Study links intestinal bacteria to rheumatoid arthritis

Contact: Craig Andrews craig.andrews@nyumc.org 212-404-3511 NYU Langone Medical Center / New York University School of Medicine

Findings suggest bacterial disturbances in the gut may play a role in autoimmune attacks on the joints, point the way to novel treatments and diagnostics

Researchers have linked a species of intestinal bacteria known as Prevotella 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. copri found 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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In addition to researchers from the NYU School of Medicine, investigators from Memorial Sloan Kettering Cancer Center and from the Harvard School of Public Health contributed to the study.  Funding for this research comes from the National Institutes of Health, the Howard Hughes Medical Institute, and the American Gastroenterological Association.

About NYU Langone Medical Center:

NYU Langone Medical Center, a world-class, patient-centered, integrated academic medical center, is one of the nation’s premier centers for excellence in clinical care, biomedical research, and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals—Tisch Hospital, its flagship acute care facility; Rusk Rehabilitation; the Hospital for Joint Diseases, the Medical Center’s dedicated inpatient orthopaedic hospital; and Hassenfeld Pediatric Center, a comprehensive pediatric hospital supporting a full array of children’s health services across the Medical Center—plus the NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The Medical Center’s tri-fold mission to serve, teach, and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education, and research. For more information, go to http://www.NYULMC.org, and interact with us on Facebook, Twitter, and YouTube.

BPA linked to potential adverse effects on heart and kidneys

Contact: Lorinda Klein lorindaann.klein@nyumc.org 212-404-3533 NYU Langone Medical Center / New York University School of Medicine

NEW YORK (January 9, 2013) – Exposure to a chemical once used widely in plastic bottles and still found in aluminum cans appears to be associated with a biomarker for higher risk of heart and kidney disease in children and adolescents, according to an analysis of national survey data by NYU School of Medicine researchers published in the January 9, 2013, online issue of Kidney International, a Nature publication.

Laboratory studies suggest that even low levels of bisphenol A (BPA) like the ones identified in this national survey of children and adolescents increase oxidative stress and inflammation that promotes protein leakage into the urine, which is a biomarker for early renal impairment and future risk of developing coronary heart disease, according to Leonardo Trasande, MD, MPP, associate professor of pediatrics, environmental medicine, and population health, and co-lead author of the study.

The study adds to the growing concerns about BPA, which was recently banned by the U.S. Food and Drug Administration but is still used as an internal coating for aluminum cans. Manufacturers say the chemical provides an antiseptic function, but studies have shown the chemical disrupts multiple mechanisms of human metabolism.

“While our cross-sectional study cannot definitively confirm that BPA contributes to heart disease or kidney dysfunction in children, together with our previous study of BPA and obesity, this new data adds to already existing concerns about BPA as a contributor to cardiovascular risk in children and adolescents,” says Dr. Trasande. “It further supports the call to limit exposure of BPA in this country, especially in children,” he says. “Removing it from aluminum cans is probably one of the best ways we can limit exposure. There are alternatives that manufacturers can use to line aluminum cans.”

Children in the United States are exposed to the chemical early in life and surveys have shown that by age six nearly 92 percent of children have some trace of BPA in their urine. Its use has been banned in the European Union and Canada, and in the United States for use in baby bottles and sippy cups. Last September Dr. Trasande’s group published a study showing a significant association between obesity and children and adolescents with higher concentrations of BPA in their urine in the Journal of the American Medical Association.

In the new study Dr. Trasande, Teresa Attina, MD, PhD, MPH, and Howard Trachtman, MD, of NYU School of Medicine’s Department of Pediatrics, analyzed data on 710 children and adolescents aged 6 to 19 collected in a national survey to assess the health and nutritional status of adults and children in the United States. The data was from the 2009-2010 National Health and Nutrition Examination Survey (NHANES), which contained measurements on urinary BPA, and a protein called albumin, which is not normally found in urine because the spaces in the glomerular membrane of the kidney are too small to allow protein molecules to escape. If there is membrane damage as in some kidney diseases like glomerulonephritis, albumin can leak through into the urine.

The researchers controlled for risk factors such as hypertension, insulin resistance, elevated cholesterol, exposure to tobacco smoke, race/ethnicity, caregiver education, poverty to income ratio, age, weight and gender in these children.  Children with the highest amount of BPA in their urine, compared to those with the lowest amount, had a higher albumin to creatinine ratio, a potential early marker of renal impairment and future risk of developing coronary heart disease, according to the study.

“While we excluded children with pre-existing kidney disease from our analysis, I am concerned that BPA exposure may have even greater effects on children with kidney disease,” says Dr. Trachtman, co-lead author of the study. “Because their kidneys are already working harder to compensate and have limited functional reserve, they may be more susceptible to the adverse effects of environmental toxins. We clearly need further study of BPA exposure and its effects on the kidney both in healthy children and in children who have pre-existing kidney disease.”

The researchers concluded their analysis by emphasizing the need for further research on environmental chemicals and cardiovascular disease, noting that further study may well transform our understanding “from one that focuses on dietary risks to an approach that recognizes the role of environmental chemical factors that may independently impart the risk of … future cardiovascular disease.”

