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C. J. Edmonds
318
be carried out on the distal colon and rectum and
some factors which influence the pd have been
examined. The pd is of significance both because it
considerably influences the flows of charged particles
across the epithelium and also because it is a measurable variable which reflects something of the functional state of the tissue. Since, however, it is affected
by a variety of factors, these must be defined and
considered if any meaningful interpretation is to be
made.
References
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and potential difference at astroduodenal junction in man.
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Archampong, E. Q., and Edmonds, C. J. (1972). Effect of luminal
ions on the transepithelial electrical potential difference of
human rectum. Gut, 13, 559-565.
Archampong, E. Q., Harris, J., and Clark, C. G. (1972). The absorption
and secretion of water and electrolytes across the healthy and
the diseased human colonic mucosa measured in vitro. Gut, 13,
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Barry, R. J. C. (1967). Electrical changes in relation to transport. Brit.
med. Bull., 23, 266-269.
Dalmark, M. (1970). The transmucosal electrical potential difference
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Diamond, J. M., and Harrison, S. C. (1966). The effect of membrane
fixed charges on diffusion potentials and streaming potentials.
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Edmonds, C. J., and Marriott, J. (1967). The effect of aldosterone
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short circuit current of an in vitro preparation of rat colon
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Edmonds, C. J., and Nielsen, 0. E. (1968). Transmembrane electric
potential differences and ionic composition of mucosal cells of
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Edmonds, C. J., and Pilcher, D. (1973). Electrical potential
difference and sodium and potassium fluxes across rectal
mucosa in ulcerative colitis. Gut, 14, 784-789.
Edmonds, C. J., and Richards, P. (1970). Measurement of rectal
electrical potential difference as an instant screening test for
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(1969). Measurement of gastrointestinal transmural electric
potential difference in man. Gut, 11, 34-37.
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capacity and electrical potentials of the normal and the
inflamed human rectum in vivo. Scand. J. Gastroent., 8, 169-175.
Schultz, S. G. (1972). Electrical potential difference and electromotive
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Smyth, D. H., and Wright, E. M. (1966). Streaming potentials in the
rat small intestine. J. Physiol. (Lond.), 182, 591-602.
Thompson, B. D., and Edmonds, C. J. (1974). Aldosterone, sodium
depletion and hypothroidism on the ATPase activity of rat
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The normal colonic bacterial flora
M. J. HILL AND B. S. DRASAR
From the Bacterial Metabolism Research Laboratory, Central Public Health Laboratory,
Colindale Hospital, London
Interest in the human intestinal bacterial flora has
increased greatly in recent years. To a large extent
this is because techniques have now been developed
which permit the study of the dominant members of
the gut flora, the non-sporing strictly anaerobic
bacteria.
There are two major approaches to the study of
the gut flora. The first is the classical bacteriological
approach, the identification and the enumeration of
the major groups of bacteria. The second is the study
of the biochemical activities of the flora. These two
aspects of the flora will be discussed in turn.
The Normal Colonic Flora
The normal colonic flora is usually inferred from the
composition of the normal faecal flora, since
suitable techniques for sampling various levels of
the colon have yet to be developed. Data from animal
studies would support the assumption that the flora
does not alter during defaecation, indicating that the
faecal flora adequately represent that of the rectosigmoid. We know that the flora of the recto-sigmoid
differs from that at the ileocaecal junction (table I)
and can infer, but no more, that the change takes
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Species
319
Mean Loglo Viable Count/Gram
Intestinal Material
Terminal
Ileum
3-3
Enterobacteria
2-2
Enterococci
<2
Lactobacilli
<2
Clostridia
Bacteroides
57
Gram-positive non-sporing
anaerobes (Eubacteria
58
and Bifidobacteria)
Number of samples studied 6
Caecum
Faeces
6-2
3-6
6-4
30
7-8
7-4
5-6
6-5
54
9-8
8-4
2
10-0
100
Table I The bacterial flora of the lower intestine in man
place in the upper rather than the lower parts of the
colon.
