Download When We Eat, Which Bacteria Should We Be Feeding?

When We Eat, Which Bacteria
Should We Be Feeding?
Probiotics and prebiotics to alter the gut flora might usefully curtail
metabolic activities of problematic gut pathogens
Glenn R. Gibson and Robert A. Rastall
he human digestive tract, particuditions, including obstetric techniques, whether
larly the colon, is one of the most
a delivery is vaginal or caesarean, and the type of
microbially active ecosystems in exfeeding the newborns receive affect the level,
istence, containing a massive variety
frequency, and varieties of species that colonize
of bacteria, viruses, yeasts, and other
a newborn’s gut.
fungi. One novel approach to combating disease
When microorganisms are transferred into
revolves around diet, using foods with novel
the infant gut, the initial colonizers are facultaingredients to stimulate indigetive anaerobes that rapidly remove
nous bacteria while avoiding nontraces of oxygen, rendering the gut
indigenous microbial species along
strictly anaerobic within one week
Shortly after
with the diseases that they someof birth. Soon, breast- and formutimes provoke. Indeed, this conla-fed infants develop differences
birth, an array
cept is known as the prebiotic efin microflora profiles, with
of bacteria
fect.
Meanwhile,
probiotics
bifidobacteria dominating the
begin to
represent a more traditional apformer while the latter tend to decolonize the
proach to altering gut flora— one
velop a more complicated commuformerly sterile
that entails individuals consuming
nity structure.
gut
live microorganisms with the exHuman milk contains a compectation that those microbes will
plex mixture of glycoproteins and
remain intact and will interact
oligosaccharides that stimulate biwith the resident gut flora to make it more
fidobacteria. Because they have powerful inhibbenign.
itory properties against various gastrointestinal
Virtually everyone experiences a gastrointespathogens, the predominance of the bifidobactinal complaint that relatively harmless prebiotteria more than likely accounts for the “breast is
ics and probiotics might help to redress. Even
best” hypothesis. In general, bottle-fed infants
ignoring the benefits of a flora that is rich in
experience higher infection rates than those who
lactic acid-producing bacteria, using them to
are breast fed. Hence, infant-formula manufacdisplace a distinctly pathogenic flora is surely an
turers are seeking to alter their products to more
approach worthy of consideration.
effectively stimulate bifidobacteria.
Once weaned from an exclusive milk or forThe Gastrointenstinal Tract Acquires Flora
mula diet, children consume increasingly varied
Soon after Birth
foods, leading microbial gut populations toward greater complexity. When children reach
Shortly after birth, an array of bacteria begin to
about 2 years of age, the gut microbial populacolonize the formerly sterile gut. Newborns tyption assumes an adult-like composition, conically first contact bacteria when they move
taining at least 500 bacterial species.
through the birth canal and are exposed to miThe numbers of bacteria in the human stomcrobial flora within the genital tract. Other con-
T
Glenn R. Gibson is
Professor of Food
Microbiology and
Robert A. Rastall is
Senior Lecturer in
Food Biotechnology
in the School of
Food Biosciences,
The University of
Reading, Whiteknights Reading,
United Kingdom.
224 Y ASM News / Volume 70, Number 5, 2004
FIGURE 1
Bacterial and physicochemical interactions in different areas of the human gut.
ach typically remain low, approximately 103 per
ml of contents, because their transit time is rapid
and stomach acidity is high (Fig. 1). One notorious occupant, Helicobacter pylori, resides in
the gastric mucosal layer and is associated with
type B gastritis, dyspepsia, and stomach carcinomas. Extensive studies of this microorganism
lend support to the idea that carriage of this or
other pathogens can predispose individuals towards particular illnesses. Such studies also
continue to raise the profile of gut microbiology, emphasizing its important health consequences.
The small intestine provides a very different
story because it is a compartment where microbial numbers rise to 1 million per ml. A brief
transit in the ileum and jejunum plus inputs of
bile salts and pancreatic enzymes maintain the
flora at this higher level.
