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Summary: A new study reveals chronic cocaine users have a global impairment of the ventromedial prefrontal cortex.

Source: Mount Sinai Hospital.

Cocaine-addicted individuals say they find the drug much less enjoyable after years of use, but they have great difficulty quitting. A new brain imaging study led by researchers at the Icahn School of Medicine at Mount Sinai reveals why this might be so, as well as why a common psychological therapy may not work in addicted cocaine users.

Their study, published September 5 in Addiction Biology, finds that chronic users have a “global impairment” in the ventromedial prefrontal cortex (VMPFC), an area of the brain that is linked to impulse and self-control, and is responsible for the kind of learning that assigns value to objects and behaviors.

The Mount Sinai study investigated a specific type of learning called extinction – the process by which a new, affectively neutral, association replaces an old, affectively arousing association – to identify the neurobiological mechanism that underlies the persistence of drug seeking in addiction despite negative consequences and a reduction in the drug’s rewarding affects.

To investigate these questions, the research team collected functional magnetic resonance imaging (fMRI) data on a three-phase classical conditioning paradigm in individuals with a history of chronic cocaine use and healthy control individuals without the drug habit. They found that in drug-addicted individuals, there was a VMPFC-mediated impairment in forming and maintaining new associations for stimuli that were previously, although no longer, predictive of both drug and non-drug related outcomes.

“Our study data suggests that it will be hard for longtime cocaine users to unlearn what once was a positive experience if this ‘unlearning’ or new learning relies on this brain region to be effective,” says the study’s lead investigator, Anna Konova, PhD, who worked on the study while at the Icahn School of Medicine, but who is now a postdoctoral fellow at the Center for Neural Science at New York University.

Extinction forms the basis for exposure therapy, which is often used to treat anxiety disorders like phobias.

“There is a strong impetus for extinction-based therapy in addiction, but our findings highlight potential limitations of these existing therapies in their reliance on the VMPFC to achieve therapeutic benefits,” says the study’s senior investigator, Rita Z. Goldstein, PhD, who directs Mount Sinai’s Neuropsychoimaging of Addiction and Related Conditions research group.

Dr. Goldstein is an international expert in the use of functional neuroimaging methods to examine the neurobiological basis of impaired cognitive and emotional functioning in human drug addiction and other disorders of self-control. Dr. Konova was a graduate student in Dr. Goldstein’s lab.

A well-known example of the kind of learning that Dr. Konova and the research team studied in this study is the famous “Pavlov’s dog” experiment in which dogs learned to associate a food treat with the sound of a bell. Dogs soon started salivating when the bell rang. But if the bell rang enough times without being followed by the treat the salivation response of the dogs was reduced or extinguished.

“The idea behind extinction learning as a therapeutic intervention is that a user can learn to substitute a relaxing thought–such as taking a nature stroll–for the thought of procuring cocaine when walking by their neighborhood park where they might have previously purchased or consumed the drug. By relying on these new associations, an addicted individual may be able to control their habit,” says Dr. Konova.

Fear-based extinction learning is now widely used to treat anxiety, such as in phobias and post-traumatic stress disorder (PTSD). In this technique, a person is exposed to the thing that makes them afraid until the fear response to that thing (which is no longer associated with any real harm) is reduced and eventually extinguished, perhaps by forming a new, neutral or positive, association with their originally feared object or situation.

While previous experiments have suggested VMPFC impairment in addicted individuals who have long used stimulants such as cocaine–a consistent finding is that the gray matter (a marker of neuronal morphological integrity) is altered in that brain area in these individuals–this is the first experiment to examine if these changes have implications for extinction learning in drug users and non-users using functional magnetic resonance imaging (fMRI) brain scans.

The study participants — 18 chronic cocaine users and 15 control individuals from the same community — completed three rounds of learning over two days. The cocaine-using individuals had an average lifetime history of 17 years of cocaine use and currently used cocaine about twice a week. None were seeking treatment to stop.

On the first day, while in the fMRI scanner, participants were shown, say, a colored square (a neutral cue) followed by a picture of a pleasant stimulus (such as a puppy), a different colored square this time followed by a drug-related picture (such as a crack pipe), and a third one followed by a picture of a household item. Like Pavlov’s dogs, the control individuals learned to anticipate the corresponding picture once they saw the specific square (anticipating the puppy, the drug item, or the household item). Their VMPFC also responded accordingly. They had learned the first association.