Non-sporing anaerobic, rod-shaped organisms
overwhelmingly predominate in the human faecal
flora, accounting for more than 99% of the total
organisms. The major species present are Bacteroides
fragilis, Bifidobacterium adoloscentis, and Eubacterium aerofaciens (Peach, Fernandez, Johnson, and
Drasar, 1974). The remainder are mainly Escherichia
coli, Streptococcus viridans, and Streptococcus
salivarius and lactobacilli, but there are in addition
a host of minor components of the flora including
veillonellae, bacilli, peptococci and peptostreptococci, clostridia, Strep faecalis, and coliform
organisms other than Esch. coli (eg, Klebsiella spp,
Proteus spp). It must be stressed that, although these
are minor components of the average normal flora,
they may be of major importance in an individual
selective media are available for the individual
species of non-sporing anaerobes it will be necessary
to pick 1000 colonies in order to be able to detect
an organism present in considerable numbers. Thus
there are still many problems remaining to be
solved before we can characterize the normal faecal
flora.
It must be noted, too, that the faecal flora represents only the luminal flora of the recto-sigmoid
region and that the mucosal flora (the bacteria
growing in close association with the mucosal
surface and in the villous crypts) may differ markedly
from this. This criticism also applies to the data on
the small intestinal flora. Determination of the
mucosal flora presents great difficulties which will
not readily be overcome; however, it is suspected
that the mucosal flora is more important than the
luminal flora in, for example, urea metabolism.
THE EFFECT OF DIET ON THE FLORA
People living in Uganda on a diet of matoke (boiled
mashed banana) have a faecal flora which differs
markedly from that of English people living on a
normal western diet (Aries, Crowther, Drasar, Hill,
and Williams, 1969) and this difference has been
assumed to be due to the difference in diet. Alteration of the flora of adults by modifying their diet has
proved to be extremely difficult to demonstrate,
however. The flora of people on a low-fat diet for
four weeks was not detectably different from that of
the same people on a control diet; a diet rich in
bagasse (fibre from sugar cane) had no detectable
effect even in 12 weeks. However, differences in the
person.
flora of three dietary groups living in Hong Kong
There are difficulties in interpreting the data on the could be demonstrated. Our conclusions from these
normal flora. For example, the enumeration of data are that (a) the effects of dietary alteration are
clostridia is very difficult due to the lack of a suitable only slowly manifest, and in controlled studies
selective or diagnostic medium. Consequently, prolonged periods on a diet (more than a year) may
although the numbers of clostridia producing be necessary before the effects can be demonstrated
lecithinase can readily be determined there is no using the classical bacteriological techniques; (b)
means of counting vegetative clostridia which do not classical bacteriological techniques are unsuitable
produce this enzyme. In the case of the latter for the study of faecal micro-ecology. If total faecal
organisms only the numbers of spores can be P-glucuronidase is measured then the effects of diet
counted and this may be totally unrelated to the on the flora can be demonstrated readily in four
vegetative count; it is possible, therefore, that weeks (Wynder and Reddy, 1974). Using a battery
clostridia may be far more numerous in the colonic of such tests, together with the results of screening
flora than is realized at present. Within the genus studies to determine the mean enzymic activity of
Bacteroides there are more than 20 species. More strains of each genus, such finer alterations in the
than 95 % of faecal bacteroides belong to the species flora might be detected.
B. fragilis and consequently the enumeration of the
minor species is extremely time consuming. It is Metabolic Activity of the Flora
important to recognize, therefore, that a species of
non-sporing anaerobe that represents only 01 % In the colon there is approximately 1-5 kg wet weight
of the organisms of that genus would nevertheless of bacteria and therefore it would be amazing if their
be present in numbers comparable to those of the metabolic activity did not play a significant role in
coliforms, streptococci, or lactobacilli. Until good the overall economy of the human body. There has
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320
been considerable interest in this subject in recent
years and it would be impossible to cover this
subject adequately. In the subsequent section three
selected topics will be discussed in some depth
rather than an attempt to cover the full range of the
subject.
