Immune surprise: recently evolved alarm molecule drives inflammation

Inflammatory cytokines


Human cells expressing inflammatory cytokines (stained green). CREDIT Professor Martin Laboratory; Trinity College Dublin

Scientists from Trinity College Dublin have made an important breakthrough in understanding how inflammation is regulated. They have just discovered that a key immune alarm protein previously believed to calm down the immune response does the opposite.

Their work has numerous potential impacts, especially in understanding and responding to autoimmune disorders and inflammation.

While our immune system serves a very important function in protecting us from infection and injury, when immune responses become too aggressive, this can lead to damaging inflammation, which occurs in conditions such as rheumatoid arthritis and psoriasis. Inflammation is triggered when our bodies produce “alarm proteins” (interleukins), which ramp up our defences against infection and injury by switching on different immune system components.

Understanding how and when such alarm proteins are produced and how they activate our immune system has led to breakthroughs in treating many immune conditions.

Now, scientists from the Smurfit Institute of Genetics at Trinity College Dublin, led by Seamus Martin, Smurfit Professor of Genetics, have found that Interleukin-37 has an unexpected function as an immune-activating molecule, as previous studies suggested that this interleukin instead served as an “off switch” for the immune system.

Professor Martin said:

“Interleukins play key roles in regulating our immune systems in response to bacterial and fungal infections. However, Interleukin-37 has long remained an enigma, as it isn’t found in mammals such as mice. This has presented a major obstacle to figuring out what it does as much of what we know about the human immune system has first been discovered in model organisms whose biological make-ups are similar to ours.”

Before the new study, Interleukin-37 was thought to have immune-suppressive functions, but how it switched off inflammation was hotly debated. However, the Trinity scientists now report that, when activated in the correct way, Interleukin-37 displays potent pro-inflammatory activity.

Professor Martin added:

“This pro-inflammatory impact was highly unexpected. Our work shows that the protein binds to an interleukin receptor in the skin known to play a key role in driving psoriasis. And, to add further intrigue to the story, this brings the total number of immune alarm molecules that signal via this particular interleukin receptor to four.

“Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate it may be because this receptor serves a very important sentinel function in our skin, and that one alarm protein may simply not be enough to respond to the many different infectious agents that our skin encounters. Our skin is the major barrier between our bodies and the outside world that microbes must breach if they are to gain entry to our bodies and, in many respects, represents the first line of defense in our immune systems.” 

As such, Interleukin-37 and other immune alarm proteins may have evolved to become distinct variations on the same theme that enable our bodies to detect different types of infection by activating enzymes that are distinct to each infectious agent.

Poor gut health may drive multiple sclerosis — better diet may ease it


Poor gut health may drive multiple sclerosis — better diet may ease it


Researchers from Rutgers Robert Wood Johnson Medical School’s Department of Neurology have traced a previously observed link between microscopic organisms in the digestive tract — collectively known as the gut microbiome — and multiple sclerosis (MS).

Their study in genetically altered miceand people supports the belief that dietary adjustments such as increased fiber may slow MS progression, and they are already working to test the effect of dietary interventions in MS patients.

“Unhealthy dietary habits such as low fiber and high fat consumption may have contributed to the steep rise of MS in the US,” said Kouichi Ito, an associate professor of neurology and senior author of the study published in Frontiers in Immunology. “In nations where people still eat more fiber, MS is far less common.”

MS is a degenerative condition in which the body’s immune system attacks the protective covering of nerves in the brain, spinal cord and eyes. According to the National Multiple Sclerosis Society, it affects nearly 1 million adults in the United States.

Several previous studies have differentiated the microbiomes of MS patients and healthy subjects, but, Ito said, they all noted different abnormalities, so it was impossible to tell what change, if any, was driving disease progression.

The Rutgers study, which was led by research associate Sudhir Kumar Yadav, used mice engineered with MS-associated genes to trace the link between alterations in the gut bacteria and an MS-like condition called experimental autoimmune encephalomyelitis (EAE).

As these mice matured — and simultaneously developed EAE and a gut inflammatory condition called colitis — the researchers observed increased recruitment of inflammatory cells (neutrophils) to the colon and production of an anti-microbial protein called lipocalin 2 (Lcn-2).

The study team then looked for evidence that the same process occurred in people with MS and found significantly elevated Lcn-2 levels in patient stool. This marker correlated with reduced bacterial diversity and increased levels of other markers of intestinal inflammation. Additionally, bacteria that seem to ease inflammatory bowel disease were reduced in MS patients with higher levels of fecal Lcn-2.

The study suggests that fecal Lcn-2 levels may be a sensitive marker for detecting unhealthy changes in the gut microbiome of MS patients. It also provides further evidence that high-fiber diets, which reduce gut inflammation, may help fight MS.

Rutgers is looking to test that hypothesis soon. Suhayl Dhib-Jalbut, a co-senior author of the paper who heads the medical school’s neurology department, is recruiting patients with MS for a trial that will determine how their microbiomes and immune systems are affected by a high-fiber supplement developed by Rutgers Microbiologist Liping Zhao.

