The Brainstem Fine-Tunes Inflammation Throughout the Body

    

Last month, researchers discovered cells in the brainstem that regulate inflammation throughout the body. In response to an injury, these nerve cells not only sense inflammatory molecules, but also dial their circulating levels up and down to keep infections from harming healthy tissues. The discovery adds control of the immune system to the brainstem’s core functions — a list that also includes monitoring heart rate, breathing and aspects of taste — and suggests new potential targets for treating inflammatory disorders like arthritis and inflammatory bowel disease.

During an intense workout or high-stakes exam, your brain can sense the spike in your heart rate and help restore a normal rhythm. Likewise, the brain can help stabilize your blood pressure by triggering chemical signals that widen or constrict blood vessels. Such feats often go unnoticed, but they illustrate a fundamental concept of physiology known as homeostasis — the capacity of organisms to keep their internal systems working smoothly and stably amid shifting circumstances.

Now, in a paper published on May 1 in Nature, researchers describe how homeostatic control extends even to the sprawl of cells and tissues that comprise our immune system.

The team applied a clever genetic approach in mice to identify cells in the brainstem that adjust immune reactions to pathogens and other outside triggers. These neurons operate like a “volume controller” that keeps the animals’ inflammatory responses within a physiological range, said paper author Hao Jin, a neuroimmunologist at the National Institute of Allergy and Infectious Diseases.

The discovery may come as a surprise to immunologists who assume that the strength of an immune response is governed by the immune system’s own set of regulatory mechanisms, said a immunobiologist  who was not involved in the study. “We’ve never suspected that there will be something else on top of it, that we need an additional control. But clearly we do,” he said. “That’s what this work revealed: There are parts of the brainstem dedicated to this control.”

Perhaps it took a change in perspective to make the discovery. The new research doesn’t come from a traditional immunology lab but from one dedicated to the study of taste.

A Taste for Homeostasis

For as long as he can remember, the Chilean neurobiologist Charles Zuker has been captivated by the senses. After an early stint studying specialized light-sensing cells in the eyes of fruit flies, he became intrigued by the mammalian taste system. He has spent more than 25 years probing how organisms discern sweet, sour and other tastes, and how they use those signals to guide their behaviors.

Some of these behaviors are hard-wired, said Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia University. When a sweet taste “hits the brain, the brain knows that this is good. When it gets a bitter signal, it knows it is bad,” he said. These signals “trigger predetermined actions and behaviors” — such as reaching for a second piece of cake or spitting out rotten fruit. In the 2000s, Zuker and his colleagues cloned the genes for receptors that detect sweet, bitter, umami, sour and salty tastes to work out how this wisdom gets carried out at the molecular level.

At the time, Jin was finishing his doctorate at the National University of Singapore, studying immune cell development in zebra fish and pondering a shift to a more challenging system for the next phase of his career. He joined Zuker’s lab to study the brain in 2011.

In 2020, Jin’s colleagues published a landmark paper that proved an unexpected connection between the brainstem and the body. They had engineered a mouse with no sugar receptors. This animal could not distinguish plain water from sugar water; it drank equally from both bottles. That much was expected. Yet in the same cage, 48 hours later, the sugar water was gone and the plain water untouched.

What happened? They found that the animal’s preference for sugar was not mediated exclusively by the taste system. Rather, its sugar craving derived from a neural pathway that started in the gut and extended into the brain. Even though the mouse could not taste that the water was sweet, cells in the gut sensed the sugar and sent signals along the vagus nerve — a superhighway connecting body to brain — that taught the animal to want more. These gut-brain signals had activated a cluster of nerve cells in the brainstem.

Even though the mice didn’t get the immediate feedback of taste, they “learned there is something in there that makes them feel good — and that is what they want,” Zuker said.

