Neurohormonal control of intestinal transit

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Neurohormonal control of intestinal transit

L Bueno, Jean Fioramonti

To cite this version:

Neurohormonal

control

of intestinal transit

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. Motilin is the

major

homone involved in

triggering

the

gastric migrating

motor

complex

while somatostatine and

enkephalins

are

implicated

in the

_{propagation along}

the small intestine. Other hormones, like CCK8, insulin,

gastrin,

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.

gastrointestinal

tract / 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.

INTRODUCTION

The

_major

function of the intestine is to

_digest

food,

assimilate nutrients and

_expel

non-digestible

residues. These functions are

directly

related to its

_motility

_{which is} respon-sible for the intestinal

_delivery

and

_transport

of

_digesta.

The fact that

_feeding

affects

gastro-intestinal

_motility

has been known since the last

_century

when Beaumont

₍₁₈₃₃₎

described the

_changes

in

_amplitude

and fre-quency of

gastric

contractions associated with

_feeding.

From

1940,

improvements

of

our

_knowledge

of mechanical events

occur-ring

in the

_digestive

tract were associated with the

_development

of manometric methods which

permitted

the

_recognition

of the

_major

patterns

of

_{gastrointestinal motility.}

However,

r,

a

_{major step}

was linked to the use of

elec-tromyographic techniques,

which have allowed a clear identification of the charac-teristics of the fasted

_pattern,

ie the

_migrating

motor

_{(or myoelectric) complex (MMC)}

in

dogs (Szurszewski,

1969)

and in other animal

species

(Bu6no

et al,

1975;

Ruckebusch and

Fioramonti, 1975).

Recently,

it has been shown that the motor

_changes

associated with

_feeding

are related to the nature of food and caloric intake and that some

_peptides

play

a specific

role in their

_genesis.

PATTERNS OF MOTILITY AND DIGESTIVE STATUS

Stomach

In _many

_species,

manometric

_recordings

of

antral

_{motility during fasting}

or

interdiges-tive

_periods

exhibit a

_{cyclic pattern}

of

high-amplitude

contractions

_grouped

in

_phases

separated by periods

of

_quiescence

and

appearing

at 90-120 min intervals. The

important property

of the

_proximal

stomach is

_{receptive relaxation,}

mediated

_by

_inhibitory

neurons in

_vagal

nerves

_{(Abrahamsson,}

1973),

which enables it to accomodate food

delivery by

the

_cesophagus.

The

contrac-tions of the corpus and the antrum are

coor-dinated and a slow contraction of the

cor-pus

lasting approximately

30 s is associated with 3-5 more

_rapid

contractions of the

antrum

_(Gill

et al,

1985).

After a

_meal,

the

digestive

pattern

is characterized

_by

_steady

low-amplitude

contractions

_(4-5

_per

_min)

in the

_gastric

antrum with no

_significant

motor

activity

in the

_{gastric body.}

A

_{cyclic pattern}

of

_{gastric motility}

has been found in the

_dog

_(Itoh

et al,

₁₉₇₇₎

and in man

_(Rees

etal,

1982).

In the rat

_(Bueno

et

al,

1982)

and the rabbit

_(Deloof

and

Rousseau, 1985)

there is no

_cyclic

organi-zation of the

_{gastric motility,}

and

_feeding

induces an increase of both the

_amplitude

and

_frequency

of the contractions.

Small intestine

The basic motor

_pattern

of _many animal

species investigated

consists of

MMCs,

first identified as &dquo;a caudad band of

large-ampli-tude action

_potentials

_starting

in the

duode-num and

_traversing

the small bowel&dquo;

(Szurszewski, 1969).

Each MMC

corre-sponds

to 3 consecutive

_{phases: phase}

1

has little or no contractile

_{activity (quiescent}

phase), phase

2 has intermittent and

_irregular

contractions,

while the contractions of

_phase

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

digesta (Ruckebusch

and

Bueno,

1977).

Depending

on the animal

_species,

the MMC

cycle length

varies between 60 and 120 min

(Bueno

and

_Ruckebusch,

₁₉₇₈₎

_except

in

rats in which MMCs recur at 15-20 min inter-vals

_(Ruckebush

and

Fioramonti,

1975).

Feeding

is

_accompanied

_by

a

_disruption

pattern

characterized

_by

the

_irregular

occur-rence of contractions similar to those observed

_during

_phase

2 of the MMC

(Bueno

et

al, 1975;

Code and

Marlett,

1975).

