and that some peptides (Szurszewski, 1969). Each MMC corre- play a specific role in their genesis. sponds to 3 consecutive phases: phase 1 has little or no contractile activity (quiescent phase), phase 2 has intermittent and irregular PATTERNS OF MOTILITY contractions, while the contractions of phase AND DIGESTIVE STATUS 3 occur at their maximal rate, which is deter- mined by the frequency of the slow waves. The duration of phase 3 activity is relatively constant, but that of other phases varies from cycle to cycle, depending on the flow of In many species, manometric recordings of digesta (Ruckebusch and Bueno, 1977). antral motility during fasting or interdiges- Depending on the animal species, the MMC tive periods exhibit a cyclic pattern of high- cycle length varies between 60 and 120 min amplitude contractions grouped in phases (Bueno and Ruckebusch, 1978) except in separated by periods of quiescence and rats in which MMCs recur at 15-20 min inter- appearing at 90-120 min intervals. The vals (Ruckebush and Fioramonti, 1975). important property of the proximal stomach Feeding is accompanied by a disruption is receptive relaxation, mediated by inhibitory of the intestinal MMC to give a ’postprandial’ pattern characterized by the irregular occur- faeces in pellets, such as the rabbit or the rence of contractions similar to those sheep (Fioramonti, 1981).). observed during phase 2 of the MMC The typical characteristic of colonic motil- et Code and (Bueno al, 1975; Marlett, ity in man, not seen in animals, consists of 1975). a very low activity during the night (Frexi- This disruption of the MMC pattern is nos et al, 1985). After a 3 000-4 000 kJ related to the energy content of the meal, meal the frequency of colonic contractions is the nature of nutrients and the frequency increased for 2-3 h. Such an increase in of meals. However, non-nutrient factors are colonic motility after a meal seems to be a also involved in the postprandial disruption common feature. of the MMC pattern, since sham-feeding delays the next phase 3 in man (Defilippi and Valenzuela, 1981). On the other hand, RELATIONSHIPS BETWEEN MOTILITY meal frequency modulates the effects of AND FLOW OF DIGESTA feeding on small intestinal motility. For example, in pigs (Ruckebusch and Bueno, 1976) and in rats (Ruckebusch and Ferre, Stomach 1973) ingestion of a daily large meal dis- rupts the MMC for several hours, while In terms of transit of digesta, the 3 major under ad libitum feeding the MMC fre- functions of the stomach are the receipt of quency is similar to that observed in the food, the storage of ingested food and the fasted state. However, in adult and neona- emptying of liquids and solids. tal pigs, feeding a standard meal only induces a 1-h delay in the onset of the next The entry of a large amount of food into phase 3 (Burrows et al, 1986; Rayner and the stomach leads to adaptive (or recep- Wenham, 1986). tive) relaxation of the proximal part of the stomach acting as a reservoir (Jahnberg, 1977). The rhythmic contractions of the dis- tal stomach are thought to control the tritu- ration and emptying of solids, whereas the tonic contractions of the proximal stomach A common feature of the colon in all mam- govern the rate of emptying of liquids. The malian is a of species investigated duality pylorus prevents duodenogastric reflux, but the contractile activity: tonic contractions is also a true sphincter which controls the to myoelectrical events char- corresponding empyting of food from the stomach. acterized by prolonged series of short spike bursts and phasic contractions corre- to isolated and sponding propagated long Small intestine spike bursts. However, the spatial and tem- poral organization of these 2 kinds of con- tractions, which form the colonic motor pat- The greatest flow of digesta occurs during tern, is specific to each mammalian species the postprandial disruption of the MMC pat- so far investigated. This pattern is inde- tern, but the role of MMCs in the propulsion pendent of colonic anatomy and of the tra- of digesta is not negligible since, at least in ditional regimen of the animal species, but dogs, gastric emptying in not terminated gross similarities exist within species pro- when the MMCs reappear on the ducing moulded faeces such as the pig, (Banta et al, 1979). However the propulsive dog or man, and within species that form role of each phase of the MMC still remains controversial depending on the experimen- Postprandial contractile patterns and tran- tal model: the maximal transit rate of a sit and the distance over which the con- marker has been found associated with tractions are propagated vary according to phase 3 using a jejunal isolated loop (Sarr et the nature of the ingesta (fig 2) (Schemann al, 1980) or with phase 2 when experiments and Hans-J6rg, 1986). were on an intact intestine in the performed Eventhough there are clear relationships same species. between motility patterns and chemical con- Using an electromagnetic flowmeter to tents of the food, the physical nature of the measure digesta flow continuously and elec- digesta and particularly its viscosity plays tromyography to record intestinal motility, it an important role in the efficacy of propulsive has been observed in sheep that the major- waves. In dogs, it has been established that ity of intestinal contents flowed intermittently similar patterns of intestinal motility are for periods of 10-15 min at the same fre- induced by bran and cellulose but with very quency as the MMC (fig 1 Two-thirds of different rates of propulsion while bran and this flow occurred in the 4-6 min immedi- guar gum induce similar transit time (fig 3) ately preceding the periods of phase 3 but with different motor patterns (Bueno et migration (Bueno et al, 1975). al, 1981).).

