INTESTINAL BACTERIA LINKED TO RHEUMATOID ARTHRITIS
Researchers have
linked a species of intestinal bacteria known asPrevotella copri to the onset of rheumatoid arthritis,
the first demonstration in humans that the chronic inflammatory joint disease
may be mediated in part by specific intestinal bacteria. The new findings by
laboratory scientists and clinical researchers in rheumatology at NYU School of
Medicine add to the growing evidence that the trillions of microbes in our body
play an important role in regulating our health
Using
sophisticated DNA analysis to compare gut bacteria from fecal samples of
patients with rheumatoid arthritis and healthy individuals, the researchers
found that P. copri was more abundant in patients newly
diagnosed with rheumatoid arthritis than in healthy individuals or patients
with chronic, treated rheumatoid arthritis. Moreover, the overgrowth of P.
copri was associated
with fewer beneficial gut bacteria belonging to the genera Bacteroides.
"Studies
in rodent models have clearly shown that the intestinal microbiota contribute
significantly to the causation of systemic autoimmune diseases," says Dan
R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Pathology
and Microbiology and a Howard Hughes Medical Institute investigator.
"Our
own results in mouse studies encouraged us to take a closer look at patients
with rheumatoid arthritis, and we found this remarkable and surprising
association," says Dr. Littman, whose basic science laboratory at NYU
School of Medicine's Skirball Institute of Biomolecular Medicine collaborated
with clinical investigators led by Steven Abramson, MD, senior vice president
and vice dean for education, faculty, and academic affairs; the Frederick H.
King Professor of Internal Medicine; chair of the Department of Medicine; and
professor of medicine and pathology at NYU School of Medicine.
"At
this stage, however, we cannot conclude that there is a causal link between the
abundance of P. copri and the onset of rheumatoid
arthritis," Dr. Littman says. "We are developing new tools that will
hopefully allow us to ask if this is indeed the case."
The
new findings, reported today in the open-access journal eLife,
were inspired by previous research in Dr. Littman's laboratory, collaborating
with Harvard Medical School investigators, using mice genetically predisposed
to rheumatoid arthritis, which resist the disease if kept in sterile
environments, but show signs of joint inflammation when exposed to otherwise
benign gut bacteria known as segmented filamentous bacteria.
Rheumatoid
arthritis, an autoimmune disease that attacks joint tissue and causes painful,
often debilitating stiffness and swelling, affects 1.3 million Americans. It
strikes twice as many women as men and its cause remains unknown although
genetic and environmental factors are thought to play a role.
The
human gut is home to hundreds of species of beneficial bacteria, including P.
copri, which ferment undigested carbohydrates to fuel the body and
keep harmful bacteria in check. The immune system, primed to attack foreign
microbes, possesses the extraordinary ability to distinguish benign or
beneficial bacteria from pathogenic bacteria. This ability may be compromised,
however, when the gut's microbial ecosystem is thrown off balance.
"Expansion
of P. copri in the intestinal microbiota
exacerbates colonic inflammation in mouse models and may offer insight into the
systemic autoimmune response seen in rheumatoid arthritis," says Randy S.
Longman, MD, PhD, a post-doctoral fellow in Dr. Littman's laboratory and a
gastroenterologist at Weill-Cornell, and an author on the new study. Exactly
how this expansion relates to disease remains unclear even in animal models, he
says.
Why P.
copri growth seems to
take off in newly diagnosed patients with rheumatoid arthritis is also unclear,
the researchers say. Both environmental influences, such as diet and genetic
factors can shift bacterial populations within the gut, which may set off a
systemic autoimmune attack. Adding to the mystery, P.
copri extracted from
stool samples of newly diagnosed patients appears genetically distinct from P.
coprifound in healthy individuals, the researchers found.
To
determine if particular bacterial species correlate with rheumatoid arthritis,
the researchers sequenced the so-called 16S gene on 44 fecal DNA samples from
newly diagnosed patients with rheumatoid arthritis prior to immune-suppressive
treatment; 26 samples from patients with chronic, treated rheumatoid arthritis;
16 samples from patients with psoriatic arthritis (characterized by red, flaky
skin in conjunction with joint inflammation); and 28 samples from healthy
individuals.
Seventy-five
percent of stool samples from patients newly diagnosed with rheumatoid
arthritis carried P. copri compared to 21.4% of samples from
healthy individuals; 11.5% from chronic, treated patients; and 37.5% from
patients with psoriatic arthritis.
Rheumatoid
arthritis is treated with an assortment of medications, including antibiotics,
anti-inflammatory drugs like steroids, and immunosuppressive therapies that
tame immune reactions. Little is understood about how these medications affect
gut bacteria. This latest research offers an important clue, showing that
treated patients with chronic rheumatoid arthritis carry smaller populations of P.
copri. "It could be that certain treatments help stabilize the
balance of bacteria in the gut," says Jose U. Scher, MD, director of the
Microbiome Center for Rheumatology and Autoimmunity at NYU Langone Medical
Center's Hospital for Joint Diseases, and an author on the new study. "Or
it could be that certain gut bacteria favor inflammation."
The
researchers plan to validate their results in regions beyond New York, since
gut flora can vary across geographical regions, and investigate whether the gut
flora can be used as a biological marker to guide treatment. "We want to
know if people with certain populations of gut bacteria respond better to
certain treatment than others," says Dr. Scher. Finally, they hope to
study people before they develop rheumatoid arthritis to see whether overgrowth
of P. copri is a cause or result of autoimmune
attacks.
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