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Authors: Leonardo Trasande, MD, MPP, associate professor, Departments of Pediatrics, Environmental Medicine and Population Health, NYU School of Medicine, associate professor of health policy, NYU Wagner School of Public Service and associate professor of public health, NYU Steinhardt School of Culture, Education and Human Development; Teresa Attina, MD, PhD, Departments of Pediatrics, and Medicine; and Howard Trachtman, MD, professor of clinical pediatrics, Department of Pediatrics.

Funding: Funding was provided by KiDS of NYU.

Disclosure:  All authors have declared no competing interests.

About NYU School of Medicine:

NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence. For 172 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care.  The School also maintains academic affiliations with area hospitals, including Bellevue Hospital Center, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population.

Obesity and metabolic syndrome associated with impaired brain function in adolescents

Contact: Jessica Guenzel Jessica.Guenzel@nyumc.org 212-404-3591 NYU Langone Medical Center / New York University School of Medicine

NEW YORK, September 3, 2012 – A new study by researchers at NYU School of Medicine reveals for the first time that metabolic syndrome (MetS) is associated with cognitive and brain impairments in adolescents and calls for pediatricians to take this into account when considering the early treatment of childhood obesity.

The study, funded by the National Institutes of Health under award number DK083537, and in part by award number 1ULIRR029892, from the National Center for Research Resources, appears online September 3 in Pediatrics.

As childhood obesity has increased in the U.S., so has the prevalence of metabolic syndrome – a constellation of three or more of five defined health problems, including abdominal obesity, low HDL (good cholesterol), high triglycerides, high blood pressure and pre-diabetic insulin resistance. Lead investigator Antonio Convit, MD, professor of psychiatry and medicine at NYU School of Medicine and a member of the Nathan Kline Research Institute, and colleagues have shown previously that metabolic syndrome has been linked to neurocognitive impairments in adults, but this association was generally thought to be a long-term effect of poor metabolism. Now, the research team has revealed even worse brain impairments in adolescents with metabolic syndrome, a group absent of clinically-manifest vascular disease and likely shorter duration of poor metabolism.

“The prevalence of MetS parallels the rise in childhood obesity,” Dr. Convit said. “There are huge numbers of people out there who have problems with their weight. If those problems persist long enough, they will lead to the development of MetS and diabetes. As yet, there has been very little information available about what happens to the brain in the setting of obesity and MetS and before diabetes onset in children.”

For the study, the researchers compared 49 adolescents with metabolic syndrome to 62 teens without the disorder. Of those who were not in the MetS group, 40 percent were considered overweight or obese, so while they were not in ideal health, they did not have three out of the five health issues needed to fall into the MetS group. The findings reported, therefore, are conservative and reflective of the real world.

Dr. Convit and colleagues balanced each group according to age, socioeconomic status, school grade, gender and ethnicity to ensure things like cultural differences in diet and access to quality healthcare did not cloud the data. They then conducted endocrine, MRI and neuropsychological evaluations on the adolescents and found that those classified as having MetS showed significantly lower math and spelling scores, as well as decreased attention span and mental flexibility. They also showed differences in brain structure and volume, presenting with smaller hippocampal volumes – involved in the learning and recall of new information, increased brain cerebrospinal fluid and reductions of microstructural integrity in major white matter tracts in the brain. The more MetS-characterizing health problems the participants had, the more profound the effect across the board.

“The kids with MetS took longer to do tasks, could not read as well and had poorer math scores,” Dr. Convit said. “These findings indicate that kids with MetS do not perform well on things that are very relevant to school performance.”

The researchers concluded that even a few years of problems with metabolism may cause brain complications. They suggest the adverse impact of MetS on brain function in children could be used by pediatricians as a powerful motivator to get families more involved in meaningful lifestyle change.

“Only now are pediatricians becoming aware of some of these issues,” Dr. Convit explained. “Many pediatricians don’t even take a blood pressure, and they certainly are not taking cholesterol levels and testing insulin resistance.” He added that about one third of children who are obese have abnormal cholesterol levels and more than 40 percent of those who are really obese have insulin resistance. “Obesity in kids is sky-high. Nearly 40 percent of the U.S. population is considered obese. Parents need to understand that obesity has medical consequences, even in children, and some of those consequences may be impacting more than just the long term health of the cardiovascular system. We need to do what our grandmothers have told us all along: ‘Eat well, don’t overeat and try to move as much as possible.'”

Dr. Convit added that simple changes in daily routine would go a long way in preventing MetS – changes like walking more and taking the stairs. Future research is needed to determine whether the reductions in cognitive performance and structural brain abnormalities are reversible with significant weight loss, he explained.

“The take home message is that just being overweight and obese is already impacting your brain,” Dr. Convit said. “Kids who are struggling with their weight and moving toward having MetS may have lower grades, which could ultimately lead to lower professional achievement in the long run. These are run-of-the-mill, garden-variety kids, not kids that came into the hospital because they were sick. It is imperative that we take obesity and physical activity seriously in children. In this country, we’re taking away gym class in order to give children more class time in an effort to improve school performance, but that effort may be having the exact opposite effect.”