Over the years, scientists have used advances in molecular tools to fill in the details on some of the vagus nerve circuits that control key bodily functions. Studies led by Stephen Liberles, a cell biologist at Harvard Medical School, suggest that the vagus nerve has a few dozen types of sensory neurons. One measures the volume of air in the lungs and triggers muscles for exhalation. Another picks up changes in blood pressure. Others sense the stretch of the stomach during a meal and prompt a feeling of fullness. “The brain receives this dizzying array of stimuli and needs to sort out all these incoming signals to ensure that physiology is appropriately controlled,” Liberles said.

Such studies helped usher in a “transformation in the way we think about the brain,” Zuker said. Historically considered the seat of memory and emotion, the brain may devote far less energy to these higher-order functions than to monitoring the body’s organs, physiology and metabolism to maintain homeostasis. “Everyone in the lab began to think about that,” he said. “How far does the brain’s control over body biology go?”

However, the immune system wasn’t a part of their view of homeostasis — until Jin went back to his roots.

Tracking Immunity to the Brain

On first pass, our sense of taste and our immune system appear to have little in common. The former allows us to savor textures and flavors from different cuisines, while the latter protects us from germs. But at their essence, both are defense systems against foreign substances going into the body, Jin said: The taste system is the gateway for food and drink, while the immune system handles bacteria and viruses.

Research decades ago suggested that the vagus nerve controls inflammatory responses — pointing to a body-brain connection. Jin wondered if he could use genetic approaches in the Zuker lab’s mouse models to trace inflammatory responses in the brain. These methods allow scientists to target never cells with high precision “so we can not just identify but also access and manipulate those neurons that respond to inflammation,” Jin said. “We can change their activity to study their function.”

He injected mice with a substance that mimics an infection and then scanned their brains to see which regions activated. Curiously, many of the activated neurons were located in the same area of the brainstem that lit up in the mice that couldn’t taste sugar.

He and his colleagues wanted to figure out which brain circuits were involved. In one experiment, they cut the vagus nerve and saw that, without its input, the brainstem neurons remained inert — demonstrating the vagus nerve’s central role in this brain-body immune circuit. Then they used genetic techniques to dial the brainstem neurons’ activity up or down. When dialed down, the mice experienced an out-of-control inflammatory response, with a corresponding rise in pro-inflammatory molecules and a dip in anti-inflammatory molecules. Dialing up the brainstem cells’ activity did the opposite: Anti-inflammatory molecules shot up, while levels of pro-inflammatory molecules plummeted, putting a damper on inflammation.

The findings raise intriguing questions, Liberles said. For example: What other cells and circuits partner with these neurons to regulate immune reactions? Are there additional central controllers in the nervous system? There may be “multiple highways of communication” between the brain and the immune system, he said.

“The big question is what aspects of the internal state are actively monitored by specialized neuronal circuits,” Medzhitov wrote in an email. “We knew about some of them for a while (heart rate, blood pressure, blood oxygen, etc.). But we are now learning that the inflammatory state and immunity are also somehow monitored and actively controlled by the brain.”

Perhaps the most exciting part of the discovery is its implications for medicine. In a final set of experiments, the team showed that, in mice, activating the vagal-brainstem circuit could restore immune balance and prevent inflammatory states resembling ulcerative colitis and sepsis. This suggests potential new strategies for treating conditions such as rheumatoid arthritis, inflammatory bowel disease, Type 1 diabetes and other inflammatory disorders, Zuker said.

Similar mechanisms likely exist in people, Liberles said. In mice and humans, “the general blueprints for how the sensory systems work are actually quite similar.” The eventual goal would be to design a way to control these immune-balancing circuits in people to tamp down inflammation in specific organs or diseases. “That would be the dream,” he said, “and I think it’s possible.”

 

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You Won't Get the Vitamin D You Need If You Suffer From.

For those of us who live in North America, there is a very good chance that we don't get all the Vitamin D we need. In fact, about 42% of American adults are deficient in this nutrient. Though other studies suggest that the number is actually closer to 75%. Being deficient in vitamin D is associated with a number of health concerns including risk for Alzheimer's disease, diabetes, osteoporosis and heart disease. 

