THE HUMAN body contains 100 000 000 000 000 cells, a tenth of which belong to
the body proper. The remaining 90 per cent are the 90 trillion or so bacteria
that live on or in us. These microbes coat our skin, the inside of our noses and
throats, and the whole length of our guts from mouth to anus. True, our cells
are between ten and a hundred times larger than theirs. But the fact remains,
we’re not just individuals, we’re walking communities.
And these are not polite, keep-your-distance communities. Far from it.
Studies of the guts of mice, rats and pigs are revealing a vastly sophisticated
symbiotic system in which bug and mammalian cells engage in acts of intimacy
rarely seen outside a single organism. That relationship is clearly good for the
bugs—they get free board and lodging—but it also has an impact on
the bugs’ multicellular ally, helping mould the gut, the immune system and
perhaps even parts of the nervous system as they develop in young animals. And
by taking their cue from what happens in such disparate species as squid and
peas, researchers believe that bacterial and mammalian cells may make that
happen by, in effect, exchanging the keys to one another’s genomes.
“All these things—the microbes, the immune system, the cells of the
intestine—are intertwined,” says Jeff Gordon, a molecular biologist at
Washington University in St Louis, Missouri. “Each component influences the
other and nothing happens independently.”
Advertisement
The most dramatic evidence that, rather than simply enjoying the gut’s
bounties, the resident bacteria have something to give back comes from observing
what happens when the bugs are removed from the scene. Mice that have been
delivered by Caesarean section and raised in germ-free incubators have massively
swollen guts that also show other physical changes from the norm. What’s more,
germ-free mice are far more susceptible to infection, getting sick on a single
dose of just 100 live, pathogenic bacteria. It takes a million times as many to
make normal mice sick, because, it is thought, the resident bacteria physically
block disease-causing outsiders, preventing them from gaining a foothold, or
spew out chemicals to repel them.
And the generosity of gut bacteria doesn’t end there. They also produce
vitamin K, which an animal cannot get from its food, and in ruminants such as
cows they break down the cellulose in plant tissue, releasing digestible
glucose.
For decades, this largely benign relationship has had microbiologists
scratching their heads. Some of these “commensal”—that is
friendly—bacteria are found only in the mucus that lines the intestine,
while others hang out in its various cracks and crevices. How do they know where
to go when they colonise the gut in the first hours of an animal’s life? And
once there, how do they hold their own against the constant influx of new
bacteria? And why do some of these Lilliputians live peacefully with us for
years, only to turn on us in mean, even deadly, ways? Why, for that matter,
isn’t the immune system engaged in a constant battle with these intestinal
interlopers? After all, they are bristling with the same proteins that trigger
violent, sometimes fatal immune responses when found on nonresident
bacteria.
“We call it the commensal paradox,” says Brian Henderson, a cell biologist at
University College London. “If all the microflora is there and all the
epithelial cells are there and you put them together you would expect
inflammation. But you don’t get it.”
The idea that chemical communication might be the key to this curiously
stable relationship emerged from studies of the bond between plants such as peas
and the nitrogen-fixing bacteria that live in their roots. These symbiotic
bacteria can activate some of the plants’ genes causing tiny nodules to morph
from their roots, which provide housing for the bacteria. In return, the plant
gets a ready supply of nitrogen (“Let’s make nodules”, New Scientist,
11 January 1997, p 22). Researchers have now identified dozens of genes in both
plant and microbe that encode chemicals that regulate the transmogrification of
the plant roots. The back-and-forth jabbering is so extensive that it has been
compared to the chatter that goes on between the body’s own cells during
development. But in this case it involves communication between the genomes of
two separate species from two separate kingdoms.
Evidence is mounting that a similar intimacy sometimes exists between
bacteria and animals. Take the relationship between the bobtail squid,
Euprymna scolopes, and Vibrio fischeri, a light-generating
bacterium that inhabits an area of the animal’s mantle cavity known as its light
organ. The squid spends its days buried beneath the sand in shallow coastal
waters. When it comes out at night to hunt, the bacteria in its light organ
start to glow, generating light that could help the animal blend in with the
starlight when seen by predators from below.
But what has really grabbed the attention of researchers like Gordon is how
the bacteria affect the development of the various tissues associated with the
squid’s light organ. Before a squid has picked up its cargo of V.
fischeri, specialised cells lining the entrance to the light organ use tiny
hair-like filaments to wave water past the pores where the bacteria will take up
residence, possibly to facilitate infection. But according to studies by
Margaret McFall-Ngai and her student Jamie Foster at the Pacific Biomedical
Research Center in Manoa in Hawaii, once the bacteria have arrived, they kill
these cells off by somehow hijacking the squid genes that trigger programmed
cell death.