This

_disruption

of the MMC

_pattern

is related to the energy content of the

meal,

the nature of nutrients and the

_frequency

of meals.

However,

non-nutrient factors are

also involved in the

_{postprandial disruption}

of the MMC

_pattern,

since

_sham-feeding

delays

the next

_phase

3 in man

_(Defilippi

and

_{Valenzuela, 1981). On}

the other

hand,

meal

_frequency

modulates the effects of

feeding

on small intestinal

_motility.

For

example,

in

_{pigs (Ruckebusch}

and

Bueno,

1976)

and in rats

_(Ruckebusch

and

Ferre,

1973)

ingestion

of a

_{daily large}

meal

dis-rupts

the MMC for several

hours,

while under ad libitum

_feeding

the MMC

fre-quency is similar to that observed in the

fasted state.

However,

in adult and

neona-tal

_{pigs, feeding}

a standard meal

_only

induces a 1-h

_delay

in the onset of the next

phase

3

_(Burrows

et al, 1986;

Rayner

and

Wenham, 1986).

Large

intestine

A common feature of the colon in all

mam-malian

_species

_investigated

is a

_duality

of

the contractile

_activity:

tonic contractions

corresponding

to

_{myoelectrical}

events char-acterized

_by

_prolonged

series of short

_spike

bursts and

_phasic

contractions

corre-sponding

to isolated and

_{propagated long}

spike

bursts.

However,

the

_spatial

and

tem-poral organization

of these 2 kinds of

con-tractions,

which form the colonic motor

pat-tern,

is

_specific

to each mammalian

_species

so far

_{investigated.}

This

_pattern

is

inde-pendent

of colonic

_anatomy

and of the

tra-ditional

_regimen

of the animal

_species,

but gross similarities exist within

species

pro-ducing

moulded faeces such as the

_pig,

dog

or man, and within

species

that form

faeces in

_pellets,

such as the rabbit or the

sheep

(Fioramonti, 1981).

).

The

_typical

characteristic of colonic

motil-ity

in man, not seen in

animals,

consists of a very low

_{activity during}

the

_night

(Frexi-nos et

_{al, 1985).}

After a 3 000-4 000 kJ

meal the

_frequency

of colonic contractions is increased for 2-3 h. Such an increase in colonic

_motility

after a meal seems to be a common feature.

RELATIONSHIPS BETWEEN MOTILITY

AND FLOW OF DIGESTA

Stomach

In terms of transit of

_digesta,

the 3

_major

functions of the stomach are the

_receipt

of

food,

the

_storage

of

_ingested

food and the

emptying

of

_liquids

and solids.

The

_entry

of a

_large

amount of food into the stomach leads to

_{adaptive (or}

recep-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 govern the rate of

_emptying

of

_liquids.

The

pylorus

prevents

duodenogastric

reflux,

but is also a true

sphincter

which controls the

empyting

of food from the stomach.

Small intestine

The

_greatest

flow of

_digesta

occurs

_during

the

_{postprandial disruption}

of the MMC

pat-tern,

but the role of MMCs in the

_propulsion

of

_digesta

is not

_negligible

since,

at least in

dogs, gastric emptying

in not terminated when the MMCs _reappear on the

_jejunum

controversial

_depending

on the

experimen-tal model: the maximal transit rate of a

marker has been found associated with

phase

3

_using

a

_jejunal

isolated

_loop

_(Sarr

et

al,

1980)

or with

_phase

2 when

_experiments

were

_performed

on an intact intestine in the

same

_species.

Using

an

_{electromagnetic}

flowmeter to

measure

_digesta

flow

_continuously

and

elec-tromyography

to record intestinal

_motility,

it has been observed in

_sheep

that the

major-ity

of intestinal contents flowed

_{intermittently}

for

_periods

of 10-15 min at the same

fre-quency as the MMC

_(fig

₁

_Two-thirds

of this flow occurred in the 4-6 min

immedi-ately preceding

the

_periods

of

_phase

3

migration (Bueno

et al,

1975).

Postprandial

contractile

_patterns

and

tran-sit and the distance over which the

con-tractions are

_propagated

_vary

_according

to

the nature of the

_{ingesta (fig}

₂₎

_(Schemann

and

_Hans-J6rg,

_1986).