The human adult colon is about 150 cm in
length with a typical transit time of 24 –72
hours, providing a significant period for bacteria
to reach extremely high numbers. Moreover,
nutrients are plentiful at around 100 g of dietary
residues, including carbohydrates, proteins,
amino acids, and lipids, entering the colon daily
and fortifying endogenous nutrient sources such
as mucus and epithelial cells (Fig. 2). Here,
bacterial numbers can soar to 1012 per ml of
contents—in other words, probably as many
bacteria as can be contained in 1 ml— of which
several hundred types exist in an adult.
This microbial mass makes the colon one of
the most metabolically active organs in the body
and certainly the most heavily colonized. Indeed, about 95% of the total cells in the body
are bacteria within the large intestine, making
humans manyfold more microbial in composition than mammalian. In considering what types
and numbers of bacteria are being fed when an
individual eats dinner, it is easy to imagine the
impact that gut bacteria can exert in health and
disease.
Appreciating the Role of Gut Flora in
Health and Disease
Through their metabolic activities, the colonic
microbiota have a significant impact upon host
welfare. For example, the principal end products of anaerobic fermentations are organic acids. Some of these are absorbed from the gut to
be metabolized systemically, providing perhaps
10% of an individual’s daily energy requirement.
Volume 70, Number 5, 2004 / ASM News Y 225
Prebiotics versus Probiotics in the Lab, and during a Cricket Match
Glenn R. Gibson envisions a day
when people will have their own
designer diets, consuming meals
based on their personal genotypes—a health strategy that will
work only if food also continues
to be fun, he says. “Food is something social and enjoyable, so perhaps we should not be too prescriptive. There has to be some
enjoyment too. Hence, the best
functional foods will also taste
good.”
Gibson, professor of food microbiology at the University of
Reading in the United Kingdom,
leads a multidisciplinary research
program on how gut microbiology affects human health and
disease. His research includes
projects on pro- and prebiotics,
molecular genotyping of gut bacteria, diet and cancer, the molecular biology of bifidobacteria,
colonic gas metabolism and hydrogen sulfide production, the
role of gut bacteria in lipid reduction, and colonic homeostasis.
“I think that foods that target
gut bacteria have the ability to
help a lot of people with acute or
chronic ailments,” Gibson says.
“Maybe with big moves in individual genotyping, the same may
be done for gut flora—that is, sequence and quantify all the bacteria present and predict susceptibility to disorder and define a
food intervention to protect. Using diet to reduce disease risk is
user-friendly and relatively free of
side effects.” But for this strategy
to be successful, individuals and
health professionals will need to
learn a great deal more about microbiology, nutrition, and related
subjects, he says. That educational process is beginning to happen, at least in his country, he
adds.
“Awareness is increasing quite
rapidly now in the United Kingdom,” Gibson says. “Family
doctors are becoming more and
more interested, especially as
many gut disorders are not ef-
Thus, the microbiota in the colon can affect
mood and other markers of well-being. For instance, dietary fiber that is readily metabolized
by gut flora has positive effects upon energy,
stress, and cognitive performance, according to
Andrew Smith and colleagues at the University
of Wales, Cardiff, United Kingdom. Meanwhile,
other, more specific end products of gut bacterial metabolism, such as propionic acid, are
thought to interfere with cholesterol synthesis in
the liver and may therefore be useful for protecting against coronary heart disease. Moreover,
the gut serves as a major immune organ of the
body, in part through the antigenic status of its
resident microbiota.
Building upon research with H. pylori, several
digestive disorders are being researched for their
link with specific gut flora components, with
some of these associations more tentative than
others:
226 Y ASM News / Volume 70, Number 5, 2004
fectively dealt with by pharmaceuticals. This is impressive, as
diet and health is not part of the
normal training. It takes some effort.”
Gibson, 42, grew up in the coalmining village of Horden in
County Durham, which is in the
northeast of England, very similar, he says, to the town portrayed
in the film Billy Elliot. The older
of two children— he has a sister—
Gibson remembers his hometown
as a “great place and a tight-knit
community.” His late father
worked as a sawmill operator in
nearby Hartlepool, and his
mother was an occupational therapist and served for a time as the
director of a home for the elderly.
