Crohn's disease and the enterohepatic circulation

Medical

Hypotheses

7: 695-701, 1981

CROHN'S DIEEASE AND THE ENTEROHEPATIC CIRCULATION

H. Nyhlin and M.A.Eastwood, Wolfson Gastrointestinal Laboratories, Gastrointestinal Unit, Department of Medicine, Western General Hospital, Edinburgh EH4 2XU

ABSTRACT Crohn's disease is a chronic inflammatory process which may affect any part of the alimentary tract. The cause is unknown. Overall the distribution of the lesions coincides with that of the enterohepatic circulation. A possible causative agent is a metabolic or ingested substance excreted into the bile In the form of a polar and inacthte conjugate. The agent would have to have a prolonged half life in the enterohepatic circulation. In the ileocaecal region and elsewhere when bacterial colonisation occurs the inactive conjugate may be hydrolysed to release the active substance. This would act locally on the intestinal tissues either as a result of altering the physicochemistry of mucus or during passage through the gut wall.

ACKNOWLEDGEMENTS We wish to agknowledge financial support for this study from the University of Umea, Sweden, the Wellcome Trust and British Bakeries Ltd. We would also like to thank Dr. A.Busuttil for assistance with biopsy examinations and helpful discussions.

695

INTRODUCTION Crohn's is

disease

is affected, lesion

involve derangement

Microscopically characterised by

is

any

discontinuous

functional

malabsorption. The

may

characteristically

part

of

the

alimentary

or

segmental.

When

may

produce

a variable

tract

the

and

small

bowel

degree

of

all layers of the bowel wall are ulcers which progress to fissures

involved. or

sinuses which may affect neighbouring structures. Granulomatous collections of multinucleate giant cells and lymphocytes are found the

bowel An

wall

and

explanation

challenge ever this entity in the

cause

aetiology Crohn's to the

in

for

of

Crohn's

of

the

with

regional

the

disease

disease

will

and

pathogenic

diseases

of

is currently with the aim

mechanisms

In Crohn's circulating question role in

whether Crohn's

case for any disease also immune

and

disease

anti

of

Studies

of

and

of

disease Crohn

has

first

In Crohn's affected

been

a

described

it is unlikely because the

unknown

origin major of an

there

groups, ingested

is

secondary

effects

specific

(51,

have

of non

been

no

shortage

an infection, substance.

the

of an

disease.

cytopathogenic

demonstrated

pathogenic role of immunological unproven (91 as does any possible with

Crohn's

transmissibility

diseaee but

the

that

of immunology primary

LSI (71.

The

ileocaecal colon,

rectum

The

factors in Crohn's aberration of the

disease. of Crohn's

disease

have

produced reproducible results (101 and no bacteria or viruses been found to be of aetiological significance [Ill, though an of Crohn's disease can produce lymphoma in nude mice (121.

manifestation

(11.

(31. The incidence of rapidly over the last decade in contrast ulcerative colitis appears to present 141.

antibodies

patients the

in

cases

such circulating immuno complexes play a mediating disease remains unresolved by recent studies (81.

primary remains

status

Crohn's

60-70%

concentrated on the field of differentiation between

non

colon

in

been suggested that ever be discovered,

These fall into three aberration or a consequence

Interest infection

of

Ginzburg

hypotheses. immune

nodes

is multifactorial

has increased rate at which

all

lymph

aetiology

since Oppenheimer, 1932 (21. It has

disease constant

As

the

involvement and

perineum

is

the may

most also

not have extract

common be

[Il. CROHN'S

AND

THE

ENTEROHEPATIC

CIRCULATION

It has been recognised for many years that if the continuity of the bowel is changed so that there is diversion or bypass of the inflamed area, the disease activity in the bypassed area frequently heals (131. Unfortunately the disease continues at the sites that remain in contact with the luminal contents and recurs in the

696

bypassed areas if continuity a medical hypass by prolonged intravenous feeding [141.

