New paradigms for the pathophysiology of infectious diarrhea

June 1994

EDITORIALS

rameters committee of the American College of Gastroenterology. Ann Intern Med 1993;119:836-843. Rickert RR, Auerbach 0, Garfinkel L, Hammond EC, Frasca JM. Adenomatous lesions of the large bowel: an autopsy survey. Cancer i979;43:1847-1857. DiSario JA. Foutch PG, Mai HD. Pardy K, Manne RK. Prevalence of malignant potential of colorectal polyps in asymptomatic, average-risk men. Am J Gastroenterol 1991;86:941-945. Surveillance, epidemiology and end-results: incidence and mortality data, 1973-77. NCI Monogr, No. 57. Morson B. The polypcancer sequence in the large bowel. Proc Roy Sot Med 1974;67:451-457. O’Brien MJ, Winawer SJ, Zauber AG, Gottlieb LS, Sternberg SS, Diaz B, Dickersin GR, Ewing S, Geller S, Kasimian D, Komorowski R, Szporn. and the National Polyp Study Workgroup. The national polyp study: patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology i990;98:37i-379. Knoernschild HE. Growth rate and malignant potential of colonic polyps: early results. Surg Forum 1963; 14:137-138. Kozuka S, Nogaki M, Ozeki T, Masumori S. Premalignancy of the

16.

17.

la. 19. 20.

21. 22.

mucosal polyp in the large intestine. II. Estimation of the periods required for malignant transformation of mucosal polyps. Dis Colon Rectum 1975; l&494-500. Spencer RJ, Melton Ill IJ, Ready RL, llstrup DM. Treatment of small colorectal polyps: a population-based study of the risk of subsequent carcinoma. Mayo Clin Proc 1984; 59:305-310. Atkin WS, Morson BC, Cuzick J. Risk of colorectal cancer up to 30 years after adenoma-removal. New Engl J Med 1992; 326:658-662. Lieberman D. Prospective evaluation of risk factors for large (sl cm) colonic adenomas in asymptomatic subjects. VA Cooperative Studies Program (manuscript in preparation). Lilienfeld AM, Lilienfeld DE. Foundations of epidemiology. 2nd ed. New York: Oxford, 1980:217-218.

23.

24.

25.

26.

Address requests for reprints to: Joe V. Selby, M.D., M.P.H., Division of Research, Kaiser Permanente Medical Care Program, 3451 Piedmont Avenue, Oakland, California 94611. Fax: (510) 450-2071. 0 1994 by the American Gastroenterological Association 0016=5085/94/53.00

New Paradigms for the Pathophysiology

S

tudies of the pathophysiology parallel

of infectious

those of other diarrhea1 diseases.

diarrhea New con-

of Infectious

Diarrhea

diarrhea and began to pursue studies of the mechanisms of intestinal

secretion

in enterotoxigenic

cepts come about when there is a critical mass of informa-

as cholera and Escherichia coli heat-stable

tion and a paradigm

fection.

A major paradigm diminishing

on which to frame the new findings. shift came about in the mid-1960s

changes in motility

in water and electrolyte ical cause of diarrhea. on cholera,

and toxin production

cal damage,‘.*

and on salmonellosis,

characterized

by changes

intestinal

secretion

cause of diarrhea. established

intestinal

both

Soon after the initial

became well

for the diarrhea

secretory phenomenon

of this infection.‘-a

failed to progress

basic paradigm

to explain

secretion

secretion,

nucleotides) secretory

most investigators. others,

stopped

concepts

However,

this

and no one clearly

knew

Further-

of a purified cholera toxin

of the concept as a mechanism mechanisms

to couple toxins

proved too powerful

Both Giannella

our investigation

of second messengers to for

embodied

plain how intestinal vation.‘-‘* formed

lating

inflammatory

mediators

such

leukotrienes,

oxygen

intestinal

the enterocyte

reduce the intestinal

peroxide)

both by directly stimu-

and acting

on enteric intestinal

mechanism

that might

infection

by

and muscle

and I, as well as many

by cross-linking lin G receptors

These

and reinfection

changes

in

function.