HYDROLYSIS OF GLYCOSIDES AND
GLUCURONIDES
A high proportion of taxonomic tests in bacteriology
are fermentation reactions that involve an initial
hydrolysis of a glycosidic bond followed by fermentation of the released monosaccharide. Examples of
such reactions are thefermentation ofaesculin, salicin,
and amygdalin. All three examples given are of figlucosides and such compounds are poorly metabolized by intestinal enzymes. Many plant products are
glucosides of toxic compounds and it is the ability
of the colonic flora to hydrolyse these compounds to
release the toxic aglycone that renders an item of
food dangerous. Thus, untreated cassava contains
amygdalin which is hydrolysed by the flora to release
cyanide. Untreated cassava is highly toxic and in
areas where cassava lis a staple source of starch the
raw product is extracted exhaustively to remove
the amygdalin before converting the 'purified'
cassava into flour.
In other parts of the world cycad nuts are a staple
source of starch but, again, untreated cycads are
extremely hepatotoxic because they contain the
glucoside cycasin, which is hydrolysed by the gut
flora to release methylazoxy-methanol. In germ-free
rats cycasin administered orally is harmless at a dose
which would kill a conventional rat in 48 hours
(Spatz, Smith, McDaniel, and Laqueur, 1967). To
render them harmless the cycads are extracted
repeatedly with water to remove the cycasin.
The ability of the flora to hydrolyse plant glucosides has been used extensively in medicine. The
glucoside cathartics senna and cascara are hydrolysed to release their active agents. It has been
demonstrated (Hardcastle and Wilkins, 1970) that
whereas cascara sagrada has no effect on the colon
the aglycone increases colic motility of rabbits. If
the free aglycone is fed to the animals it has no
cathartic action, indicating that it is sensitive to either
gastric or small intestinal secretions. Thus the
glucose moiety protects the aglycone during its
transit through the upper digestive tract allowing it
to be released in an active form in the colon.
The ability of the bacterial flora to hydrolyse
glucuronides is important in the enterohepatic
circulation of compounds (Smith, 1966). This has
both beneficial and harmful effects. For example,
chloramphenicol, which undergoes extensive enterohepatic circulation, is retained within the body for a
M. J. Hill and B. S. Drasar
prolonged period of time and therefore has a better
opportunity to exert its antibacterial effect. Similarly
phenolphthalein and morphine are also retained
thereby improving their therapeutic effect. However,
retention within the enterohepatic circulation also
allows more time for bacterial degradative enzymes
to be induced. If we use chloramphenicol as the
example there is a wide range of bacterial modifications that can occur (Smith, 1966), all of which
result in loss of antibacterial activity and some of
which may result in the formation of toxic products.
Lactose is readily metabolized by bacterial figalactosidase but this is normally of no consequence
in western human adults since the intestinal ,Bgalactosidase degrades any dietary lactose long
before it reaches the large bowel. In most parts of
the world, however, intestinal P-galactosidase is lost
during childhood and ingestion of lactose results in
fermentative diarrhoea. This has been reviewed by
Neale (1971). Bacterial ,-galactosidase is utilized in
lactulose therapy. Lactulose is the ketoisomer of
lactose; it is not hydrolysed by intestinal P-galactosidase but is readily degraded by the bacterial enzyme.
By carefully controlling the dose of lactulose the
amount of acid produced in the colon, and therefore
the colonic pH, can be controlled.
Cellulose and hemicelluloses are complex glycosides which are susceptible to bacterial attack; it has
been shown that normally 20% of a dose of hemicellulose is degraded during transit through the gut.
This degradation will result in the formation of shortchain fatty acids which by their osmotic effect might
well explain the bulking effect of fibre.