LARGE INTESTINE In dogs, the spontaneous fluctuations of the phasic activity are positively correlated The 2 kinds of colonic contractile activity have with the spontaneous changes in the veloc- opposite effects on the propulsion of digesta. ity of transit of a marker introduced in the Phasic contractions ensure the mixing and proximal colon (Fioramonti etal, 1980). Sim- the aboral progression of colonic contents ilarly in pigs, a low-residue diet induces a while the tonic activity acts as a brake. 3-fold increase in colonic mean retention time which was related to a decrease in pha- insulin (Bueno and Ruckebusch, 1976), sic activity and an increase in tonic activity (CCK) (Mukhopadhyay et (Fioramonti and Bueno, 1980) (fig 4). al, 1977; Wingate et al, 1978a), , and neu- However, in humans, despite the many glucagon (Wingate et al, 1978b), rotensin Saffar and Thor et studies of colonic motility or colonic transit (AI Rosell, 1981; time, relations between muscle activities al, 1982) alter the pattern of intestinal motil- and digesta movement have not been fully ity and/or transit when infused intravenously. elucidated. However, it is unlikely that a single hormone is responsible for the postprandial change of the gastrointestinal motor pattern since for NEUROHORMONAL FACTORS each hormone there are arguments against a physiological motor action. For example, a long-lasting disruption of the MMC occurs Hormones involved after fat ingestion in dogs, but with no sig- nificant increase in plasma gastrin and insulin (Eeckhout et al, 1978). Indeed sig- Among the hormones released during a nificant increases in gastrin and insulin con- meal, et al, 1974; Marik gastrin (Weisbrodt centrations in blood induced by glucose and Code, 1975; Wingate et al, 1978a), ingestion or intravenous infusion are not associated with a disruption of the MMC pattern (Eeckhout et al, 1978). Similarly the disruptive effect of insulin infusion on MMCs is abolished in pigs when a normal blood glucose level is maintained by a concomitant glucose infusion (Rayner et al, 1981 On the other hand, infusions of CCK or gastrin, or both, disrupt the duodenal MMC in dogs, but the cyclic peaks of motilin concentra- tions in blood persist, while in the same ani- mals plasma motilin is reduced after a meal (Lee et al, 1980). In both rats and humans, neurotensin infusion induces a pattern of intestinal con- tractions very similar to that observed after feeding and accelerates intestinal transit (AI Saffar and Rosell, 1981; Thor et al, 1982; Shaw and Buchanan, 1983). In rats intesti- nal neurotensin exhibits circadian variations, with a maximum during the night which cor- responds to a period of intense ingestive behaviour associated with the disruption of MMCs (Ferris et al, 1986). Regulation of the postprandial motility and transit by hormones is a very attractive hypothesis and hormones are undoubtedly involved in the disruption of the MMC, at least in the stomach, since feeding abolishes the MMC in an autotransplanted denervated iological role for these hormones in the con- fundic pouch (Thomas and Kelly, 1979). trol of the colonic motor response to eating However, nervous factors are also of impor- for which a neural mechanism seems prob- tance since vagotomy delays the onset of able (Snape et al, 1979), associated with the fed pattern (Ruckebusch and Bueno, the entry of digesta into the colon in dogs 1977) and reduces the intestinal transit. Fur- (Fioramonti and Bueno, 1983). thermore, an experimentally induced Numerous findings indicate a link increase in digesta flow lengthens the dura- between the brain and the digestive tract in tion of phase 2 (Bueno and Fioramonti, both physiological and pathological states. 1980). Table I summarizes most of the studies evi- The motility of the colon is stimulated dencing an effect of centrally administered after feeding and intravenous infusion of peptides on gastrointestinal and colonic tran- postprandially released hormones, such as sit. gastrin (Snape etal, 1978), CCK (Renny et These peptides may be divided into 2 al, 1983) or neurotensin (Thor and Rosell, groups according to the digestive state and 1986), stimulates colonic motility. However, the corresponding effects on intestinal tran- no information is available to confirm a phys- sit. The first group includes peptides, like ruption can be blocked by icv administra- CCK, which