Ultrasound device for pain gets ‘nod’ from Shark Tank and NIH funding

Non-invasive, Non-opioid Neuropathic Pain Treatment


Julie Pilitsis, M.D., Ph.D., FAU’s principal investigator, dean and vice president for medical affairs in the Schmidt College of Medicine. CREDIT Florida Atlantic University

Researchers from Florida Atlantic University’s Schmidt College of Medicine, in collaboration with Albany Medical College (AMC) in New York, are among seven institutions nationwide selected to receive funding from the National Institutes of Health (NIH) for their innovative pilot projects to enable new medical devices to diagnose and treat both acute and chronic disorders from neuropathic pain to mental illness.

The one-year, $100,000 awards are the first for a new program within the NIH Blueprint for Neuroscience Research, called Blueprint MedTech. The seven projects selected for the pilot phase for funding by the NIH all received successful reviews from ABC’s “Shark Tank.”

Along with funding, MedTech will provide an array of specialized support from mentors who bring decades of experience commercializing neurotechnology devices. Project teams will learn to navigate business, manufacturing and regulatory aspects of developing their respective technologies, and prepare to build human-grade prototypes. While the science supporting each technology has met rigorous standards, clinical studies will be needed before they authorise patient use.

The FAU/AMC project is titled “External Low-intensity Focused Ultrasound Device for Treatment of Neuropathic Pain.” Focused ultrasound is a noninvasive therapeutic technique that directs ultrasonic waves to a specific location. For the project, researchers are developing a handheld probe to provide a noninvasive, non-opioid-based treatment for aggravated chronic pain, also referred to as neuropathic pain, for use in a physician’s office or potentially even at home.

The device directs low-intensity ultrasound at the dorsal root ganglia – small bundles of nerves along the spine that control pain signals reaching the spinal cord. Neuropathic pain occurs if the nervous system is damaged or not working correctly. Pain is felt from various levels of the nervous system, from the peripheral nerves to the spinal cord and the brain.

“Pain is one of the most common reasons patients seek medical care. Importantly, neuropathic pain, when treated with opioid-based drugs, has led to addiction in some patients,” said Julie Pilitsis, M.D., Ph.D., FAU’s principal investigator, dean and vice president for medical affairs in the Schmidt College of Medicine. “In addition to medications such as opioids, traditional pain treatment also involves physical therapy and steroid injections. However, adverse effects and tolerance occur with many of these therapies and a significant number of patients remain in pain. There is a great unmet need to provide more effective, safer and financially sustainable therapies for patients in pain.”

The handheld applicator under development integrates ultrasound imaging and therapy and is designed to accommodate differences in human anatomical size. As a result, the treatment device and methodology will provide means for precise treatment of back and leg pain.

“It is the noninvasive aspect and all-in-one nature of our device that is highly significant as an advancement in treatment of neuropathic pain,” said Pilitsis. “The cost of pain therapies and missed wages secondary to pain results in about $536 million dollars spent each year. Ideally, with this therapy, patients can avoid hospitalization and days off work by reducing pain and enabling function.”

Over the last eight years, the FAU/AMC researchers have shown efficacy of low intensity focused ultrasound in alerting nociceptive responses related to the perception or sensation of pain in multiple pain models over multiple species in both sexes and with repeated treatments.

Intermittent fasting may reverse type 2 diabetes.

Intermittent fasting may reverse type 2 diabetes
Intermittent fasting may reverse type 2 diabetes


After an intermittent fasting diet intervention, patients achieved complete diabetes remission, defined as an HbA1c (average blood sugar) level of less than 6.5% at least one year after stopping diabetes medication, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Intermittent fasting diets have become popular in recent years as an effective weight loss method. With intermittent fasting, you only eat during a specific window of time. Fasting for a certain number of hours each day or eating just one meal a couple of days a week can help your body burn fat. Research shows intermittent fasting can lower your risk of diabetes and heart disease.

“Type 2 diabetes is not necessarily a permanent, lifelong disease. Diabetes remission is possible if patients lose weight by changing their diet and exercise habits,” said Dongbo Liu, Ph.D., of Hunan Agricultural University in Changsha, China. “Our research shows an intermittent fasting, Chinese Medical Nutrition Therapy (CMNT), can lead to diabetes remission in people with type 2 diabetes, and these findings could have a major impact on the over 537 million adults worldwide who suffer from the disease.”

The researchers conducted a 3-month intermittent fasting diet intervention among 36 people with diabetes and found almost 90% of participants, including those who took blood sugar-lowering agents and insulin, reduced their diabetes medication intake after intermittent fasting. Fifty-five percent of these people experienced diabetes remission, discontinued their diabetes medication and maintained it for at least one year.

The study challenges the conventional view that diabetes remission can only be achieved in those with a shorter diabetes duration (0-6 years). Sixty-five percent of the study participants who achieved diabetes remission had a diabetes duration of more than 6 years (6-11 years).

