Posted on Pain Management

Pain-sensing gut neurons protect against inflammation

The image shows neurons (red) in the smooth muscle layers (green) of the mouse colon


The image shows neurons (red) in the smooth muscle layers (green) of the mouse colon CREDIT Peng Zeng.

Neurons that sense pain protect the gut from inflammation and associated tissue damage by regulating the microbial community living in the intestines, according to a study from researchers at Weill Cornell Medicine.

The researchers, whose report appears Oct. 14 in Cell, found in a preclinical model that pain-sensing neurons in the gut secrete a molecule called substance P, which appears to protect against gut inflammation and related tissue damage by boosting the population of beneficial microbes in the gut. The researchers also found that these pain-sensing nerves are diminished in number, with significant disruptions to their pain-signaling genes, in people who have inflammatory bowel disease (IBD).

“These findings reshape our thinking about chronic inflammatory disease, and open up a whole new approach to therapeutic intervention,” said study senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine.

The study’s first author, Dr. Wen Zhang, a postdoctoral researcher in the Artis laboratory, added, “Defining a previously unknown sensory function for these specific neurons in influencing the microbiota adds a new level of understanding to host-microbiota interactions”.

IBD covers two distinct disorders, Crohn’s disease and ulcerative colitis, and is believed to affect several million people in the United States. Typically it is treated with drugs that directly target elements of the immune system. Scientists now appreciate that gut-dwelling bacteria and other microbes also help regulate gut inflammation.

As Dr. Artis’s laboratory and others have shown in recent years, the nervous system, which is “wired” into most organs, appears to be yet another powerful regulator of the immune system at the body’s barrier surfaces. In the new study, Dr. Artis and his team specifically examined pain neurons that innervate—extend their nerve endings into—the gut.

These gut-innervating pain neurons, whose cell bodies sit in the lower spine, express a surface protein called TRPV1, which serves as a receptor for pain-related signals. TRPV1 can be activated by high heat, acid, and the chili-pepper compound capsaicin, for example—and the brain translates this activation into a sense of burning pain. The researchers found that silencing these TRPV1 receptors in gut nerves, or deleting TRPV1-expressing neurons, led to much worse inflammation and tissue damage in IBD mouse models, whereas activating the receptors had a protective effect.

The investigators observed that the worsened inflammation and tissue damage in TRPV1-blocked mice were associated with changes in the relative populations of different species of gut bacteria. When this altered bacterial population was transplanted into normal mice, it caused the same worsened susceptibility to inflammation and damage. By contrast, broad-spectrum antibiotic treatment could reverse this susceptibility even in TRPV1-blocked mice. This result demonstrated that TRPV1-expressing nerves protect the gut mainly by helping to maintain a healthy gut microbe population.

The scientists found strong evidence that a large part of this microbe-influencing effect of TRPV1-expressing nerves comes from a molecule the nerves secrete called substance P—which they observed could reverse, on its own, most of the harmful effects of blocking TRPV1. Experiments also suggested that the signaling between neurons and microbes was two-way—some bacterial species could activate TRPV1-expressing nerves to get them to produce more substance P.

To confirm the relevance to humans, the researchers examined gut tissue from IBD patients, and found abnormal TRPV1 and substance P gene activity as well as fewer signs of TRPV1 nerves overall.

“These patients had disrupted pain-sensing nerves, which may have contributed to their chronic inflammation,” Dr. Zhang said.

Precisely how substance P exerts its effects on the gut microbe population, and how these microbes “talk back,” are questions that the researchers are now trying to answer in ongoing studies. But the results so far suggest that the next generation of anti-inflammatory drugs for IBD and other disorders could be compounds that target the nervous system.

“A lot of current anti-inflammatory drugs work in only some patients, and pharma companies really haven’t known why,” Dr. Artis said. “Maybe it’s because, when it comes to chronic inflammation, we’ve been seeing only some of the picture—and now the rest, including the role of the nervous system, is starting to come into focus.”

Posted on Multiple Sclerosis

Brain discovery holds the key to boosting the body’s ability to fight Multiple Sclerosis

Brain discovery holds key to boosting body’s ability to fight Alzheimer’s, MS


UVA neuroscientist John Lukens, PhD, said the new discovery “provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease.” CREDIT Dan Addison | University of Virginia Communications

UVA Health researchers have discovered a molecule in the brain responsible for orchestrating the immune system’s responses to Alzheimer’s disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body’s ability to fight those and other devastating neurological diseases.