Intimate relationship
The cells lining the pore-like crypts where the bacteria reside are also
transformed under the influence of V. fischeri. They swell to four
times their normal size, and the stalks covering their surfaces grow thicker,
longer and more numerous, in what appears to be an attempt to swaddle the
incoming guests. The cells in the light organ even turn down their production of
a powerful toxin that researchers suspect is there to keep other bacteria at bay
until V. fischeri has become established. Just as in the pea plant
roots, under the bacteria’s influence the squid tissue goes through some radical
physical changes. “The bacteria are actually participating in the development of
the organism,” says McFall-Ngai.
Is a similar thing happening in the more complex arena of the mammalian gut?
Studies on rats, mice and pigs suggest so. For one thing, this would explain
what is now a long list of physical differences between the intestines of
germ-free lab animals and those of their normal counterparts. In germ-free
animals, the tongue-like villi that line the insides of the gut are longer, and
the crypts of Lieberkühn, cup-shaped structures around the base of each
villus, are shallower with fewer cells. In addition, the immune tissue scattered
along the length of the intestines is underdeveloped in germ-free mice, while
the nerves that control gut movements are sparser than normal.
The first clear evidence of a link between changes in the gut and specific
bacteria came in 1995, when a team led by Yoshinori Umesaki at the Yakult
Central Institute for Microbiological Research in Tokyo fed friendly bugs known
as segmented filamentous bacteria to germ-free mice. The bugs triggered a number
of changes, including an increase in the ratio of columnar-shaped epithelial
cells to mucus-producing goblet cells and in the rate of production of new gut
cells. There was also a change in the types of certain fatty compounds on the
surface of the cells lining the intestines.
The next step was to find out how the bugs and the gut cells communicate,
which is where Gordon comes in. He had spent the past decade trying to
understand how the small intestines develop in young mice, and, by
extrapolation, in human babies. The crypts of Lieberkühn in the gut churn
out unspecialised cells that migrate up the villi, where they become any one of
four specialised cells. The type of cell they become depends on which genes they
turn on and off. Gordon had discovered that this depended solely on a cell’s
position on the villus, and that had made him suspect that something in the
environment—perhaps the bacteria on the surface of the villi—was
activating the genes.
To find out more, Gordon needed to simplify things. So he selected a single
gut characteristic—the presence on cell surfaces of a sugar called
fucose—and watched how it changed when he fed germ-free mice different
bacteria.
During a mouse’s first 21 days, fucose molecules coat the cells in the lower
region of the small intestine. Later, fucose levels fall, at least in germ-free
mice. As soon as gut bacteria are added, however, the cells start making the
sugars again.
To work out which bacteria were responsible, Lynn Bry, a student in Gordon’s
lab, fed germ-free mice one species of bacterium at a time. The first bacterium
did not affect sugar production. Nor did the second. But when she added
Bacteroides thetaiotaomicron, not only did sugar production start up, but
there was a correlation between the number of bugs and the number of sugar
molecules, suggesting delicate signalling between the bug and gut cells. The
nature of that signal remains a mystery, but at a meeting of the American
Society for Microbiology in Chicago this month, Gordon and his postdoc Lora
Hooper reported that the bugs only send out their chemical signal when they
sense that supplies of the sugar are getting low, rather than have the gut cells
constantly churning out the molecule.
Gordon envisages other species of bacteria engaged in intimate conversations
all along the length of the gastrointestinal tract—part of an intensely
interactive community that has been honed by millions of years of coevolution.
“At birth there is probably a nutrient foundation laid out by the [gut] that
guides early colonisation,” he suggests. That would explain how colonising
bacteria find their correct niche in the gut, and why all mice produce fucose in
the lower region of their small intestine before they are 21 days old. The
ability of bugs to keep those food supplies coming once they have settled in
could explain how they manage to keep a foothold despite constant competition
from hoards of fresh bacteria that come in with the food an animal eats.
Does the multicellular partner have a say in what goes on, or is it simply a
passive food provider? The squid—which for the moment remains the paradigm
of such animal-bacteria partnerships—certainly gets a vote. Firstly, it
regulates the size of its V. fischeri bacterial colony by varying the
amount of oxygen it lets into the crypts of its light organ. Second, it somehow
stops other bacteria setting up shop in the crypts. And third, it kicks out
mutant V. fischeri that are incapable of producing light. As
McFall-Ngai sees it, the bacteria and the squid have “a really delicate
conversation . . . our bacterium says, `are you the right squid?’ and the squid
says, `are you the right bacterium?’ and they do this several times.”
