Scientists are pursuing some intriguing possibilities. One is that
breast-feeding
may protect against the disease. Another is that we have neglected the
teeming ecosystem of microbes in the gut — bacteria that may determine
whether the immune system treats gluten as food or as a deadly invader.
Celiac disease is generally considered an autoimmune disorder. The name
celiac derives from the Greek word for “hollow,” as in bowels. Gluten
proteins in wheat, barley and rye prompt the body to turn on itself and
attack the small intestine. Complications range from
diarrhea and
anemia to
osteoporosis
and, in extreme cases, lymphoma. Some important exceptions
notwithstanding, the prevalence of celiac disease is estimated to range
between 0.6 and 1 percent of the world’s population.
Nearly everyone with celiac disease has one of two versions of a
cellular receptor called the human leukocyte antigen, or H.L.A. These
receptors, the thinking goes, naturally increase carriers’
immune response to gluten.
This detailed understanding makes celiac disease unique among
autoimmune disorders.
Two factors — one a protein, another genetic — are clearly defined; and
in most cases, eliminating gluten from the patient’s diet turns off the
disease.
Yet the more scientists study celiac disease, the more some crucial
component appears in need of identification. Roughly 30 percent of
people with European ancestry carry predisposing genes, for example. Yet
more than 95 percent of the carriers tolerate gluten just fine. So
while these genes (plus gluten) are necessary to produce the disease,
they’re evidently insufficient to cause it.
Animal studies have reinforced that impression. In mice engineered to
express those H.L.A.’s, tolerance to gluten must be deliberately
“broken.” Without an immunological trigger of some kind, the rodents
happily tolerate the protein.
A recent
study,
which analyzed blood serum from more than 3,500 Americans who were
followed since 1974, suggested that such a trigger could strike adults
at any time. By 1989, the prevalence of celiac disease in this cohort
had doubled.
“You’re talking about an autoimmune disease in which we thought we had
all the dots connected,” says Alessio Fasano, head of the
Center for Celiac Research and Treatment
at the Massachusetts General Hospital for Children in Boston, and the
senior author of the study. “Then we start to accumulate evidence that
there was something else.”
Identifying that “something else” has gained some urgency. In the United
States, improved diagnosis doesn’t seem to explain the rising
prevalence. Scientists use the presence of certain self-directed
antibodies to predict celiac disease.
They have analyzed
serum stored since the mid-20th century and compared it to serum from
Americans today. Today’s serum is more than four times as likely to
carry those antibodies.
BLAME for the increase of celiac disease sometimes falls on gluten-rich,
modern wheat varietals; increased consumption of wheat, and the
ubiquity of gluten in processed foods.
Yet the epidemiology of celiac disease doesn’t always support this idea. One
comparative study
involving some 5,500 subjects yielded a prevalence of roughly one in
100 among Finnish children, but using the same diagnostic methods, just
one in 500 among their Russian counterparts.
Differing wheat consumption patterns can’t explain this disparity. If
anything, Russians consume more wheat than Finns, and of similar
varieties.
Neither can
genetics.
Although now bisected by the Finno-Russian border, Karelia, as the
study region is known, was historically a single province. The two study
populations are culturally, linguistically and genetically related. The
predisposing gene variants are similarly prevalent in both groups.
What’s the Russians’ secret?
“It’s a remote territory of Russia,” says Heikki Hyoty, a scientist at
the University of Tampere in Finland. “They live like Finns 50 years
ago.”
At the time of this research, roughly a decade ago, Russia’s per-capita income was one-fifteenth of Finland’s.
Analysis of house dust and
potable water
suggests that the Russian Karelians encountered a greater variety and
quantity of microbes, including many that were absent in Finland.
Not surprisingly, they also suffered from more fecal-oral infections.
For example, three of four Russian Karelian children harbored
Helicobacter pylori, a corkscrew-shaped bacterium, while just one in 20 Finnish children did. The bacterium can cause
ulcers and
stomach cancer, but
mounting evidence suggests that it may also protect against
asthma.
Professor Hyoty suspects that Russian Karelians’ microbial wealth
protects them from autoimmune and allergic diseases by, essentially,
strengthening the arm of the immune system that guards against such
illnesses.
Meanwhile, Yolanda Sanz, a researcher at the Institute of Agrochemistry
and Food Technology in Valencia, Spain, makes a compelling case for the
importance of intestinal microbes.
Years ago, Dr.
Sanz noted
that a group of bacteria native to the intestine known as
bifidobacteria were relatively depleted in children with celiac disease
compared with healthy controls. Other microbes, including native E. coli
strains, were
overly abundant and oddly virulent.
How to determine cause or consequence?
In a test tube, she found that those E. coli amplified the inflammatory
response of human intestinal cells to gluten. But bifidobacteria
switched the response from inflammation to tolerance.