Gibson credits failure with
sending him on the path to microbiology—more specifically, the
fact that he flunked his school exams at the age of 18. “I made a
real blunder in my first scientific
exams, my ‘A’ levels in 1979,” he
says. “But I found my subsequent
• Ulcerative colitis (UC), a disorder principally of
Western origin that typically first appears
among young adults, is one example of an inflammatory bowel disorder (IBD). UC, which is
confined to the colon, cannot be induced in
animal models lacking a gut flora. Our research
and that of others implicate sulfate-reducing
bacteria, which are virtually always present in
the colitic gut but are rarely present in the gut of
healthy individuals. These bacteria produce sulfide, which is a cell toxin and also interferes with
butyric acid oxidation in colonocytes. Our
group is currently conducting a dietary intervention study designed to curtail sulfate-reducing
bacterial activity in UC patients.
• The etiology for Crohn’s disease, a form of
IBD that can affect any area of the alimentary
tract, is far from certain. However, several
investigators suspect mycobacteria.
exams progressively easier, perhaps because my focus narrowed.
In fact, to become a professor
there are no exams involved!” Despite the momentary setback, he
graduated from the University of
Dundee in 1983. He received his
Ph.D. there three years later, and
conducted postdoctoral work
there as well, studying the genetics of sulfate-reducing bacteria.
From 1987 until 1995, he
served as a research microbiologist at the Medical Research
Council Dunn Clinical Nutrition
Centre in Cambridge, then
headed the microbiology department of the Biotechnology and Biological Sciences Research Council Institute of Food Research in
Reading. He was awarded a personal chair at the university in
1999. He also heads the Food Microbial Sciences Unit in the school
of food biosciences. The unit has
about 50 researchers working on
gut microbiology and microbial
food safety. In 1991, he received
the W. H. Pierce memorial prize,
which is awarded for microbiology by the Society for Applied
Bacteriology and Unipath.
Perhaps it is no wonder that
Gibson’s wife sometimes tells their
dinner guests that he is a painter
or decorator. She claims that this
deception makes for more tasteful mealtime conversation than
would discussing what he really
does for a living.
Gibson and his wife, who is
studying for a degree at Open
University, United Kidngom, have
two children, a girl, 12, and a boy,
9, both athletes. “Because England won the rugby World Cup
last December and beat arch-rival
Australia in the final, my son has
just taken the game up,” he says.
“And my daughter is a very good
swimmer indeed.”
Gibson plays squash and badminton, and likes to swim and
bowl with his family. “I play a lot
• Irritable bowel syndrome (IBS), a prevalent
disorder affecting up to 20% of individuals in
some countries, such as the United States,
United Kingdom, France, and Germany, is
often related to stress. IBS symptoms include
diarrhea or constipation, and attacks occur
unpredictably. Candida albicans, which is involved in recurrent vaginal thrush, is suspected as a trigger factor for IBS. We have
isolated a probiotic Lactobacillus plantarum
with potent anticandida activity that is being
evaluated in a clinial trial involving IBS patients.
• Bowel cancer—specifically, colorectal tumors—is considered the second most prevalent form of cancer in humans and is responsible for one in five fatalities in the United
States. Components of the gut flora have the
capacity to produce carcinogens and tumor
promoters, including nitrosamines, heterocy-
of squash and am in a league system in the university here,” he
says. “You don’t know your opponent until they turn up—and
my heart sinks when it is a young,
fit student. I used to play football,
but my knees are past it now.”
He also recalls one memorable
cricket match among microbiologists on a very hot August afternoon in Reading during a break
from an international scientific
conference. “The teams were the
probiotics versus the prebiotics,”
he says, failing to mention which
team was his. “I’m not sure who
won, as the rules seemed to be
mostly ignored. It was great
watching the Americans bowl a
very hard cricket ball like they
would fast-pitch a baseball. There
were no hospital cases, but a few
bruises did ensue.”