Next, the groups were shown just the cues (squares) repeatedly and depending on the picture that had been linked to them before, their brain responses again responded accordingly: VMPFC responses now were not as high to the cues that predicted the picture of the puppy (a pleasant stimulus) and not as low as to the cues that predicted the crack pipe (an unpleasant stimulus). This was the first extinction phase, when extinction learning should occur. That is, new learning was taking place that the affectively charged pictures no longer followed the cues.

Participants stayed overnight, and the next morning, they were shown the cues again. The extinction response was even more pronounced this time due to retention of some of the extinction association from the previous day.

However, VMPFC signals in the cocaine-using group did not resemble that of the control group. Their data revealed that extinction learning did not engage the VMPFC to the same degree, which could result in failures in extinction learning, Dr. Konova says.

“It may be possible to train other areas of the brain, such as the striatum, which we found did have normal responses in the drug users, to update the strong and well-established drug associations,” she says. “Or there could be ways to increase VMPFC function through cognitive retraining or pharmacologically. But our findings suggest that neither extinction learning for positive outcomes–anticipating seeing a cute puppy when this is no longer likely–or drug-related outcomes–anticipating seeing a crack pipe when this too is no longer likely–using that critical brain area will help longtime cocaine users quit.”

“This really highlights the importance of neuroscience-informed treatment development for addiction, as this study and others like it can help speak to why some current approaches might fail or discover new, more effective ways to intervene,” says Dr. Goldstein.

Among other researchers from the Icahn School of Medicine who co-authored the study were Muhammad Parvaz, PhD, graduate student Vladimir Bernstein, Anna Zilverstand, PhD, and Nelly Alia-Klein, PhD; Mauricio Delgado, PhD, from Rutgers University also contributed.

Funding: The study was supported by National Institute of Drug Abuse grants 1F32DA039648, 5F32DA033088, 1K01DA037452, 5R21DA020626, 2R21DA034954-01 and 5R01DA023579. The authors report no conflicts of interest.

Source: Elizabeth Dowling – Mount Sinai Hospital
Image Source: NeuroscienceNews.com image is credited to Patrick J. Lynch and is licensed CC BY 3.0.
Original Research: The study will appear in Addiction Biology.

Source: UC Davis.

Researchers at UC Davis and other institutions have shown that mothers who take recommended amounts of folic acid around conception might reduce their children’s pesticide-related autism risk.

In the study, children whose mothers took 800 or more micrograms of folic acid (the amount in most prenatal vitamins) had a significantly lower risk of developing autism spectrum disorder (ASD) – even when their mothers were exposed to household or agricultural pesticides associated with increased risk. The study appears today in the journal Environmental Health Perspectives.

“We found that if the mom was taking folic acid during the window around conception, the risk associated with pesticides seemed to be attenuated,” said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences and first author on the paper. “Mothers should try to avoid pesticides. But if they live near agriculture, where pesticides can blow in, this might be a way to counter those effects.”

In the paper, which used data from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, researchers looked at 296 children between 2 and 5 who had been diagnosed with ASD and 220 who had developed typically. Mothers were interviewed about their household pesticide exposure during pregnancy, as well as their folic acid and B vitamin intake. The team also linked data from California Pesticide Use reports, which provide important details about agricultural spraying, with the mothers’ addresses.

Mothers who took less than 800 micrograms and encountered household pesticides had a much higher estimated risk of having a child who developed an ASD than moms who took 800 micrograms of folic acid or more and were not exposed to pesticides. The associated risk increased for women exposed repeatedly. Women with low folic acid intake who were exposed to agricultural pesticides during a window from three months before conception to three months afterward also were at higher estimated risk.

“Folic acid intake below the median and exposure to pesticides was associated with higher risk of autism than either low intake or exposure alone,” said Schmidt, a UC Davis MIND Institute faculty member. “The mothers who had the highest risk were the ones who were exposed to pesticides regularly.”

While folic acid did reduce the associated risk of a child developing autism, it did not entirely eliminate it.