The molecule the researchers identified, called a kinase, is crucial to both removing plaque buildup associated with Alzheimer’s and preventing the debris buildup that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have, in recent years, proved vital players in brain health.

UVA’s important new findings could one day let doctors augment the activity of microglia to treat or protect patients from Alzheimer’s, MS and other neurodegenerative diseases, the researchers report.

“Unfortunately, medical doctors do not currently possess effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer’s, Parkinson’s or ALS [amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease]. In our studies, we have discovered a master controller of the cell type and processes that are required to protect the brain from these disorders,” said senior researcher John Lukens, PhD, of the University of Virginia School of Medicine and its Center for Brain Immunology and Glia (BIG), as well as the Carter Immunology Center and the UVA Brain Institute. “Our work further shows that targeting this novel pathway provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease.”

Brain discovery holds key to boosting body’s ability to fight Alzheimer’s, MS

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“Our work has described a critical element of microglial function during Alzheimer’s disease and MS,” said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. “Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions.”

Toxic Brain Buildup

Many neurodegenerative diseases, including Alzheimer’s and MS, are thought to be caused by the brain’s inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in removing harmful debris from the brain, but UVA’s new discovery offers practical insights into how this cleaning process occurs – and the dire consequences when it doesn’t.

Using a mouse model of Alzheimer’s disease, the UVA researchers found that a lack of the molecule they identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused the mice to suffer memory loss – like the symptoms seen in humans with Alzheimer’s. Further, the neuroscientists were able to reduce the plaque buildup by activating this molecule and microglia in the brain, suggesting a potential treatment approach for human patients, though that would require significantly more research and testing.

“Our work has described a critical element of microglial function during Alzheimer’s disease and MS,” said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. “Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions.”

A lack of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, the cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. The UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is “critically involved” in the crucial removal of myelin debris.
“If boosting SYK activity in microglia can decrease the amount of myelin debris in MS lesions, developing new drugs to target SYK could stop the progression of MS and help to reverse the damage,” said Elizabeth L. Frost, PhD, a critical researcher on the project. “This is an especially promising option given that most of the currently available drugs for MS treatment dampen adaptive immunity. These immunosuppressive drugs lead to susceptibility to infection and higher risk of potentially fatal side effects like progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for those patients.”

“Targeting SYK in microglia,” she noted, “would circumvent multiple limitations of present-day therapeutics for MS.”

Based on their promising results, the researchers report that targeting the molecule to stimulate the brain’s immune activity could offer a way to treat not just Alzheimer’s and MS but a “spectrum” of neurodegenerative diseases.

“These findings are especially exciting because they point to a treatment avenue in which we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way,” said researcher Coco Holliday, a UVA undergraduate working in the Lukens lab. “It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It’s been a very exciting project to be a part of.” 

Posted on Diabetes

Findings support repurposing the rheumatoid arthritis drug auranofin for diabetes

Auranofin-from-xtal-3D-balls.png

Researchers at Baylor College of Medicine and collaborating institutions discovered that the rheumatoid arthritis drug auranofin can potentially be repurposed to improve diabetes-associated symptoms. The study, which was conducted in mice, appeared today in the journal Cell Metabolism.

Although scientists have identified definitive associations between inflammation in white adipose tissue and insulin resistance in humans and rodents, broad anti-inflammatory treatments lack durable clinical efficacy on diabetes. In the current study, the researchers explored in more detail this association between inflammation and diabetes by looking for existing drugs that might affect both conditions.

“We computationally screened a small-molecule dataset and identified auranofin, an FDA-approved drug that has been used to treat rheumatoid arthritis, a condition involving inflammation,” said first and co-corresponding author Dr. Aaron R. Cox, instructor of medicine–endocrinology, diabetes and metabolism at Baylor. “Auranofin exerts anti-inflammatory properties, which many people suspected would be beneficial in obesity and diabetes; however, nothing was really known about how it might affect metabolism.”

The team evaluated the metabolic effects of auranofin in a mouse model of diabetes in which the animals consume a high-fat diet.