Eventhough

there are clear

_{relationships}

between

_motility

patterns

and chemical

con-tents of the

food,

the

_physical

nature of the

digesta

and

_particularly

its

_viscosity

_plays

an

_important

role in the

_efficacy

of

_propulsive

waves. In

_dogs,

it has been established that similar

_patterns

of intestinal

_motility

are

induced

_by

_{bran and cellulose but with very} different rates of

_propulsion

while bran and

LARGE INTESTINE

The 2 kinds of colonic contractile

_activity

have

opposite

effects on the

_propulsion

of

_digesta.

Phasic contractions ensure the

_mixing

and the aboral

_progression

of colonic contents

while the tonic

_activity

acts as a brake.

In

_dogs,

the

_spontaneous

fluctuations of

the

_{phasic activity}

are

_positively

correlated

with the

_spontaneous

_changes

in the

veloc-ity

of transit of a marker introduced in the

proximal

colon

_(Fioramonti

_{etal, 1980).}

Sim-ilarly

in

_pigs,

a low-residue diet induces a

time which was related to a decrease in

pha-sic

_activity

and an increase in tonic

_activity

(Fioramonti

and

_{Bueno, 1980)}

_(fig

_4).

However,

in

humans,

despite

the many studies of colonic

_motility

or colonic transit

time,

relations between muscle activities and

_digesta

movement have not been

_fully

elucidated.

NEUROHORMONAL FACTORS

Hormones involved

Among

the hormones released

_during

a

meal,

gastrin (Weisbrodt

et al, 1974;

Marik and

Code,

1975;

Wingate

et al,

1978a),

insulin

_(Bueno

and

Ruckebusch,

1976),

cholecystokinin (CCK) (Mukhopadhyay

et

al, 1977;

Wingate

et al,

1978a),

secretin,

glucagon

(Wingate

et al, 1978b),

and

neu-rotensin

_(AI

Saffar and

Rosell, 1981;

Thor et

al,

1982)

alter the

_pattern

of intestinal

motil-ity

and/or transit when infused

_{intravenously.}

However,

it is

_unlikely

that a

_single

hormone

is

_responsible

for the

_postprandial

_change

of

the

_{gastrointestinal}

motor

_pattern

since for each hormone there are

_arguments

_against

a

_{physiological}

motor action. For

_example,

a

_long-lasting

_disruption

of the MMC occurs

after fat

_ingestion

in

_dogs,

but with no

sig-nificant increase in

_{plasma gastrin}

and insulin

_(Eeckhout

et al,

1978).

Indeed

sig-nificant increases in

_gastrin

and insulin

con-centrations in blood induced

_{by glucose}

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

the MMC in an

_{autotransplanted}

denervated fundic

_{pouch (Thomas}

and

_{Kelly, 1979).}

However,

nervous factors are also of

impor-tance since

_vagotomy

_delays

the onset of

the fed

_pattern

_(Ruckebusch

and

Bueno,

1977)

and reduces the intestinal transit.

Fur-thermore,

an

_{experimentally}

induced increase in

_digesta

flow

_lengthens

the dura-tion of

_phase

2

_(Bueno

and

Fioramonti,

1980).

The

_motility

of the colon is stimulated

after

_feeding

and intravenous infusion of

postprandially

released

hormones,

such as

gastrin (Snape

etal,

1978),

CCK

_(Renny

et

al,

1983)

or neurotensin

_(Thor

and

Rosell,

1986),

stimulates colonic

_motility.

However,

no information is available to confirm a

phys-iological

role for these hormones in the

con-trol of the colonic motor _response to

_eating

for which a neural mechanism seems

prob-able

_(Snape

et al,

1979),

associated with the

_entry

of

_digesta

into the colon in

_dogs

(Fioramonti

and

_{Bueno, 1983).}

Numerous

_findings

indicate a link between the brain and the

_digestive

tract in both

_{physiological}

and

_pathological

states.

Table I summarizes most of the studies

evi-dencing

an effect of

_centrally

administered

peptides

on

_{gastrointestinal}

and colonic

tran-sit.