AMMONIA METABOLISM
Intestinal bacteria produce ammonia by deamination
of amino acids but the principal route is by urea
hydrolysis. Urea undergoes an enterohepatic circulation, being produced in the liver then entering the
colon by passive diffusion, where it is hydrolysed
to ammonia and carbon dioxide. The ammonia reenters the portal blood, again by diffusion, and
returns to the liver to be converted back to urea or
to be incorporated into protein. Approximately 1530% of the total urea pool, ie, about 7 g, is hydrolysed each day (Walser and Bodenlos, 1959; Jones,
Smallwood, Craigie, and Rosenoer, 1969). The
major source of colonic urease is the gut bacterial
flora. Treatment of patients with neomycin or other
antibiotics reduces the faecal urease activity (Evans,
Aoyagi, and Summerskill, 1966) and germ-free
animals fail to catabolize urea to any significant
extent (Levenson, Crowley, Horowitz, and Malm,
1959). Interestingly, it appears that it is the mucosal
flora that is important in urea metabolism rather than
the luminal flora. This conclusion was reached by
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Symposium on colonic function
Wolpert, Phillips, and Summerskill (1971) following
the observation that urea delivered luminally was
much less efficiently hydrolysed by the flora than that
administered systematically. Hardly any urea is
detectable in faeces so that virtually all of the urea
entering the gut is hydrolysed to ammonia.
In the normal healthy person, the ammonia
generated in the gut is restricted to the portal blood
system, but in hepatic disease the liver fails to
detoxify the ammonia and it enters the general
circulation (White, Phear, Summerskill, and Sherlock, 1955). This is said to result in the chronic or
recurrent neuropsychiatric disorders related to protein intolerance, ultimately resulting in hepatic
coma due to the direct cerebrotoxic action of
ammonia (Schenker, McCandless, Brophy, and
Lewis, 1967). Similar symptoms arise, for the same
reasons, in protein intolerance due to portal systemic anastomosis (Riddell, 1955). Hyperammonaemia has been reviewed by Summerskill (1970).
The major course of therapy of hepatic coma is the
control of intestinal ammonia production and
nitrogen metabolism. This has been attempted
either by (a) reducing the supply of nitrogen compounds to the gut, (b) reducing the number of
ammonia-producing bacteria, (c) reducing the time
available for bacteria to produce ammonia, and (d)
preventing the escape of ammonia from the gut.
Attempts to reduce the numbers of ammoniaproducing bacteria take two forms: antibiotic
therapy and replacement therapy. A number of
antibiotics have been shown to be effective for a short
time but these have the usual side effects which
accompany disturbance of the gut flora, namely,
diarrhoea, steatorrhoea, and staphylococcal enterocolitis (Walker, Emlyn-Williams, Craigie, Rosenoer,
Agnew, and Sherlock, 1965). Replacement therapy
is based on the concept that, since some bacteria are
ureolytic while others are not, replacement of the
normal (ureolytic) flora by one which fails to
hydrolyse urea (eg, lactobacilli) will be beneficial. It
might well be so if such a replacement were possible;
as it is this method of therapy has little success, and
only serves to emphasize the remarkable stability of
the gut flora. The amount of ammonia produced
should be reduced if the time available for its
production is reduced, and this is the rationale
behind the use of enemas and purgatives. There is
still some question regarding the amount of agent
to be used, and the ultimate effectiveness of this
treatment which would inevitably appeartobeashortterm measure.
Prevention of the escape of ammonia from the gut
is the basis of lactulose therapy. Ammonia is readily
absorbed from the gut in its free form. When the
colonic pH is reduced the ammonia will be in an
ionized form and will be on a pH gradient; under
these conditions the ammonia should theoretically
move from the blood to the colon rather than the
reverse, resulting in reduced blood ammonia levels
and increased faecal excretion of ammonia. This is
the rationalization of the use of lactulose, the dose of
which is carefully controlled to give a faecal pH of
4 to 5 (Bircher, Muller, Guggenheim, and Haemmerli, 1966; Elkington, Floch, and Conn, 1969).