“It would be better for women to avoid chronic pesticide exposure if they can while pregnant,” Schmidt said.

The authors caution that this is a case-control study that relied heavily on participants’ memories. In addition, they have yet to establish a causal link. However, these results certainly warrant larger studies to validate them. The team is also eager to investigate the mechanisms that contribute to folic acid’s possible protective effects.

“Folate plays a critical role in DNA methylation (a process by which genes are turned off or on), as well as in DNA repair and synthesis,” said Schmidt. “These are all really important during periods of rapid growth when there are lots of cells dividing, as in a developing fetus. Adding folic acid might be helping out in a number of these genomic functions.”

Other researchers included Janie F. Shelton, Lora Delwiche, Robin L. Hansen, Sally Ozonoff, Deborah H. Bennett, Irva Hertz-Picciotto and Daniel Tancredi at UC Davis; Vladimir Kogan and Heather E. Volk at UCLA; and Claudia C. Ma Erin and C. McCanlies at the National Institute for Occupational Safety and Health.

Funding: This study was funded by the National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, part of the National Institutes of Health (R21-ES021330, R01-ES015359, P01-ES11269, 2K12HD051958, R21-ES19002, P30-ES023513 and U54-HD079125); The Environmental Protection Agency STAR program (R-42 829388 & R833292) and the UC Davis MIND Institute.

Source: Dorsey Griffith – UC Davis
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder” by Rebecca J. Schmidt, Vladimir Kogan, Janie F. Shelton, Lora Delwiche, Robin L. Hansen, Sally Ozonoff, Claudia C. Ma, Erin C. McCanlies, Deborah H. Bennett, Irva Hertz-Picciotto, Daniel J. Tancredi, and Heather E. Volk in Environmental Health Perspectives. Published online September 2017 doi:10.1289/EHP604

Abstract

Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder

BACKGROUND:
Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals.

OBJECTIVE:
We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD).

METHODS:
Participants were California children born from 2000–2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case–control study at age 2–5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003–2011. High vs. low daily FA intake was dichotomized at 800 μg (median). Mothers’ addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure.

RESULTS:
High FA intake (≥800 μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800 μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models.

CONCLUSIONS:
In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed.

“Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder” by Rebecca J. Schmidt, Vladimir Kogan, Janie F. Shelton, Lora Delwiche, Robin L. Hansen, Sally Ozonoff, Claudia C. Ma, Erin C. McCanlies, Deborah H. Bennett, Irva Hertz-Picciotto, Daniel J. Tancredi, and Heather E. Volk in Environmental Health Perspectives. Published online September 2017 doi:10.1289/EHP604

Source: UCSF.

Researchers at UC San Francisco have identified specific gut microbes associated with multiple sclerosis (MS) in human patients, and show that these microbes take part in regulating immune responses in mouse models of the disease.

The new findings — to be published during the week of September 11, 2017 in the Online Early Edition of Proceedings of the National Academy of Sciences (PNAS) — suggest that gut microbes may play a role in the neurodegeneration that characterizes MS. The authors hope the finding will help scientists understand the origins of MS and potentially lead to treatments, such as dietary changes or drugs based on microbial byproducts, that could improve the course of the disease.

MS is an autoimmune neurodegenerative disorder that affects approximately 2.5 million people worldwide with progressive loss of vision, weakness and tremors, and problems with coordination and balance. It is caused when the immune system attacks the layers of insulation that surround nerve cells. Researchers have learned a great deal about MS over the past decades, but continue to puzzle over why the immune system turns against the nervous system’s insulation, known as myelin, in the first place.

“The field has been very successful in identifying genes associated with susceptibility to MS, but I’ve never been satisfied with amount of risk that we’ll be able to explain with just genetics,” said Sergio Baranzini, PhD, a professor of neurology at UCSF and the senior author on the new study. “Even identical twins, who share the same genetic inheritance, only share an MS diagnosis about 35 percent of the time. It’s clear the genome is important, but environmental factors must also play a major role.”

Many suspected environmental contributors to MS, such as history of smoking, diet, and environmental exposures, are very hard to pin down and associate with a biological impact on patients, Baranzini said.