is restored. feeding with

It is possible elemental diets

to achieve or

This distribution of Crohn’s disease coincides with the enterohepatic circulation where in addition to bile acids, other substances of exogenous and endogenous origins are circulated (151. The enterohepatic circulation contributes to the conservation of compounds in the body and in the case of bile salts, and possibly other this is of physiological import compounds of intermediate metabolism, For example, the formerly used radio-opaque medium iophenoxic (161. acid, because of the enterohepatic circulation of its conjugates has Similarly, recycling an estimated plasma half-life of 2f years (171. contributed to the persistence of stilboestrol (181, butlyated hydroxy toluene (191, antibiotics such as rifomycin SV, chlorinated hydrocarbon pesticides and carcinogenic hydrocarbons (161. In the discussion of a causative agent for Crohn’s disease it may be postulated that a metabolite is excreted in the bile in the form of Such a causative agent should possess a polar and inactive conjugate. definable physico-chemical characteristics. The inactive conjugate may be hydrolysed so releasing the active substance which may then act This may occur mainly in the terminal locally on intestinal tissues. ileum before it is absorbed and recirculated but also in the colon and This could also rectum and perineum where it may be concentrated. account for the extension of the disease distally once it is manifested (201, as a result of secondary bacterial colonisation. THE ENTEROHEPATICCIRCULATION Compounds excreted in the bile must possess defined physicochemical characteristics. Substances with a molecular weight below 300 are normally excreted by the kidneys, or if volatile, in the expired air. The biliary elimination becomes progressively more with molecular weights in the approximate range of 300-600. Marked species variations occur, e.g. biliary excretion of polar compounds or polar metabolites with molecular weight in the region of 500-1000 occurs in man (161. It has been found that the introduction of a group or the change in relative position of groups in a molecule may alter the extent of biliary excretion disporportionately to any effect on molecular size or polarity (21 I. Biliary excretion is affected by changing lipid solubility, changing the shape of the molecule or the relative intramolecular relationship of the polar and non polar parts of the molecule. The introduction of heavy atoms, iodine, or cyclic [aromatic, cycloalkyl aliphatic groups into simple aromatic hepatic elimination.

697

e.g. halogen, particularly and heterocyclicl or structures can enhance their

The presence of a strongly polar group in a molecule appears to be a requirement for extensive biliary secretion to occur. Drugs and other compounds are excreted in the bile in the form of polar conjugates, particularly as conjugates with glucuronic acid or glutathionine and occasionally with sulphate or glycine (16). In general it is this group of substances which are likely to become involved in the enterohepatic circulation, since the enteric tract contains conjugate splitting hydrolases, probably of bacterial origin. The products, because of their greater lipophilicity, can then be absorbed from the gut (22). Compounds extensively excreted in bile generally have a critically balanced amphipathic character, i.e. they contain both polar and non polar groups in their molecular structures, e.g. bile salts. This may also determine these compounds ability in orientate at a membrane, or to interact with a carrier molecule or to undergo aggregation T161. It may also influence the stability of the muco polysaccharides in the small intestine (231. The problems of studying those substances in animal models include differences in bile excretion between animal species and This would account for the relative even between genders (241. inability of previous studies to demonstrate Crohn’s disease in experimental animals. In general the rat is a better excretor of foreign compounds in bile than is the rabbit though it is not always justified to extrapolate from rat experimental models to man. Chloramphenical (251 and morphine undergo marked enterohepatic circulation in rat [I61 but excretion is very limited. not in man, in whom biliary In the pathogenesis of inflammatory bowel diseases it seems logical that any extrinsic factor involved should act through the gut lumen. To find an aetiological agent in Crohn’s disease among the unlimited non nutrient additives in the food seems at the moment futile, although interest is concentrated upon a hexose containing polysaccharide carrageenin because of its known ability to induce inflammatory bowel disease in animals [261. In the last year the most interesting contribution to the discussion of dietary factor has been the suggestion that a diet high in refined sugar and low in raw fruit and vegetables precedes and may favour the development A refined diet may contain Crohn’s inducing of Crohn’s disease (271. compounds, possibly concentrated in the absence of fibre which holds water in the intestine. Though of course there may be a deficiency of compounds or factors in a refined diet which predispose to a Crohn’s situation. There are differences in the gel properties of mucus in the small intestine and colon (281. There may well be differences of the goblet cells in disease areas of Crohn’s disease compared to normal (291.

698

TESTING THE HYPOTHESIS Studies are necessary to demonstrate whether any agent circulating within the enterohepatic circulation causes pathological changes in the gut. For example, rats might be given bile collected from patients with Crohn's disease by the ERCP technique or following a cholecystectomy. The rat gut could then be examined for histopathological changes at time intervals. The problem of obtaining the vast amount of bile required limits the feasibility of such a study. Instead we performed another theoretically similar study. Freeze dried stools from patients with Crohn's disease were mixed with rat powdered pellet food in a ratio of 1 : 19 and given to five three month old rats for a period of 35 days. A control group of identical rats were given a similar amount of stool from normal individuals for the same period. At the end of the study the rats were weighed before being killed and the small intestine and the colon were taken for histopathological scrutiny. The Crohn's group had grown less than the control group, the difference in average weight between the two groups were small however at IO grams. No pathological changes could be detected though there These include the short period of are many possible explanations. feeding, that any potent causative agent may have been degraded in the faeces or differences between animal species. Arguments for this hypothesis are the increasing prevalence of Crohn's disease and the possibility of a compound such as we are proposing becoming more prevalent in our diet. Against the hypothesis is the curious distribution of the disease with areas of Crohn's disease alternating with areas which are free from inflammation. CONCLUSIONS A Crohn's inducing compound would be characterised by being of molecular weight, between 300-500, probably dietary in origin and with an aromatic structure, possibly substituted with a halogen and readily conjugated to form an amphipathic structure. Such a compound would have a prolonged half-life in the enterohepatic circulation and would be concentrated at surfaces in the ileocaecal, colonic and perineal region during passage along the intesU.ne. It might also alter the physical properties of the gastrointestinal mucus.

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