 

It has also been found that if you have been diagnosed with breast or prostate cancer, your chances of survival may be lower than someone with normal levels of vitamin D. This may sound alarming, though it shouldn't come as a surprise. After all, vitamin D isn't found in too many foods - with the exception of salmon and fortified milk and yogurt. The only other way to get the nutrient, is to expose your bear skin to the sun. But if you work indoors all day, this is highly unlikely. 

 

The best way to discover whether you are deficient in vitamin D is to take a blood test. Your levels should be between 45 to 50 µg/mL. This is something you may want to consider if you form part of these groups: 

 

1. You are over 55 vitamin D deficiency

Of course, aging does have its perks: you are smarter, more confident and may be enjoying a leisurely life of retirement. Nevertheless, there are some downside. As we age, we tend to become less mobile, making it difficult to spend time outdoors, which would result in getting less vitamin D. In addition, ageing skin cannot synthesize vitamin D as efficiently. According to a 2007 Canadian study, about 50% of older American adults with hip fractures were found to have low levels of vitamin D in their blood. So, you're likely falling short on the nutrient unless you are taking a daily supplement.

2. You work in an office

Working a 9 to 5 job would mean that you don't get much sun. According to the National Institutes of Health (NIH), people with occupations that limit sun exposure are unlikely to obtain adequate vitamin D from sunlight. This makes supplementation and a smart diet key to staying healthy. 

 

 

3. You have dark skin

Reports continue to show lower levels of vitamin D in those that identify themselves as black in comparison to those who identify themselves as white. This is because darker skin makes it more challenging for the body to produce vitamin D from sunlight, according to experts from the National Academies of Sciences, Engineering and Medicine's Foods and Nutrition Board. If you're darker skinned, you should rely on dietary sources of the nutrient, rather than sunlight to reach your daily vitamin D mark.

4. You suffer from inflammatory bowel disease

Vitamin D is a fat-soluble vitamin, this means its absorption depends on the gut's ability to take in fat. Fat malabsorption is associated with inflammatory bowel disease (IBD) - this includes conditions like Crohn's disease and ulcerative colitis. In fact, it has been shown that up to 70% of people with IBD have insufficient vitamin D levels, according to a Journal of Gastroenterology and Hepatology report. If you suffer from IBD, speak to your doctor and check whether you are getting enough vitamin D. 

 

 

5. You have a high body fat percentage

If your body mass index (BMI) is over 30 or you have a high body fat percentage, it may be more challenging for vitamin D to circulate throughout your body, the NIH reports. Nevertheless, this doesn't mean that you will always be deficient. Be sure to speak to your doctor and find out just how much vitamin D you will need. 

 

 

6. You are taking certain medications

We do need certain medications to keep our health on track, however, corticosteroid medications such as prednisone, as well as weight-loss drugs like orlistat, and the cholesterol-lowering drug cholestyramine can impair vitamin D metabolism. If you take any one of these drugs, be sure to check in with your doctor to find out the best way for you to get the right dose.

7. You suffer from depression

Did you know that people with low levels of vitamin D in their blood are more than twice as likely to be diagnosed with depression, than those with higher levels? Medical experts aren't sure why this is the case, however one hypothesis is that the vitamin may alter hormones and areas of the brain that affect and regulate mood. 

 

 

8. You suffer from chronic headaches

If you suffer from regular headaches, low blood levels of vitamin D may be to blame, according to a 2017 study of 2,600 men. Study participants with the lowest vitamin D levels had a twofold risk of chronic headaches compared to study participants with the highest levels. The specific link between headaches and vitamin D remains unclear, researchers believe the nutrient may help combat the inflammation that causes migraines and headaches.