disrupt the MMC pattern after tion of calcitonin, neurotensin or growth-hor- central administration. After feeding, CCK- mone-releasing factor (Bueno et al, 1985) as like immunoreactivity increases in the well as interleukin (IL) 13 at doses that are hypothalamus (Schick etal, 1987) and cen- ineffective by systemic route. tral administration of CCK induces a fed pat- tern in both rats (Bueno and Ferre, 1982) and dogs (Karmeli et al, 1987). More NUTRITIONAL IMPLICATIONS recently, it was shown in rats that the CCKA receptor antagonist devazepide injected Intestinal transit, digestive secretions and into the ventromedial nucleus of bilaterally intestinal absorption are closely related pro- the (VMH) reduces hypothalamus greatly cesses that control nutrient absorption and the duration of the after postprandial pattern the of food. Thus, the influence of a given meal, an effect not reproduced by food components on the release of gas- similar administration into the lateral trointestinal hormones may be considered etal, 1990). In addi- hypothalamus (Liberge as a link between nutrition, digestive motil- tion while CCK into the VMH microinjected ity and intestinal transit. mimics the increase in colonic motility observed after a meal, devazepide injected in the same brain nucleus just prior to feed- Digestive secretions ing abolishes the colonic response to the meal in rats. This result supports the hypoth- esis that CCK released in the central ner- Exocrine secretion and mucosal absorption vous system (CNS) of rats mediates the vary synchronously with patterns of motor motor adaptation of the small intestine and activity and may also be affected by pep- the proximal colon to the postprandial state tides that alter motility. (Liberge et al, 1991). Pancreatic and biliary flow are associ- At a peripheral level, the postprandial ated with duodenal MMC. In dogs, maximal role of CCK in the control of the gastroin- outputs of lipase (EC 3113) and bilirubin testinal motor pattern and intestinal transit appear during the duodenal propagation of may also be neuronal since CCK immunore- phase 3 activity (Dimagno et al, 1979). Sim- activity has been demonstrated in axons ilarly acids, trypsin and bicarbonate out- and nerve cell bodies of the enteric nervous puts are maximal during phase 3 activity system (Larsson and Rehfeld, 1979). Cir- (Keane et al, 1980) (fig 5). However, the culating CCK may alter the motor activity amount of pancreatic enzymes secreted directly by binding to specific receptors during phase 3 activity was found to be 50% located on the smooth-muscle cell mem- of that secreted during a similar time fol- brane (Morgan et al, 1978). lowing ingestion of meal. The second group of peptides with a cen- tral site of action on intestinal transit are Intestinal absorption those that restore a MMC pattern in the jeju- mum when given intracerebro-ventricularly after a meal. Such an effect is insufficient Studies of absorption in animals prepared to prove a central physiological action, but it with isolated intestinal loops indicate that suggests that the CNS is involved in the the rate of digesta passage affects the normal postprandial disruption of the intesti- uptake of nutrients (Sarr et al, 1980). In nal MMC pattern. For example, MMC dis- experiments with intact animals the maxi- mal absorption of glucose occurs during the later stages of phase 2 activity of the MMC (fig 6), when the rate of transit was fastest compared with other phases of the intestinal motor complex (Fioramonti and Bueno, 1983). These relationships between intesti- nal motility and absorption have been indi- rectly confirmed by the presence of the high- est values of potential difference across the mucosa during phase 3 activity in dogs as well as in humans (Read, 1980). Moreover, mesenteric arterial blood flow, which con- trols passive paracellular absorption but also active transcellular transport through the oxygen supply, exhibits cyclic variations at the same frequency as recurrent MMC. Min- imal blood flow occurs during the periods of intestinal motor quiescence (Fioramonti and Bueno, 1983) and maximal mesenteric blood flow is observed after a meal (Vatner et al, 1970). Digestive hormones act on smooth muscles of both the arteries and the small intestine, but their effects can be sim- ilar or opposite. 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