Dr. Convit’s focus on combating and raising awareness about the impact of childhood obesity led him to create the The BODY Project, a program that works with New York City schools and parents to evaluate students’ height, weight, blood pressure, test for insulin resistance and record other measures of health, giving parents an overview of their child’s health status. Simply receiving this report motivates visits to the pediatrician, meal-planning changes at home and other interventions to prevent MetS and obesity. The program has impacted more than 3,400 children since its creation four years ago.

“If we can help one kid not become diabetic, that’s one kid’s life we’ve saved,” Dr. Convit said.

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About NYU School of Medicine:

NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care.  The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/.

Antibiotic use in infants before 6 months associated with being overweight in childhood

Contact: lorinda klein lorindaann.klein@nyumc.org 212-404-3533 NYU Langone Medical Center / New York University School of Medicine

New York City (August 21, 2012)  – Treating very young  infants with antibiotics may predispose them to being overweight in childhood, according to a study of more than 10,000 children by researchers at the NYU School of Medicine  and the NYU Wagner School of Public Service and published in the online August  21, 2012, issue of the International Journal of Obesity.

The study found that on average, children exposed to antibiotics from birth to 5 months of age weighed more for their height than children who weren’t exposed.  Between the ages of 10 to 20 months, this translated into small increases in body mass percentile, based on models that incorporated the potential impacts of diet, physical activity, and parental obesity. By 38 months of age, exposed children had a 22% greater likelihood of being overweight. However, the timing of exposure mattered: children exposed from 6 months to 14 months did not have significantly higher body mass than children who did not receive antibiotics in that same time period.

The NYU School of Medicine researchers, led by Leonardo Trasande, MD, MPP, associate professor of pediatrics and environmental medicine, and Jan Blustein, MD, PhD, professor of population health and medicine, caution that the study does not prove that antibiotics in early life causes young children to be overweight.  It only shows that a correlation exists. Further studies will need to be conducted to explore the issue of a direct causal link.

“We typically consider obesity an epidemic grounded in unhealthy  diet and exercise, yet increasingly studies suggest it’s more complicated,” said Dr. Trasande. “Microbes in our intestines may play critical roles in how we absorb calories, and exposure to antibiotics, especially early in life, may kill off healthy bacteria that influence how we absorb nutrients into our bodies, and would otherwise keep us lean.”

In recent years there has been a growing concern about the overuse of antibiotics, especially in children. Preliminary studies of the microbiome, the trillions of microbial cells inhabiting our bodies and outnumber our own cells 10 to 1, implicate obesity, inflammatory bowel disease, asthma, and other conditions with changes in the microbiome. It is still a field in its infancy, however, and no one has yet proved that altering the composition of bacteria in the body leads to disease.

This is the first time that a study has analyzed the association between the use of antibiotics and body mass starting in infancy.  One previous study had identified a link between antibiotic use in early infancy and obesity at seven years of age, but was unable to examine potential impacts of antibiotic use later in infancy on body weight in childhood.

The NYU School of Medicine researchers evaluated the use of antibiotics among 11,532 children born in Avon, United Kingdom, during 1991 and 1992. The children are part of the Avon Longitudinal Study of Parents and Children (ALSPAC), a long-term study that provides detailed data on the health and development of these children.

The NYU School of Medicine researchers analyzed health information on these children during three periods: from birth to 5 months of age; 6 months to 14 months; and, finally from 15 to 23 months. They also examined body mass or weight at five different points of time—6 weeks, 10 months, 20 months, 38 months, and 7 years of age.

Antibiotic use only appeared to have an effect in very young infants (those given antibiotics from birth to 5 months of age.) Although children exposed to antibiotics at 15 to 23 months had somewhat greater BMI (Body Mass Indices) for their age and gender by the age of 7, there was no significant increase in their being overweight or obese.

“For many years now, farmers have known that antibiotics are great at producing heavier cows for market,” said Dr. Blustein. “While we need more research to confirm our findings, this carefully conducted study suggests that antibiotics influence weight gain in humans, and especially children too.”

In addition to Dr. Trasande, who is also associate professor of health policy, NYU Wagner School of  Public Service, and Dr. Blustein, who is also a professor of health policy at the NYU Wagner School of  Public Service, the authors of the study are: Mengling Liu, PhD, associate professor  of environmental medicine, NYU School of Medicine; Elise Corwin, BA, NYU Wagner School of  Public Service; Laura M. Cox, BA, Department of Microbiology, NYU School of Medicine;  Martin J. Blaser, MD, the Frederick H. King Professor of Internal Medicine and chair Department of Medicine, and professor of microbiology, NYU School of Medicine.

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Support for this preliminary work with the ALPSAC database was provided through a pilot grant from the NYU Global Public Health Research Challenge Fund, and by NIH grants 1GM090989 and 1UL1RR029893.

Disclosures:

All authors have no financial relationships or conflicts of interests to declare.

About NYU School of Medicine:

NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence.  For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care.  The School also maintains academic affiliations with area hospitals, including Bellevue Hospital Center, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training.  Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/