Unfortunately for the theory, under conditions in
which lactulose was being used successfully, ie,
when the blood ammonia level was reduced, there
was no increase in faecal ammonia levels. It is
apparent that some rethinking is necessary.
In hepatic failure the production of ammonia by
the gut flora is detrimental to the patient; in renal
failure the reverse is true. Here the blood urea
increases to toxic levels unless the nitrogen intake
is controlled. As the blood urea level increases so
does the faecal urease (Brown, Hill, and Richards,
1971), resulting in the release of ammonia which
returns via the portal system to the liver where a
proportion is incorporated into protein. The
increased faecal urease could be the result either of
an increased proportion of organisms producing
urease, or to an increased output of enzyme from a
constant number of active organisms. In fact, the
former is true, with the proportion of urease-positive
organisms in the faecal flora increasing with the
blood urea level. There is no apparent reason for
this; the production of urease is not known to
confer any ecological advantage in the presence of
high urea levels.
METABOLISM OF BILE ACIDS
The metabolism of bile acids is of interest from two
points of view: these are (1) the major metabolic
reactions which give rise to the secondary bile acids
in bile and faeces; (2) the minor reactions which may
give rise to carcinogens and be implicated in the
aetiology of colon cancer.
The major metabolic reactions carried out by the
gut bacteria are (1) hydrolysis of bile conjugates to
release the free bile acids; (2) hydroxyl oxidation to
a keto group, followed under certain circumstances
by reduction to a ,B-hydroxyl group; (3) removal of
the 7ac-hydroxyl group to yield the major secondary
bile acids deoxycholic acid (from cholic acid) and
lithocholic acid (from chenodeoxycholic acid).
Although the deconjugation reaction occurs
extensively in the ileum the other reactions take
place mainly in the caecum and colon. The dehydroxylation reaction yields products which are less
well absorbed than their substrates and consequently contributes to the total faecal loss of bile
acids. Although the products of these major reac-
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M. J. Hill and B. S. Drasar
322
tions may play a role in small intestinal disease, they
do not contribute in any large measure to large
intestinal disorders.
The minor reactions of bacteria upon bile acids
are of more interest to us because we have produced the hypothesis that they are important in the
aetiology of large bowel cancer. We have postulated
(Aries et al, 1969) that colon cancer is caused by a
carcinogen or cocarcinogen produced in situ in the
colon from some otherwise benign substrate; we
have also postulated that the substrate is the bile acid
moiety. We have shown (Hill, Drasar, Aries,
Crowther, Hawksworth, and Williams, 1971; Hill,
1974) that in comparisons between a number of
countries, some with high and some with low
incidences of colon cancer, the incidence of colon
cancer correlates with the total faecal bile acid
concentration and with the faecal concentration of
dihydroxycholanic acids. The latter correlation was
remarkably good.
The question which then arises is, What is the nature
of the carcinogen or cocarcinogen produced from
the bile acids? We have postulated that the carcinogen is a polyunsaturated bile acid, and have suggested
a pathway by which the bacteria could theoretically
produce a polycyclic aromatic compound from the
bile acids using only four types of nuclear dehydrogenation reaction (Hill, 1971a). These have all been
demonstrated in vitro using human gut bacteria and
we have produced in vitro a bile acid with rings A and
B of the steroid nucleus fully aromatic. One of the
four reactions is the dehydroxylation which proceeds
via an unsaturated intermediate (Samuelsson, 1960;
Goddard and Hill, 1973); this reaction is carried out
by a wide range of anaerobic organisms, the proportion of active strains being much higher in areas
with a high incidence of colon cancer than in those
with a low incidence. The other three reactions are
only carried out by certain lecithinase-negative
clostridia, principally Cl. paraputrificum, which will
subsequently be referred to as nuclear-dehydrogenating (or NDH) clostridia. These organisms are
rare in the faeces of people living in areas with a low
incidence of colon cancer but much more common
in faeces from people living in high incidence areas.