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Colorectal Cancer

Colorectal cancer is the cancer of the colon or rectum located at the lower end of the digestive tract. It is also known as bowel, colon or rectal cancer and is the third most common cancer globally, accounting for nearly 1.4 million new cases and 694,000 deaths per year. Although, colorectal cancers are not talked about widely, they are increasing at a rapid rate and early detection is the key to survival. While the prevalence of this disease was predominantly in the western countries earlier, it has been increasing exponentially in India. Colorectal cancer is one of the most preventable cancers and a healthy lifestyle alongside regular screening can safeguard against the disease significantly.

The risk factors for colorectal cancer usually spikes up over an age, usually after the age of 50. Other prevalent causes are:
The risk for colorectal cancer increases post 50 years of age
Personal history of colorectal polyps (a small clump of cells) or colorectal cancer
Personal history of inflammatory bowel disease (ulcerative colitis or Crohn's disease)
Family history of colorectal cancers
Obesity
Lack of regular physical activity/ exercise

There are also certain risk factors for colorectal cancer, which include:
Change in bowel habits such as diarrhea, constipation, or narrowing of the stool that lasts over a few days
A feeling that you need to have a bowel movement that is not relieved by doing so
Dark stool or blood in the stool
Weakness and fatigue
Weight loss
Cramping or abdominal belly pain
According to Dr. Amanjeet Singh, Associate Director, GI Surgery, GI Oncology and Bariatric Surgery, Institute of Digestive and Hepatobiliary Sciences, certain factors can help treat and prevent the risk associated to Colorectal Cancer. These include:
Prevention and myths
-3 to 4 hours of vigorous physical activity per week can help decrease risk.
-Avoid high intake of red meats including lamb, liver and pork and processed meats such as hot dogs
-Avoid smoking and limit the consumption of alcohol
-Add more vegetables, fruits, and whole grains to your diet
-Get yourself screened regularly post the age of 45 years 

Treatment
The treatment for colorectal cancer is determined basis the location and stage of the cancer and overall health of the patient. Colorectal cancer can be treated through surgery, radiotherapy or chemotherapy.

Early-stage colorectal cancer can be treated through:
Colonoscopy- if the cancer is small, localized and within a polyp, it can be removed completely during colonoscopy (test used to detect changes or abnormalities in the colonand rectum)
Endoscopic mucosal resection- this is used in case of larger polyps and involves a colonoscopy. However, a small part of the inner lining of the intestine is also removed along with the polyp using specialized tools during colonoscopy

Laparoscopic surgery (Minimally Invasive surgery)- this is used in cases where the polyp cannot be removed through a colonoscopy. Laparoscopic surgery involves making small incisions in the abdominal wall for inserting instruments with an attached camera that displays the colon on a monitor for safe and effective removal of the polyp

Advanced colorectal cancer can be treated through:
Partial Colectomy- this procedure involves removal of the part of the colon that contains the cancer along with some normal tissues surrounding the cancer. It is generally conducted through a laparoscopic approach and the surgeon reconnects the healthy portions of the colon or rectum post-surgery.
Surgery for enabling waste to be removed from the body- this is undertaken when in rare cases it is difficult to reconnect the healthy portions of the colon or rectum. The process is called ostomy and involves creating an opening in the abdominal wall (from a portion of the remaining bowel) for eliminating stool into a bag that is fitted over the opening.

Radiotherapy- this involves the use of powerful X-rays and protons for killing cancer cells and is a good option in case surgery cannot be conducted. It is also used to shrink the cancer ahead of a surgery for easy removal.

Chemotherapy- this involves the use of drugs for destroying cancer cells and is usually administered post-surgery if the cancer is large or has spread to the lymph nodes. Like radiotherapy, chemotherapy can also be used to shrink the cancer ahead of a surgery.

Targeted drug therapy- this treatment focusses on specific abnormalities within cancer cells and blocks them through targeted drug treatment, thereby killing the cancer cells.

Immunotherapy- it is a drug-based treatment that utilizes the patient’s own immune system to fight cancer cells. 