These

of immunoglobulin

intestinal

bra-

investigators

worms causes a mild inflammatory

accompanied

serve to

caused by N$postrongyltls

showed that both initial

transport

and

anaphy-

burden of nematodes during parasite spiralis.

tis

Baird et al.,”

of intestinal

Trichinella

these complex

nerves to secretion.

the concept

such as those and

mediators

species (hydrogen

secretion

laxis as a host defense infections

histamine, activating

Castro et a1.,13 Perdue and Gall,‘”

siliensis

as

platelet

induce neurotransmitter-mediated developed

acti-

it became clear that pre-

or adenosine and newly synthesized

and reactive

others”-‘*

transport.

secretion ensued after leukocyte

From these studies,

of invasive

infectious

new light on how inflamma-

were more than adequate to ex-

such as prostaglandins, factor,

in-

in this new field of intestinal

neuroimmunophysiology

role in the

because there was no

which cells in the gut produced prostaglandins. and the excitement

in

how white blood cells might

more, the lure and availability

intestinal

accompa-

et al. showed that prostaglan-

line of research intestinal

The

such

came on the

tion and white blood cells may alter electrolyte

could initiate

reports of intestinal

Giannella

scene that shed an entirely

serotonin,

pathophysiological

secretion

dins and white blood cells play an important

(cyclic

showed

infection.

salmonellosis,3-5

induce

by lumi-

with no histologi-

in histology,3-5

as the paradigm

nying intestinal

when research

an invasive enteritis

to be the major Thus,

changes

diarrhea characterized

diarrheas enterotoxin

Less than 5 years ago, a new paradigm

as the major physiolog-

This shift occurred

an infectious

nal colonization

and promoting

transport

1705

with enteri-

electrolyte

events are caused

E or immunoglobu-

on the mast cells with a resulting

explo-

1706

GASTROENTEROLOGY

EDITORIALS

sive release of mast cell inflammatory process

was not unlike

airway in allergic rhinitis an initial anaphylactic inflammation. secretion

mediators.

that experienced

This

in the upper

and asthma in which there was

response followed by conventional

In the gut, these processes cause intestinal

and intestinal

smooth

washed out and physically the intestine.

the nematodes

nellosis

is released

It is entirely possi-

ble that this could be the initiating

event in infectious

diarrheas of many types.

In summary,

the paradigm

intestinal

from phago-

secretion

by acting

enteric

laboratory

on

have clearly

et al.

shown

also involves

that white

cruit

new phagocytes

fecting tode,

to the lamina

microorganism then

mast

is a complex

cell

activation

have shown

the diarrhea on reinfection.

that E. co/i 0157:H7

these investigators

infection

ulated by pretreating

modanti-

then phagocyte

Such

pathophysiological

bodies against CD18

leukocyte

the influx of white blood cells into

adhesion molecules.

the lamina propria of the gut with resulting tion and also diminish

epithelial

inflamma-

damage and the intesti-

neutrophils

activation

studies of Clostridium dif$cicileinfection

suggest

a similar

cells and phagocytes

type of pathophysiological

process’s””

The toxins elabo-

rated by these organisms

appear to act at least in part

the activation

Are there other forms of invasive infectious

diarrhea

scheme?

Probably

and white blood cells are clearly im-

portant determinants

of intestinal

models

secretion

of protozoan

and diarrhea

infection

such as

amebiasis”

and cryptosporidiosis.2’.22

Furthermore,

lymphocyte

activation

system

recently

and crypt hyperplasia, intestinal nellosis,

of the immune

shown as a fundamental infections shigellosis,

MacDonald

of various types,

and Spencer

lymphocytes

have shown

induce stem cell division is quite

the opposite

proposed in which microorganism epithelial

cells was thought

seen in small

including

and rotavirus

plasia, which drives the development This paradigm

has been

cause of villus atrophy

which is commonly

protozoan,

T-

salmo-

infections.

that activated

T

and crypt hyperof villus atrophy.23 of that previously

invasion and death of

to drive the reactive hyper-

plasia of the crypts. Lastly, suggested

recent

studies

or luminal

mediators

what may be the initiating

have

event in the in-

is

to form a crypt

released

from

chloride

mast

and water

sodium

and

This occurs by direct effects of these

propria

release of prostaglandins

mesenchymal

cells,

and mediator

of the enteric nervous system.‘o31’ Other cyto-

kines released by the epithelium pria white

blood

or activated lamina pro-

cells may also induce

crypt cell division and hyperplasia

the process

of

in the small intestine,

an event that results in villus atrophy. This adds a component of malabsorption and deranging

to the diarrhea

surface absorptive

placing normal absorption If proteases sufficient phagocytes, epithelium cent

and reactive

quantity then

enteropathy

in the small intestine in epithelial

mast

damage

in

cells

and

to both

the

could also ensue in an “innoresulting

in erosions,

in vascular permeability and bleeding.

ulcer-

with pro-

Crypt hyperplasia

is a reparative process. Also, develcell lineage may take part

repair after ulceration

A word of warning.

cells and re-

species are released

extensive

process,

ations, and alterations

epithelial

the activated

and vasculature

bystander”

tein-losing

oxygen

from fairly

by diminishing

cells with secreting crypt cells.

opment of the ulcer-associated from several laboratories

substance

microorganisms

of neutral

on the epithelium,

activation

is

in the lumen of the bowel,

cause intestinal

chloride absorption. from lamina

organism

or perhaps even protozoa,

as well as inhibition

mediators

of white blood cells.

that share such a pathophysiological

secretion

Inflammatory

and

role in

is likely to be the major early

concentrated

abscess.27

investigators

be induced

would cross the epithelium

out that

These

may

process. If the chemotactic

point

event.