These

_peptides

_may be divided into 2

groups

according

to the

_digestive

state and the

_{corresponding}

effects on intestinal

The first group includes

peptides,

like

CCK,

which

_disrupt

the MMC

_pattern

after

central administration. After

_feeding,

CCK-like

_{immunoreactivity}

increases in the

hypothalamus

(Schick

etal, 1987)

and

cen-tral administration of CCK induces a fed

pat-tern in both rats

_(Bueno

and

Ferre,

1982)

and

_{dogs (Karmeli}

et

al,

1987).

More

recently,

it was shown in rats that the CCKA

receptor

antagonist

devazepide injected

bilaterally

into the ventromedial nucleus of the

_{hypothalamus (VMH) greatly}

reduces the duration of the

_{postprandial pattern}

after

a

_{given meal,}

an effect not

_{reproduced by}

similar administration into the lateral

hypothalamus (Liberge

etal, 1990).

In addi-tion while CCK

_{microinjected}

into the VMH mimics the increase in colonic

_motility

observed after a

meal,

devazepide injected

in the same brain nucleus

_{just prior}

to

feed-ing

abolishes the colonic _response to the

meal in rats. This result

supports

the

hypoth-esis that CCK released in the central ner-vous

_system

_(CNS)

of rats mediates the

motor

_adaptation

of the small intestine and the

_proximal

colon to the

_postprandial

state

(Liberge

et al,

1991

).

At a

_{peripheral level,}

the

_postprandial

role of CCK in the control of the

gastroin-testinal motor

_pattern

and intestinal transit may also be neuronal since CCK

immunore-activity

has been demonstrated in axons

and nerve cell bodies of the enteric nervous

system (Larsson

and

Rehfeld,

1979).

Cir-culating

CCK _{may alter the} motor

_activity

directly by binding

to

_{specific receptors}

located on the smooth-muscle cell

mem-brane

_(Morgan

et al,

1978).

The second group of

peptides

with a

cen-tral site of action on intestinal transit are those that restore a MMC

_pattern

in the

jeju-mum when

_{given intracerebro-ventricularly}

after a meal. Such an effect is insufficient

to _prove a central

_{physiological}

action,

but it

suggests

that the CNS is involved in the normal

_{postprandial disruption}

of the intesti-nal MMC

_pattern.

For

_example,

MMC

dis-ruption

can be blocked

_by

icv administra-tion of

calcitonin,

neurotensin or

growth-hor-mone-releasing

factor

_(Bueno

_{et al, 1985)}

as

well as interleukin

_{(IL) 13}

at doses that are

ineffective

_{by systemic}

route.

NUTRITIONAL IMPLICATIONS

Intestinal

transit,

digestive

secretions and intestinal

_absorption

are

_closely

_related

pro-cesses that control nutrient

_absorption

and the

_digestion

of food.

Thus,

the influence of food

components

on _{the release of}

gas-trointestinal hormones may be considered

as a link between

nutrition,

digestive

motil-ity

and intestinal transit.

Digestive

secretions

Exocrine secretion and mucosal

absorption

vary

synchronously

with

patterns

of motor

activity

and may also be affected

_by

pep-tides that alter

_motility.

Pancreatic and

_biliary

flow are associ-ated with duodenal MMC. In

_dogs,

maximal

outputs

of

_{lipase (EC}

₃₁₁₃₎

and bilirubin appear

during

the duodenal

_propagation

of

phase

3

_activity

_(Dimagno

et

_al,

_1979).

Sim-ilarly

bile

_{acids, trypsin}

and bicarbonate

out-puts

are maximal

_{during phase}

3

_activity

(Keane

et

al,

1980)

(fig

5). However,

the

amount of

_pancreatic

_{enzymes secreted}

during phase

3

_activity

was found to be 50% of that secreted

_during

a similar time

fol-lowing ingestion

of meal.

Intestinal

_absorption

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.

For

_{example, gastrin}

and

both blood flow and intestinal

_motility,

while

glucagon

inhibits

_motility

and increases blood flow

_{(Fondacaro, 1984).}

CONCLUSIONS

This review evidences that the

_regulation

of

_{gastrointestinal}

and colonic transit

depends

upon

motility patterns,

which are

under the control of both

_peripheral

and

cen-tral neurohormonal factors. These factors are released in relation to the nature of

nutri-ents to

_adapt

the

_gut

to the

_digestive

sta-tus.

However,

the transit of

_digesta

is also

governed by

the

_physical

nature of the

con-tents and a close

_reciprocal

influence exists between

_absorptive

and

_propulsive

process.

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