But a growing number of studies demonstrating that gut microbes can directly influence the function of the human immune system suggested a new possibility to Baranzini: Since “the intestine is actually the most intimate connection between the outside world and the immune system,” he explained, the human gut microbiome could play a role in the onset or progression of MS.

Mining for Microbes

When Egle Cekanaviciute, PhD, arrived in the Baranzini lab as a postdoctoral researcher in 2014, she was eager to take on the challenge of studying whether features of the gut microbiome might influence the immune system’s predisposition to trigger MS.

“This was such a novel question, especially at that time,” Cekanaviciute said. “No one had looked at the microbiome in MS — almost no one had looked at the role of gut microbes beyond digestive diseases.”

In the new study, Cekanaviciute and collaborators analyzed the gut microbiome composition of 71 MS patients as well as 71 healthy control subjects, and identified specific species of bacteria that were either more or less common in people with multiple sclerosis than the general population. Then they turned to the much more difficult task of investigating how these differences in gut bacteria might influence the immune system’s attack on myelin in MS.

“A lot of microbiome studies say, ‘These bacteria are increased in patients with a disease, and those bacteria are reduced.’ And then they stop,” Cekanaviciute said. “We wanted to know more: should we care about the ones that are increased because they are harmful or the ones that are decreased because perhaps they are helpful? What do these microbes actually do that could have an impact on people’s health?”

At the time, there were no standard techniques for answering these questions, so Cekanaviciute developed an array of new approaches for testing the functional role of the bacterial species they had identified as altered in patients with MS.

First, the team explored whether components of these bacteria could alter the behavior of human immune cells to make them either pro- or anti-inflammatory. They exposed human immune cells in laboratory dishes to blended extracts of each bacterial species, and found that two species of bacteria that were more common in people with MS — Akkermansia muciniphila and Acinetobacter calcoaceticus — triggered the cells to become pro-inflammatory, while a species of bacteria found at lower than usual levels in MS patients — Parabacteroides distasonis — triggered immune-regulatory responses.

To see how these bacteria might affect the immune system as a whole, the researchers then introduced each of these three species of bacteria into mice who otherwise lacked a microbiome (to simulate overgrowth of these strains relative to other strains of bacteria) and found that they had a similar effect: A. muciniphila and A. calcoaceticus triggered inflammatory immune responses, while P. distasonis tamped down inflammation.

But these experiments only examined the impact of one bacterial species at a time — the question remained how the complex microbial ecosystems of MS patients might impact neurodegeneration. To answer this question, the team performed fecal transplants on mice with an experimentally induced form of MS. The researchers found that replacing the microbiomes of these mice with the microbiomes of patients with MS caused the animals to lose key immune-regulatory cells and to develop more serious neurodegeneration, suggesting that the microbiome alone could contribute to the progression of MS.

A second study published in the same issue of PNAS — led by researchers at the Max Planck Institute in Germany and co-authored by Cekanaviciute and Baranzini — also found that microbiome transplants from MS patients could exacerbate symptoms in mice with a genetic model of the disease.

“Two different groups, using two separate cohorts of patients and controls, and two distinct mouse models of the disease, saw very similar results,” Cekanavicuite said. “This is very promising evidence that we’re on the right track.”

Microbe-based therapies for MS?

Together, these findings suggest that the microbiome may play a key role — alongside genetic predisposition and other environmental factors — in the origins of MS. In particular, the authors propose that particular gut microbes may trigger heightened levels of inflammation that contribute to or exacerbate the immune system’s attack on myelin in MS patients.

“To be clear, we don’t think the microbiome is the only trigger of MS,” Cekanaviciute said. “But it looks like these microbes could be making the disease progression worse or better — pushing someone with genetic predisposition across the threshold into disease or keeping them safe.”

The authors hope that future research will shine light on exactly how these bacterial populations influence the development and progression of MS. For instance, the authors note that at least one of the bacterial species found in patients with MS produces molecules that mimic proteins found in myelin, suggesting that the presence of these bacteria could confuse the immune system into attacking myelin as well as the bacteria.