If the in-

one, such as a nema-

If the offending

released by the epithelium also sufficiently

propria.

from

and re-

would play an important

a simple one, such as bacteria

could be extensively

the animals with monoclonal

antibodies

diminish

anaphylaxis

if

and/or epi-

that activate resident phagocytes

but elegant

experiment,

adherence,

many,

thelial invasion, there may be a release of cytokines

intestinal

in experimental

model for host-

that may explain

diarrhea. After initial colonization, the epithelium

nerves.

Elliott

interactions

a generic

not most, of the adherent and invasive forms of infectious

E. coli infection

so. Prostaglandins

of neuroimmunophysiol-

ogy allows us now to postulate

In a simple

through

is a potent

molecule for neutrophils.

blood cells in its disease pathophysiology.”

nal secretory

from the intestinal

and this cytokine

microoreanism

but also by activating

O’Loughlin’s

that

during infection,

8 is

but that there was a neural

In this issue of GASTROENTEROLOGY, from

one such cytokine

on either invaInterleukin

as was the case with mast

cytes not only induced

enterohemorrhagic

were in-

Ar-

Thus,

diarrhea, release of mediators

the enterocyte

by microorganisms.

chemotactic

of salmo-

et al.,”

secretion

as well.”

cell-mediated

studies

not only that prostaglandins

volved in intestinal component

further

Eckmann

are released from the intestine

inflammatory

the same time,

invasion.

sion or colonization

from

The enteric nervous system was also shown

showed

cytokines

epithelium

to have a role in this process. At about

of bacterial

No. 6

nold et al.,“’ and Crowe et a1.26 have shown that various

that

muscle contraction

expelled

flammation

Vol. 106,

Although

of the intestine.” the pathophysiological

June 1994

EDITORIALS

scheme described

above may show several specific points

in which pharmacological intervention could be directed toward infectious diarrhea1 diseases, it should be remembered that this inflammatory defense response.

response

is basically

a host

Teleologically,

it is designed

to rid the

body of invasive microorganisms

and unwanted

antigens.

Although invasion mental

diarrhea

may be severe and harmful,

and septicemia

may be ultimately

systemic

W.

15.

16.

more detri-

to the host, i.e., it may be fatal. DON

14.

17.

POWELL

Department of Internal Medicine University of Texas Medical Branch Galveston, Texas

18.

References

19.

1. Field M, Fromm D, Al-Awqati Q, Greenough WB. Effect of cholera

2. 3.

4.

5.

6.

7.

8.

9. 10.

11.

12.

13.

enterotoxin on ion transport across isolated ileal mucosa. J Clin Invest 1972; 51:796-804. Field M. Ion transport in rabbit eleal mucosa. Il. Effects of cyclic 3’,5’-AMP. Am J Physiol 1971;221:992-997. Powell DW, Plotkin GR, Maenza RM, Solberg LI, Catlin DH, Formal SB. Experimental diarrhea. I. Intestinal water and electrolyte transport in rat salmonella enterocolitis. Gastroenterology 1971;60:1053-1064. Powell DW, Plotkin GR, Solberg LI, Catlin DH, Maenza RM, Formal SB. Experimental diarrhea. II. Glucose-stimulated sodium and water transport in rat salmonella enterocolitis. Gastroenterology 1971;60:1064-1075. Powell DW, Solberg LI, Plotkin GR, Catlin DH, Maenza RM, Formal SB. Experimental diarrhea. Ill. Bicarbonate transport in rat salmonella enterocolitis. Gastroenterology 1971;60:1076-1086. Giannella RA, Gots RE, Charney AN, Greenough WB, Formal SB. Pathogenesis of salmonella-mediated intestinal fluid secretion. Gastroenterology 1975;69:1238-1245. Giannella RA, Rout WR. Formal SB. Effect of indomethacin on intestinal water transport in salmonella-infected rhesus monkeys. Infect Immun. 1977;17:136-139. Giannella RA. Importance of the intestinal inflammatory reaction in salmonella-mediated intestinal secretion. Infect lmmun 1979; 23:140-145. Castro GA. Immunological regulation of epithelial function. Am J Physiol 1982; 243:G321-G329. Powell DW. lmmunophysiology of intestinal electrolyte transport. In: Frizzell RA, ed. Handbook of physiology: the gastrointestinal system. Rockville, MD: American Physiological Society, 1991: 591-641. Stead RH, Perdue MH, Cooke H, Powell DW, Barrett KE, eds. Neuroimmunophysiology of the gastrointestinal mucosa: implications for inflammatory disease. Volume 664, Ann NY Acad Sci, 1992. Castro GA, Powell DW. The physiology of the mucosal immune system and immune-mediated responses in the gastrointestinal tract. In: Johnson LR, ed. Physiology of the gastrointestinal tract. 3rd ed. New York: Raven, 1994 (in press). Castro GE, Harari Y, Russell D. Mediators of anaphylaxisinduced