Marlene Cimons
Marlene Cimons is a freelance writer
in Bethesda, Md.
clic amines, ammonia, diacylglycerols, IQ,
and fecapentenes.
• Antibiotic-associated diarrhea occurs when
homeostasis in the gut is disturbed through
use of broad-spectrum antimicrobials. For example, pseudomembranous colitis may occur
when the usual suppressant effect of gut bacteria against Clostridium difficile fails, and it
proliferates and also produces damaging
amounts of two types of toxin.
• Translocations can occur following trauma,
such as intensive surgery, leading the gut to
become “leaky” and some of its bacterial contents to migrate into sites, such as the liver,
where microbially produced toxins can act
destructively.
• Pneumatosis cystoides intestinalis (PCI) is
characterized by gas-filled cysts lining the colon. Clostridia may generate this gas, al-
Volume 70, Number 5, 2004 / ASM News Y 227
dietary origin. What about featuring
nutrients whose effects might be more
benign and perhaps even beneficial?
Can diets be fortified to prevent specific
disorders? If so, what would be a reliable mechanism?
These questions have special relevance
because so many of these gut disorders
lack effective treatments. However, probiotics and prebiotics, which rely on dietary means to alter the gut flora, could
provide a safe and cost-effective approach for reducing the metabolic activities of problematic gut pathogens. This
approach thus might be considered a benign approach to “germ warfare.”
FIGURE 2
The Probiotic Approach Entails
Adding Microorganisms to the
Gut Ecosytem
Typical food sources for various genera of colonic bacteria.
though bacteria capable of metabolizing hydrogen, including sulfate-reducing bacteria,
methanogens, and acetogens, may be absent
from the PCI gut.
• Autistic spectrum disorders (ASDs) might also
have bacterial origins, including from toxins
that are generated in the gut but have systemic
effects. According to investigators from an
earlier era, including William ArbuthnottLane (late 19th century) and Elie Metchnikoff
(early 20th century), the gut flora can exert
nonlocal effects, such as migraine. Our own
studies have recently found that, some autistic
individuals have high levels of clostridia in
their stools; perhaps toxins from these gut
bacteria are absorbed into the bloodstream
and exert effects elsewhere.
These examples of diseases associated with excesses of specific gut bacteria (or other microorganisms) represent instances where one would
not want to expand particular microbial populations by supplying them particular nutrients of
228 Y ASM News / Volume 70, Number 5, 2004
Humans have been ingesting probiotics
in the form of soured milks for thousands
of years. Nowadays, many such products, including fermented milks, yogurts,
and cheeses, are plentiful and popular.
Among them, however, yogurt is manufactured using Lactobacillus bulgaricus
and Streptococcus thermophilus, neither
of which is recognized as probiotics,
which would entail adding strains to supplement
the fermentation-based manufacturing procedure.
The most commonly used probiotic or bioactive microorganisms include lactic acid-excreting bacteria such as L. casei, L. acidophilus,
L. fermentum, L. johnsonii, L. plantarum, and
L. rhamnosus, or bifidobacteria such as Bifidobacterium longum, B. infantis, and B. bifidum. Other microorganisms used in probiotic
products include lactococci, streptocococci, the
gram-negative Nissle Escherichia coli, and also
yeasts such as Saccharomyces species. Delivery
vehicles besides milk-based products for probiotics include fruit juices and lyophilized versions
in powders, capsules, tablets, and sprays.
Probiotics have been used for the past 40 years
to treat animals on farms, where these products
are said to reduce the risk of infection, to increase
yield and feed conversion, improve digestion, and
to improve products such as eggs, meat, and milk.
The mechanisms behind these effects are not fully
understood but are linked to decreased pathogen
load in the guts of animals being treated. Pur-
chases of probiotics for farm animals in
FIGURE 3
the United States have increased fivefold
during the past decade, and over 50% of
dairy producers are using probiotics. For
human use the market is even larger, with
a profit income of several billion Euros in
Europe. If anything, the situation is even
more advanced in Asia, principally Japan.