The authors also note that P. distasonis, the bacterial species found at lower-than-normal levels in MS patients, is thought to help the immune system learn to control its response to non-threatening gut microbes. Lacking these bacteria may allow the immune system to overreact to harmless microbes in people with MS, leading to destructive inflammation.

Baranzini says he hopes the field will be able to use these findings to develop novel therapies for patients with MS: “The microbiome is very malleable. You could relatively easily change it in an adult who has MS or is susceptible – something you cannot do with their genetics. This is not a magical approach, but it is hopeful.”

Like many autoimmune diseases, Baranzini says, the prevalence of MS has increased significantly over the past century, which many researchers attribute to modern changes in lifestyle, including diet, sanitation, and exposure to natural environmental microbes, all of which could impact the human microbiome.

“All of these factors have certainly altered the human microbiome, perhaps in a way that has led to more autoimmune disease,” Baranzini said. “Studies like this suggest there might be a way of trying to modulate our microbiota to restore the lower-risk, less inflammatory metabolism that was characteristic of humans 100 years ago.”

Funding: The research was funded by the National Multiple Sclerosis Society, the National Institutes of Health IRACDA postdoctoral fellowship, the US Department of Defense, the Valhalla Charitable foundation, the Emerald Foundation, and the Heritage Medical Research Institute.

Additional authors on the paper were Sneha Singh, Charlotte Nelson, Rachel Kanner, Stephen Hauser, MD, Elizabeth Crabtree-Hartman MD, and Bruce Cree, MD, all of UCSF; Bryan Yoo, Yun Kyung Lee, PhD, and Sarkis Mazmanian PhD, of the California Institute of Technology; Tessel Runia, MD, of Erasmus University Rotterdam; Justine Debelius, PhD, and Rob Knight, PhD, of UC San Diego; and Yadira Bencosme, Ilana Katz Sand, MD, Patrizia Casaccia, MD, PhD, Mar Gacias, PhD, and Yungjiao Zhu, PhD, of Mount Sinai Medical Center in New York.

Source: Nicholas Weiler – UCSF
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice” by Kerstin Berer, Lisa Ann Gerdes, Egle Cekanaviciute, Xiaoming Jia, Liang Xiao, Zhongkui Xia, Chuan Liu, Luisa Klotz, Uta Stauffer, Sergio E. Baranzini, Tania Kümpfel, Reinhard Hohlfeld, Gurumoorthy Krishnamoorthy, and Hartmut Wekerle in PNAS. Published online September 11 2017 doi:10.1073/pnas.1711233114

Full open access research for “Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models” by Egle Cekanaviciute, Bryan B. Yoo, Tessel F. Runia, Justine W. Debelius, Sneha Singh, Charlotte A. Nelson, Rachel Kanner, Yadira Bencosme, Yun Kyung Lee, Stephen L. Hauser, Elizabeth Crabtree-Hartman, Ilana Katz Sand, Mar Gacias, Yungjiao Zhu, Patrizia Casaccia, Bruce A. C. Cree, Rob Knight, Sarkis K. Mazmanian, and Sergio E. Baranzini in PNAS. Published online September 11 2017 doi:10.1073/pnas.1711235114

Abstract

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

“Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice” by Kerstin Berer, Lisa Ann Gerdes, Egle Cekanaviciute, Xiaoming Jia, Liang Xiao, Zhongkui Xia, Chuan Liu, Luisa Klotz, Uta Stauffer, Sergio E. Baranzini, Tania Kümpfel, Reinhard Hohlfeld, Gurumoorthy Krishnamoorthy, and Hartmut Wekerle in PNAS. Published online September 11 2017 doi:10.1073/pnas.1711233114

Abstract

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

“Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models” by Egle Cekanaviciute, Bryan B. Yoo, Tessel F. Runia, Justine W. Debelius, Sneha Singh, Charlotte A. Nelson, Rachel Kanner, Yadira Bencosme, Yun Kyung Lee, Stephen L. Hauser, Elizabeth Crabtree-Hartman, Ilana Katz Sand, Mar Gacias, Yungjiao Zhu, Patrizia Casaccia, Bruce A. C. Cree, Rob Knight, Sarkis K. Mazmanian, and Sergio E. Baranzini in PNAS. Published online September 11 2017 doi:10.1073/pnas.1711235114