In rats, the E. coli again intensified inflammation to gluten, prompting
what’s sometimes called a “leaky gut” — the milieu suspected of
contributing to celiac disease. Conversely, bifidobacteria protected the
intestinal barrier. Microbes, it seemed, could influence the immune
response to gluten.
All of which may explain a curious historical phenomenon — an “epidemic”
of celiac disease that struck Sweden some 30 years ago. Anneli
Ivarsson, a pediatrician at Umea University, recalled a sudden wave of
“terribly sick” infants.
Sleuthing
revealed that, just before the spike, official guidelines on infant
feeding had changed. In an effort to prevent celiac disease,
paradoxically, parents were instructed to delay the introduction of
gluten until their babies were six months old. That also happened to be
when many Swedish mothers weaned their children. Coincidentally,
companies had increased the amount of gluten in baby food.
This confluence produced an unwitting “experiment with a whole
population,” says Dr. Ivarsson — a large quantity of gluten introduced
suddenly after weaning. Among Swedes born between 1984 and 1996, the
prevalence of celiac disease tripled to
3 percent.
The epidemic ebbed only when authorities again revised infant-feeding
guidelines: keep breast-feeding, they urged, while simultaneously
introducing small amounts of gluten. Food manufacturers also reduced the
gluten content of infant foodstuffs. Dr. Ivarsson found that, during
the epidemic, the longer children breast-fed after their first exposure
to gluten, the more protected they were.
Not all subsequent studies have found nursing protective, but partly as a
result of Sweden’s experience, the American Academy of Pediatrics now
recommends that infants start consuming gluten while still
breast-feeding.
Research by Dr. Sanz of Spain again illuminates how this may work. Some years back, she
began following
a cohort of 164 newborns with celiac disease in the immediate family.
By four months, children with celiac-associated genotypes — 117 of them —
had accrued a microbial community with fewer bifidobacteria compared to
those without. If bifidobacteria help us tolerate gluten, these
children appeared to be edging toward intolerance.
There was one notable exception: Breast-feeding “normalized” the
microbes of at-risk children somewhat, boosting bifidobacterial counts.
Dr. Fasano of Boston has made another potentially important find.
He followed
47 at-risk newborns, regularly collecting microbes from 16 of them,
which he analyzed after two years. Like Dr. Sanz, he found these
genetically at-risk children to accumulate a relatively impoverished,
unstable microbial community.
But it’s a secondary observation that has Dr. Fasano particularly
excited. Two of these children developed autoimmune disease: one celiac
disease, another
Type 1 diabetes,
which shares genetic susceptibility with celiac disease. In both cases,
a decline of lactobacilli preceded disease onset.
Assuming that the pattern holds in larger studies, “imagine what would
be the unbelievable consequences of this finding,” he says. “Keep the
lactobacilli high enough in the guts of these kids, and you prevent
autoimmunity.”
The caveats here are numerous: the tiny sample size in Dr. Fasano’s
study; Dr. Sanz hasn’t yet revealed who actually developed celiac
disease in her cohort; and even if these microbial shifts reliably
precede disease onset — as they do in
larger studies
on allergic disease — they’re still bedeviled by the old “chicken or
the egg” question: Which comes first, the aberrant microbial community,
or the aberrant immune response?
Bana Jabri, director of research at the University of Chicago Celiac
Disease Center, notes that immune disturbances change the microbial
ecosystem. But here’s the catch: Even if the chicken comes first, she
says, the egg can contribute. Rodent experiments show that intestinal
inflammation can select for unfriendly bacteria that further inflame.
“You can have a positive feedback loop,” she says.
SO your microbes change you, but your genes also shape your microbes — as do environment, breast milk, diet and
antibiotics, among many other factors.
Such complexity both confounds notions of one-way causality and suggests
different paths to the same disease. “You have the same endpoint,” Dr.
Jabri says, “but how you get there may be variable.”
The intricacies don’t stop there.
Not all breast milk is the same. It varies according to diet and other factors.
One study found that milk from overweight mothers had fewer of those bifidobacteria than milk from thinner mothers.
Another observed
that breast milk from farming mothers, who inhabit a microbially
enriched environment, carried more anti-inflammatory proteins compared
with urban mothers’ milk. “All these things are going to matter,” Dr.
Jabri says. And they’re all potential nudge points in the quest to
prevent disease.
The tangled web of possibilities should not, however, distract us from
the facts on the ground. In a far-flung corner of Europe, people develop
celiac disease and other autoimmune diseases as infrequently as
Americans and Finns did a half-century ago. The same genes exposed to
the same quantity of gluten do not, in that environment, produce the
same frequency of disease.
“We could probably prevent celiac disease if we just give the same
environment to the Finnish children as they have in Karelia,” says Dr.
Hyoty. “But there’s no way to do it now, except to move the babies
there.”
Moises Velasquez-Manoff is the
author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases.”
Source: http://www.nytimes.com/2013/02/24/opinion/sunday/what-really-causes-celiac-disease.html?pagewanted=all&_r=1&