A survey indicates more than 50 recently published scientific reports of humans treated with probiotics having
positive results. Principally these trials
involved intestinal problems such as
gastroenteritis and IBS, but some of
them were conducted on patients with
urinary tract infections or with chronic
conditions such as cancer, coronary
heart disease, and IBD.
Despite reports of benefits, the data
The effects of prebiotic-containing biscuits on the predominant gut flora components of 31
typically are variable, perhaps reflecting
healthy adults. Study was of a crossover nature, doubly blind, placebo controlled. Microbiology was carried out using fluorescent in situ hybridization. Courtesy of K. M. Tuohy.
probiotic strain variability, poor survival of some strains in products being
evaluated, and the varying ability to
influence competitive gut ecosystems. Nonetheoligosaccharides resist digestion or absorption in
less, in the aggregate, these data suggest that
the upper gut and then are selectively metabolized
altering gut flora shows promise both prophyby gut flora. For instance, some oligosaccharides,
lactically and therapeutically.
often called prebiotics, serve as nutrients that favor
indigenous bifidobacteria and lactobacilli, stimulating their replication in a way that matches what
Prebiotics Are Nutrients That
occurs when these microbes are provided as proAlter the Gut Ecosystem
biotics. Oligosaccharides considered as prebiotics
Many different factors, including age, stress,
include the fructooligosaccharides (FOS), inulin,
antimicrobial intake, immune status, transit
galactooligosaccharides (GOS), and lactulose.
time, and availability of substrate, can alter the
Bifidobacteria produce several enzymes that
gut microbiota. However, the last of these,
are particularly suited to metabolizing oligosacwhich could be a major determinant of gut
charides, including a ␤-fructanfuranosidase that
microbial composition, is one in which the condigests FOS. Meanwhile, other commensal bacsumer can exert considerable control through
teria, notably Bacteroides thetaiotaomicron,
diet.
can signal the host to produce fucosylated glyGenerally, when gut flora metabolize dietary
cans via a molecular sensor. Hence, this microbe
proteins and lipids, they generate toxins, wherecan engineer its own niche within this ecosysas metabolizing carbohydrates yields harmless
tem. Perhaps additional molecular messages are
or beneficial organic acids. Meanwhile, metabeing sent by pathogens that prebiotics may
bolically resistant starches and fiber are simiinterfere with and thus act as anti-infective
larly considered beneficial because they provide
agents.
fecal bulk, improving digestion and transit time
while reducing the risk of colorectal cancer and
Prebiotic Oligosaccharides Are Being
diverticulitis.
Used Extensively
Oligosaccharides represent perhaps the most
interesting group of nutrients when they enPrebiotics, which were defined in 1995, are noncounter the gut microflora. Distinct from dietary
digestible food ingredients with the capacity to
fibers such as pectin, celluloses, and xylan, various
improve health when selectively metabolized by
Volume 70, Number 5, 2004 / ASM News Y 229
FIGURE 4
Fluorescent image of gut bacteria.
colonic bacteria. Typically, to achieve a prebiotic effect, producers will add enough of a prebiotic to a food product to deliver a daily dose of
at least 5 g. However, although higher daily
doses of up to 30 g yield no adverse affects,
introducing too high a prebiotic dose may compromise microbial selectivity and would risk
generating gas, which is not a problem associated with bifidobacteria or lactobacilli buildups.
In Europe, several prebiotic oligosaccharides
are being added to foods on a commercial scale.
In Japan, food producers are using an even
wider range of such materials, including isomaltooligosaccharides, soyaoligosaccharides,
gentiooligosaccharides, glucooligosaccharides,
lactosucrose, polydextrose, and xylooligosaccharides.