And although there’s no hard evidence yet, Martin Blaser, a microbiologist at
Vanderbilt University in Nashville, Tennessee, says that gut cells probably have
similar conversations with their resident aliens. Whether the gut cells send out
chemicals that directly turn genes on and off in the bacteria, or whether they
merely select for particular bacterial strains by judiciously secreting
nutrients, displaying certain receptors on their surfaces, or using antibodies
to chase off the unwanted bugs, is unknown. According to Blaser, however, all
those mechanisms probably come into play.
The cosy alliance between bugs and gut cells is raising eyebrows in medical
circles. Take Helicobacter pylori. Since its link to stomach ulcers
gained wide acceptance in the early 1990s, millions of dollars have been spent
on the quest to find ways to eradicate it from human stomachs. But the bug is
found in close to half of healthy stomachs, leading some researchers to wonder
whether it may do its host some good as part of the normal flora. A major boost
for this idea came in April, when researchers led by Staffan Normark at the
Karolinska Institute in Stockholm showed that H. pylori releases
chemicals that are toxic to Escherichia coli, salmonella and other
potentially more harmful organisms (Nature, vol 398, p 671). “I spent
many years showing that H. pylori was a pathogen,” says Blaser. “Now I
think it’s a commensal that occasionally exerts a pathogenic side.”
Besides understanding why H. pylori and other organisms occasionally
slip from their niches to wreak havoc, a closer look at bug-gut relationships
could also inject scientific legitimacy into probiotics—the centuries-old
practice of gulping down live bacteria to fend off gut infections and other
intestinal problems. And what Gordon calls “abiotics”, which would use the
actual molecules involved in gut-microbe communication for therapy, could also
become a reality. Inflammatory bowel disease, a chronic disease marked by
periodic bouts of swelling that are not dissimilar to those seen in germ-free
mice, is one condition where this might be useful. If the signals the bugs use
to suppress inflammation could be identified, this would be a big step towards
designing a drug that could do the job where the bugs themselves appear to have
failed.
Meanwhile, should we be surprised—disturbed even—at the idea that
each one of us is just a single member of a gigantic, walking community of
organisms? Probably not. After all, Henderson points out, “biology is all about
ԳٱپDzԲ”.
The guts of a three-day-old baby born into the slums of Lahore, Pakistan, are
chock-a-block with bacteria of all types—in particular enterobacteria such
as Escherichia coli. A baby born in Sweden, on the other hand, may have no
enterobacteria in its guts, even after one week.
You might think this product of better hygiene was a good thing. Mucosal
immunologist Agnes Wold at Göteborg University in Sweden, who made those
observations, does not. In fact, he says a paucity of certain types of gut flora
may predispose infants to food allergies, asthma and the other immune-related
disorders that are currently skyrocketing in industrialised countries. Other
researchers have posited a link between allergies and a lack of exposure to
disease-causing bacteria, or even the harmless mycobacteria that live in the soil
(“Let them eat dirt”, New Scientist, 18 July 1998, p 26).
Wold argues that it’s the enterobacteria that normally live harmlessly inside you that really
count.
Unlike most other types of bacteria, enterobacteria pass through the outer
layer of the gut. There they stimulate immune cells called macrophages. In turn,
these secrete chemicals that suppress another class of immune cells called
dendritic cells, which latch onto proteins and present them to T-cells for
destruction. Wold suspects that without the brake provided by the stimulated
macrophages, the dendritic cells inappropriately hook up to harmless proteins
from food or pollen, setting off allergies.
Wold will monitor 200 Swedish babies over the next three years to see what
links, if any, exist between the composition of their intestinal bacteria and
allergies. If Wold’s theory is right—and he’s the first to admit that for
the moment it is only speculation—there may be ways to head off allergies
without having to endure the high infant mortality that still plagues countries
such as Pakistan. “Maybe,” says Wold, “we could give [babies] harmless bacteria
of the type that are needed.”
Baby bugs
-
Further Reading:
Host-microbial symbiosis in the mammalian intestine: exploring an internal ecosystem
by L. V. Hooper and others, BioEssays, vol 20, p 336 (1998) -
Sepiolids and vibrios: when first they meet
by M. J. McFall-Ngai and E. G. Ruby, Bioscience, vol 48, p 257 (1998) -
Probiotics, prebiotics or conbiotics?
by R. D. Berg, Trends in Microbiology, vol 6, p 89 (1998)