Thus in support of our hypothesis that the gut flora
produce an unsaturated carcinogen from the bile
acids and that this is important in the aetiology of
colon cancer, we find that in areas with a high
incidence of colon cancer the concentration of the
postulated substrate is high and the relevant bacteria
are common, whilst in areas of low incidence the
substrate concentration is low and the relevant
bacteria are rare.
During the last year we have been testing our
hypothesis in individuals, since those with a high
faecal bile acid concentration and large numbers of
NDH clostridia should be at high risk whilst those
with low levels of only one or neither of these two
requirements should be at low risk. In the study,
which is being conducted in collaboration with
workers at Northwick Park Hospital, Harrow, and at
St Mark's Hospital, London, we have examined the
stools of patients with newly diagnosed large bowel
cancer and patients admitted to the same ward with
diseases other than colon cancer. Only the first
stool on entry to the ward was acceptable, since
later stools would have been affected by the hospital
diet, which is low in fat and would result in a low
faecal bile acid level (Hill, 1971b). The study is
being carried out blind with the code being broken
after each 50 patients. The latest analysis (Hill,
Drasar, Goddard, Peach, Williams, Meade, Cox,
Simpson, and Morson, 1974) shows that in the
large bowel cancer patients 22 of 29 belonged to the
high-risk group compared with one of 60 of the
control group (table II).
Faecal Bile
Nos. of NDH Large Bowel
Cancer
Acid
Clostridia
Concentration (per g wet wt) Patients
Control
Patients
(mg/g dry wt)
>6
<6
>6
<6
>108
>10'
<103
<10'
22
4
2
1
(76%)
(14 %)
(7%)
(3%)
1
25
6
28
(1-7%)
(42%)
(10%)
(47%)
Table II Bile acid concentration and numbers of
NDH clostridia in faeces from patients with large bowel
cancer and controls admitted to the same gastroenterology ward with diseases other than large bowel
cancer
These findings support those obtained in the
international study. The next steps are (a) to see
whether the faecal bile acids concentration together
with the numbers of NDH clostridia can be used to
predict colon cancers in a prospective study; (b) to
see whether any of the products of nuclear dehydrogenation of the bile acids obtained in vitro is carcinogenic in animal tests; (c) to see which of these
unsaturated bile acids are produced in vivo in man;
(d) to see the effect of dietary changes on the faecal
bile acid concentration and on the numbers of
NDH clostridia produced.
Conclusions
Although our knowledge of the gut flora both in
terms of its composition and of its function has
increased dramatically in recent years, the unanswered questions still greatly outnumber those
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answered. In this communication we have been able
merely to outline the problems involved and the
progress made towards solving some of them. It is
evident that this is still a new field of study which can
make a contribution to the understanding not only
of gastroenterological but also of general medical
and pharmacological problems.
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Absorption and secretion by the colon
JOHN H. CUMMINGS
From the Medical Research Council Gastroenterology Unit, Central Middlesex Hospital, London
Various aspects of colonic absorptive function in
man have been dealt with in a number of reviews
(Phillips, 1969; Turnberg, 1970; Wrong, 1971;
Shields, 1972; Sladen, 1972; Edmonds and Pilcher,
1972).
Electrolytes and Water
The role which the colon plays in conserving water
and electrolytes has been known for some time,
deduced largely from a comparison of the volume
and composition of ileostomy effluent with that of
faeces and confirmed by perfusion of the colon in
vivo. The quantity of these substances absorbed
daily by the colon has, however, to be revised,
since it has been shown that the flow of ileal
contents into the colon each day is three times
the normal volume of ileostomy effluent (Kanaghinis,
Lubran, and Coghill, 1963;Phillips and Giller, 1973).
Fasting ileal flow rates, measured by slow intestinal
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The normal colonic bacterial flora.
M J Hill and B S Drasar
Gut 1975 16: 318-323
doi: 10.1136/gut.16.4.318
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