What are the health consequences of consuming foods containing prebiotics? Clinical and
preclinical studies are under way to assess the
value of prebiotics for improving mineral bioavailability and for countering obesity, bowel
cancer, IBD, IBS, coronary heart disease, autism, necrotizing enterocolitis, vaginal thrush,
and other infectious processes. For instance, volunteers in one of our studies consumed FOScontaining biscuits, which stimulated gut bi-
230 Y ASM News / Volume 70, Number 5, 2004
fidobacteria to a level resembling that
in breast-fed infants (Fig. 3). When it
comes to analyzing how prebiotics affect the complexity of gut flora populations, researchers are using a variety of
molecular techniques, including fluorescent in situ hybridization (Fig. 4),
16S rRNA profiling, temperature/density gradient gel electrophoresis, direct community analysis, ribotyping,
pulsed-field gel electrophoresis, expression arrays, detection genes that
affect function, microchips, proteomics, metabolomics, and transcription
studies.
A major advantage of prebiotics over
probiotics is that product integrity, viability, or stability are not issues for concern. Hence, prebiotics can be added
to many food vehicles, including dairy
products, beverages and health drinks,
spreads, infant formula and weaning
foods, cereals, bakery products, confectionery chocolates, chewing gum, soups,
sauces and dressings, processed meats,
dried instant foods, canned foods, and
sports supplements. They can also be used as
powdered or syrup supplements. New product
developments are occurring at a rapid pace.
In terms of how best to feed your gut bacteria,
a balanced high fruit and vegetable intake is key.
Foods such as onions, garlic, asparagus, chicory,
milk, artichoke, leeks, and bananas contain
natural prebiotics. Consuming specially supplemented foods should not be viewed as replacing
a healthy diet but rather as an adjunct. As the
advantages of prebiotics become more apparent, steps may be needed to ensure that they do
not become overpriced.
Prebiotics also may contribute to food safety
by protecting against food- and waterborne
pathogens. For example, a gut flora dominated
by bifidobacteria or lactobacilli that produce
organic acids, compete for nutrients, improve
overall immune status, and sometime secrete
antimicrobial agents might better withstand the
effects of such pathogens. Our studies with Bo
Lönnerdal and his colleagues at the University of
California, Davis, show that newborn primates
fed prebiotics can resist becoming infected when
challenged with enteropathogenic E. coli. In
some cases, these protective effects were as robust as those offered by breast milk.
Human population groups who are especially
suited to pre- and probiotic treatments include
the elderly who are prone to gastrointestinal
infection, weaning children, formula-fed infants, global travellers, persons who are taking
antibiotics, and others who are prone to chronic
gastrointestinal complaints. Moreover, such approaches may also be suited to those living in
developing countries where conventional medical interventions are prohibitively costly.
SUGGESTED READING
Brück, W. M., S. L. Kelleher, B. Lönnerdal, K. E. Nielsen, D. Chatterton, and G. R. Gibson. 2002. Fermentation studies on
selected infant milk components using in vitro models of the human gut and rhesus monkeys. J. Paediatr. Res. 37:273–280.
Gibson, G. R., P. Berry Ottaway, and R. A. Rastall. 2000. Prebiotics: new developments in functional foods. Chandos
Publishing Limited, Oxford.
Gibson, G. R., and M. B. Roberfroid. 1995. Dietary modulation of the human colonic microbiota: introducing the concept of
prebiotics. J. Nutrition 125:1401–1412.
Perdigon, G., and R. Fuller. (ed.) 2003. Gut flora, nutrition, immunity and health. Blackwell Publishing, Oxford.
Tannock, G. (ed.). 2002. Probiotics and prebiotics. Caister Academic Press, Norfolk.
Tuohy, K. M., S. Kolida, A. Lustenberger, and G. R. Gibson. 2001. The prebiotic effects of biscuits containing partially
hydrolyzed guar gum and fructooligosaccharides—a human volunteer study. Br. J. Nutrition 86:341–348.
www.isapp.net. Website of a new international scientific association dedicated to probiotic and prebiotic research.
www.vtt.fi/virtual/proeuhealth. A collection of European Union-funded research projects on probiotics and prebiotics.
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