“Diabetes medications are costly and a barrier for many patients who are trying to effectively manage their diabetes. Our study saw medication costs decrease by 77% in people with diabetes after intermittent fasting,” Liu said.

Study finds microbiota transfer therapy provides long-term improvement in gut health in autistic children.

Microbiota transfer therapy provides long term improvement in gut health in children with autism


In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — a novel treatment for children with autism. Specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism , improved following microbiota transfer therapy. CREDIT Shireen Dooling/Arizona State University

Autismcurrently affects 1 in 44 children in the U.S., according to the Centers for Disease Control and Prevention. For reasons that remain murky, these numbers appear to be trending upward as researchers and clinicians struggle to find effective treatments.

Recently, a new approach to treat symptoms associated with this disorder has emerged, thanks to the explosion of research on the trillions of non-human cells inhabiting the gastrointestinal tract—collectively known as the gut microbiome. The treatment, called microbiota transfer therapy, is a process where healthy gut bacteria are transferred to children with autism.

In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. 

The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism, improved following microbiota transfer therapy.

In first-of-its-kind research, the research team used a whole genome sequencing technology known as “shotgun metagenomics” to extract detailed data from more than 5,000 bacterial species found in the gut of children with autism spectrum disorder before and after microbiota transfer therapy. The researchers then compared these results with bacterial populations in the guts of healthy children.  

The results showed considerable improvement in overall abundance of bacteria following the microbiota transfer therapy, and this confirmed previous findings. Also, there were substantial increases in populations of beneficial bacterial species typically found in lower numbers in children with autism.

Additionally, two genetic indicators of dysregulation in the gut microbiome of children with autism improved following microbiota transfer therapy. These key genetic markers are the metabolism of sulfur and the failure to detoxify oxidative stress.

The findings are encouraging because the severity of gastrointestinal dysfunction in autistic children appears proportional to the degree of behavioral and cognitive issues, highlighting the importance of the gut-brain axis—a topic of intense interest in the world of microbiomics. The gut-brain axis is the communication system between your brain and your gut.

“This study highlights altered levels of important bacterial species and metabolic genes in children with autism and improvements after microbiota transfer therapy,” says Khemlal Nirmalkar, lead author and post-doctoral fellow working in theRosa Krajmalnik-Brown lab at the ASU Biodesign Institute. Our long-term goal is to understand the functional role of the gut microbiome, fill the knowledge gap of the gut-brain axis in autism, and identify therapeutic targets to improve GI health and behavior in children with autism.”

“Completing more in-depth microbiome sequencing is important because it can help us better understand what microbes in the gut are doing and why they are an important part of the gut-brain axis,” said Krajmalnik-Brown, who directs the newly established Biodesign Center for Health Through Microbiomes. She is also a professor with the ASU School of Sustainable Engineering and the Built Environment in the Ira A. Fulton Schools of Engineering.

Collaborators include James Adams, President’s Professor with the ASU School for Engineering of Matter, Transport and Energy, and researchers with the Rensselaer Polytechnic Institute in New York. The study appears in a special issue of the International Journal of Molecular Sciences titled “The Microbiota–Gut–Brain Axis in Behavior and Brain Disorders.” 

The research team used shotgun metagenomics, or whole genome sequencing, to better understand the bacterial populations at the species level. They also wanted to understand bacterial genes before and after microbiota transfer therapy. The treatment not only increased the abundance of beneficial bacteria but also helped to normalize altered levels of bacterial genes, particularly those related to the synthesis of folate, oxidative stress protection and sulfur metabolism, and importantly, became similar to typically developing children.

Autism remains an enigmatic disorder, often emerging in early childhood and causing lifelong developmental disabilities that affect social skills, communication, personal relationships and self-control. So far, there is no cure for the affliction and therapies for treating associated symptoms remain limited.

The microbiota transfer procedure involves the transfer of gut microbiota from healthy donors to autistic patients over a period of seven to eight weeks. The procedure begins with a 2-week antibiotic treatment and bowel cleanse, followed by an extended transplant of fecal microbiota, applying a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. This treatment was initially studied in children with autism ages 7-16 years old.

In a follow-up study, the same 18 participants were examined two years after treatment was completed. Most improvements in gastrointestinal symptoms were maintained, while autism-related symptoms continued to improve even after the end of treatment, demonstrating the long-term safety and efficacy of microbiota transfer therapy as a therapy for autism.

The treatment reduced the severity of gastrointestinal symptoms by roughly 80% and signs of autism by about 24% by the end of treatment. After two years, the same children showed an approximate 59% reduction in gastrointestinal symptoms and 47% reduction in autism symptoms, compared with baseline levels established prior to treatment.

Krajmalnik-Brown and Adams are currently working on phase-2 double-blind placebo-controlled studies of microbiota transfer therapy for children and adults with autism, and they plan to verify whether these findings hold true in those two studies.

Future research will further explore the role of specific microbial species, functional gene expression and the production of a range of autism -related metabolites before and after microbiota transfer therapy.