“We discovered that auranofin has anti-inflammatory and anti-diabetic effects that are independent from each other,” said co-corresponding author Dr. Sean Hartig, associate professor of medicine-endocrinology, diabetes and metabolism and molecular and cellular biology at Baylor. Hartig also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Auranofin improved insulin sensitivity, or the body’s ability to respond to insulin to keep blood sugar at healthy levels. The drug also normalized obesity-associated changes such as hyperinsulinemia – blood insulin levels that are higher than normal – in the mouse model. In addition, we found that auranofin accumulation in white adipose tissue reduced inflammatory responses without altering body composition in obese mice.”

Looking into the mechanism of these metabolic changes, the team discovered that the anti-diabetic effects of auranofin involved reduction of leptin levels. Leptin is a hormone whose levels markedly increase in obesity, contributing to insulin resistance and diabetes. In addition, auranofin restored white adipose tissue’s ability to respond to catecholamines, which are signals that increase metabolic activities in adipose tissue, triggering the burning of lipids at a higher rate.

“These changes coupled together contribute to the overall improvement in insulin sensitivity of the mice, leading to blood glucose control, which is the ultimate goal of diabetes treatments,” Cox said. “High levels of glucose in the blood are detrimental to many tissues in the body. Uncontrolled, diabetes can lead to organ failure.”

“We are very excited about these findings; however, more research will be needed to determine an effective strategy to translate them to the clinic,” said Hartig.

Posted on Autism

International Society for Autism Research – Recommendations for the autism community and the criminal justice system

Revised Sequential Intercept Model


The revised version of the Sequential Intercept Model is a tool for victims, offenders, families and providers as it follows both the offender and victim perspectives as they navigate the criminal justice system. CREDIT A.J. Drexel Autism Institute

Revised Sequential Intercept Model
IMAG

Autistic individuals interact with the justice system at high rates as both victims and offenders. With a grant from the International Society for Autism Research (INSAR) in late 2019, Drexel University’s A.J. Drexel Autism Institute explored ways to improve interactions between autistic individuals and the justice system. The funding and collaboration led to the recently published policy brief, “Autism and the Criminal Justice System: Policy Opportunities and Challenges,” with wide reaching recommendations and considerations for the broader justice system.

Recommendations from the policy brief include provisions of trauma-informed supports for autistic victims and a need for nations to sign and ratify the United Nations Convention on the Rights of Persons with Disabilities. The brief also includes recommendations that are specific to different aspects of the justice system – community services, law enforcement, confinement and re-entry – that are focused on novel programing like diversionary efforts to keep autistic people out of jail, alternatives to policing and the use of peer supports.

The policy recommendations are intended to address all individuals who are impacted by the overrepresentation of autistic individuals in the justice system. This includes autistic individuals – whether a victim or witness – and their family members and caregivers. Justice system professionals who interact with autistic individuals, community service providers and other involved professionals, also need guidance, support and new practices to effectively support autistic individuals who interact with the justice system. These recommendations offer strategies for the field and focus on generating and implementing equity-informed solutions.

“This international policy brief is an important first step to ensuring equitable access to justice for autistic individuals,” said Lindsay Shea, DrPH, leader of the Policy and Analytics Center in the Autism Institute. “Future research is needed at each stage of the criminal justice system that identifies evidence-based practices and focuses on solutions.”

Anchored by a revised version of the Sequential Intercept Model (SIM), which organizes each stage of the justice system as specific intercepts, the policy brief leverages the predictable pathways that offenders and victims follow throughout the justice system. This allows for policies that address a complex and disconnected system and guides the direction of future research.

The collaboration between the International Society for Autism Research and the Policy and Analytics Center led to an international team of stakeholders from 10 countries across multiple continents convening regularly over the course of a year to produce policy recommendations at each intercept and throughout the entire justice system. The team of stakeholders was comprised of members of the autism community, including autistic self-advocates and family members, along with researchers, policymakers and justice system professionals.

Two workgroups also focused on revising the Sequential Intercept Model and developing a global survey to measure and characterize interactions between autistic individuals and the justice system across all stages.

Autistic self-advocates and justice system professionals reviewed the text of the recommendations and policy briefs for accessibility and feedback.

“We hope this brief can help spark a discourse focusing on preventing root causes for offending and levying justice grounded in supporting and rehabilitating rather than punishing,” said Shea.