20.

21.

22.

23.

24.

25.

26.

27.

28.

1707

ion transport changes in small intestine. Am J Physiol 1987;253:G540-G548. Perdue MH, Gall DG. Intestinal anaphylaxis in the rat: jejunal responses to in vitro antigen exposure. Am J Physiol 1986; 250:G427-G431. Baird AW, Cuthbert AW, Pearce FL. Immediate hypersensitivity reactions in epithelia from rats infected with Nippostrongyk~s brasilienses. Br J Pharmacol 1985;85:787-795. Brunsson I. Enteric nerves mediate the fluid secretory response due to salmonella typhmuriumR5 infection in the rat small intestine. Acta Physiol Stand 1987;131:609-617. Elliott E. Li Z, Bell C, Stiel D, Buret A, Wallace J, Brzuszczak I, O’Loughlin E. Modulation of host response to Escherichia Co/i 0157:H7 infection by anti-CD18 antibody in rabbits. Gastroenterology 1994; 106:1554-1561. Triadafilopoulos G, Pothoulakis C, O’Brien MJ, LaMont JT. Differential effect of Clostridium difficiletoxins A and B on rabbit ileum. Gastroenterology 1987;93:273-279. Triadafilopoulos G, Pothoulakis C, Weiss R, Giampaolo C, LaMont JT. Comparative study of Clostridium difkile toxin A and cholera toxin in rabbit ileum. Gastroenterology 1989;97:1186-1192. McGowan K, Piver G, Stoff JS, Donowitz M. Role of prostaglandins and calcium in the effects of Entamoeba histolytica on colonic electrolyte transport. Gastroenterology 1990;98:873-880. Argenzio RA, Liacos JA, Levy ML, Meuten DJ, Lecce JG, Powell DW. Villous atrophy, crypt hyperplasia, cellular infiltration and impaired glucoseNa absorption in enteric cryptosporidiosis of pigs. Gastroenterology 1990;98:1129-1140. Argenzio RA, Lecce J, Powell DW. Prostanoids inhibit intestinal NaCl absorption in experimental porcine cryptosporidiosis. Gastroenterology 1993; 104:440-447. MacDonald TT, Spencer J. Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine. J Exp Med 1988;167:1341-1349. Eckmann L, Kagnoff MF, Fierer J. Epithelial cells secrete the chemokine interleukin8 in response to bacterial entry. Infect lmmun 1993; 61:4569-4574. Arnold JW, Niesel DW, Annable CR, Hess CB, Asuncion M, Cho YJ, Peterson JW, Klimpel GR. Tumor necrosis factor-o mediates the early pathology in Salmonella infection of the gastrointestinal tract. Microb Pathog 1993;14:217-227. Crowe SE, Dytoc M, Hunt RH, Muller M, Sherman PM, Pate1 J, Jin Y, Ernst PB. Expression of interleukin8 and ICAM- by human gastric epithelium following Helicobacter pylori infection in vitro. Gastroenterology (in press). Parkos CA, Delp C, Arnout MA, Madara JL. Neutrophil migration across a cultured intestinal epithelium. J Clin Invest 1991;88: 1605-1612. Wright NA, Pike C, Elia G. Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in gastrointestinal stem cells. Nature 1990:343;82-85.

Address requests for reprints to: Don W. Powell, M.D., Department of Internal Medicine, University of Texas Medical Branch, 301 Unlversity Boulevard, 4.108 John Sealy Hospital, Galveston, Texas 775100567. Fax: (409) 772-3394. 0 1994 by the American Gastroenterological Association 00165085/94/$3.00