Shea added that policy changes are needed globally, as well as reimagining the role of justice.

The Policy and Analytics Center and the stakeholders of the Global Autism and Criminal Justice Consortium that helped produce this brief will continue to lead the charge on this front.

For more information, click here.

Posted on Gastrointestinal disorders

The Gut Feeling: Experts Highlight the Significance of Good Gut Health

We all know that feeling when we “gut” something out. Whether on the verge of making a difficult decision or undertaking a challenging physical feat, our guts can often be our most reliable allies in getting us through tough times. But what exactly is this “gut feeling” we experience?

 

The “gut feeling” is genuine and based on the connection between our brain and gut. This connection is known as the “gut-brain axis” and is responsible for sending signals between our heart and brain, influencing our mood, appetite, immunity, and ability to think clearly.

 

So how can we ensure our guts are always healthy and send signals to our brains efficiently?

  

Why is gut health important?

By ‘gut health’, we refer to the overall well-being of our gut and digestive system. This may sometimes be easy to forget, but the digestive system is arguably the most crucial system within the body.

Our guts are home to billions of fungi and bacteria – a thought not so pleasant and poetic but one that comprises the reality of us humans. Microorganisms play a fundamental role in preserving the well-being of our gut and entire body. Therefore, a healthy gut can have an array of benefits for both our mental and physical states.

Research exhibits a strong connection between bacteria in our guts (in the colon) and our immune system. Gut bacteria can teach the immune system to spot and recognise benign and harmful microorganisms. This is particularly useful as it means that our immune system will not end up flaring up if it comes across innocuous microbes. Instead, it will identify actual ‘threats’ and intervene accordingly.

Moreover, a healthy gut can positively affect our mood and mental well-being. The stomach produces around 90% of our body’s serotonin, a neurotransmitter that impacts our social behaviour, mood, appetite, and sleep.

Therefore, it is fair to say that a well-nourished gut can work wonders for our general well-being.

Signs of an unhealthy gut

A healthy gut and its microorganisms efficiently carry out many positive functions. Hence, it is no surprise that if – for instance – there is an imbalance in gut bacteria, your overall health gets heavily impacted.

But how do you recognise the signs of an unhealthy gut?

Here are a few symptoms to look out for:

  • Upset stomach
  • Digestion issues
  • Sleep loss
  • Migraines
  • Skin irritation

How to feed your gut

There is no denying that the symptoms of an unbalanced gut can be rather unpleasant. If you’re experiencing severe gut problems, such as abdominal pain, diarrhoea, or constipation, you must visit your GP. These could be signs of a more severe problem, such as irritable bowel syndrome or celiac disease.

You may consider investing in a private health care plan to avoid lengthy NHS waiting times but be aware that most policies won’t cover pre-existing conditions.

But prevention is better than cure, which in this case is eating the right food.

So, what should you add to the menu?

  • Fibre – Plant-based foods and fibre –fruits, vegetables, nuts, and whole grains work wonders for gut bacteria and keep them healthy. A diet that is low in fibre can increase bloating, in contrast.
  • Probiotic food – Probiotics are naturally found inside the gut and have a range of digestive benefits, such as helping irritable bowel syndrome. Live yoghurts are a great source of probiotics and can actively encourage more good gut bacteria to develop.
  • Antioxidant-rich foods – Antioxidants are compounds that help to protect cells from damage. Foods rich in antioxidants include berries, dark chocolate, and green tea.
  • Healthy fats: Healthy fats, such as those found in olive oil, avocados, and nuts, are essential for gut health. They help to keep the gut lining strong and prevent inflammation.

The human gut is home to trillions of microbes. This community of microbes, known as the gut microbiota, plays a crucial role in human health, influencing everything from digestion and nutrient absorption to the immune system and mood. While the gut microbiota is complex and unique to everyone, certain foods can promote gut health and encourage the growth of beneficial microbes. Here are ten gut-friendly foods to add to your diet.

From keeping the body energised to uplifting our mood, a healthy gut can have a significant number of benefits on our well-being. After all, a healthy gut is a happy gut.

Experts from Westfield Health – a leading British health and wellbeing company; have looked at the criticality of gut health while highlighting the possible signs of ailing intestines and what foods could help boost their well-being.