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Examining the Effects of Immunotherapy on Cancer

Using a collection of sophisticated single-cell technologies, scientists at the Mount Sinai Health System have launched an early-stage clinical trial that examines the effects of immunotherapy on hepatocellular carcinoma, non-small-cell lung cancer, and head and neck squamous cell carcinoma.

Four to six weeks before a tumor is resected, the researchers administer a neoadjuvant immunotherapy, cemiplimab, and study its effects. As soon as the tumor is removed, they continue to analyze the fresh tissue for a month or more to observe mechanisms of resistance and response. The Phase 1 trial is sponsored by Regeneron Pharmaceuticals, Inc.

“With the technologies available to us at The Tisch Cancer Institute and Mount Sinai’s Human Immune Monitoring Center, we are able to investigate at an unprecedented depth how these immune therapies are changing the microenvironment within the tumor,” says Thomas Marron, MD, PhD, Assistant Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, and Principal Investigator of the study. “This trial enables us to analyze fresh tissue immediately after resection—instead of the preserved tissue typically obtained in trials—to observe the dynamic changes that occurred.”

The study is enrolling multiple small cohorts of 21 patients. One goal is to determine which cancer patients will benefit from cemiplimab, and, more specifically, how cemiplimab can be more effective by combining it with chemotherapy and/or other novel immunotherapies. Cemiplimab was previously studied at Mount Sinai in liver and lung cancer patients and has been approved by the U.S. Food and Drug Administration for patients with metastatic cutaneous squamous cell carcinoma. The compound works by inhibiting the interaction between PD-L1, a protein on the surface of tumor cells, and PD-1, the protein on the surface of T cells, and restoring the immune system’s ability to recognize and kill cancer cells.

Another goal of the study is to identify biomarkers in human tissue and blood that will be able to predict who will respond to immunotherapy, since so many patients do not respond to anti-PD-1 therapy. “We really need to find the ideal patients to treat so we don’t unnecessarily expose those who won’t respond to the toxicity of immune therapies,” says Dr. Marron, who is also Assistant Director of Early Phase and Immunotherapy Clinical Trials at Mount Sinai. “There’s also a financial issue at stake for patients and society in general in using expensive drugs that are not improving outcomes.”

Dr. Marron and his team are using several powerful new technologies to help them with their work. These include immune mapping and monitoring technologies such as mass cytometry (CyTOF), a flow-cytometry-like technology that allows them to see up to 50 proteins on each cell so they can identify the cell type and classify the maturation and activation status of the cell, along with some of the regulatory “on/off” checkpoints.

CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) is another platform that provides an even higher resolution view of each individual cell within the tumor. This technology combines the capabilities of CyTOF and single-cell RNA sequencing to characterize both the RNA and protein in each cell.

A third technology is known as Multiple Ion Beam Imaging (MIBI), a unique form of immunohistochemistry that allows scientists, for the first time, to unravel the spatial architecture of tumors in order to better understand the mechanisms through which the immune system is infiltrating the tumor and is being hijacked by the tumor.

“For 10 years, we’ve been building the Human Immune Monitoring Center into one of the leading platforms in the world for investigating the role of the immune system in human disease, and using that knowledge to design novel, immune-based therapies,” says Miriam Merad, MD, PhD, Director of the Center, and Professor of Oncological Sciences, and Medicine, Icahn School of Medicine at Mount Sinai.

Drawing on a highly specialized team of clinicians, immunologists, mathematicians, physicists, and surgeons, the Human Immune Monitoring Center is currently involved in more than 45 federal- and foundation-funded research programs in fields such as cancer, autoimmune disease, inflammatory bowel disease, allergies, and neurodegenerative disease.

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MIT reserchers catalogue 7,757 gut microbes that can help develop new treatments

Researchers have created a comprehensive catalogue of human gut bacteria by isolating and preserving samples of 7,758 strains of the microbes-- an advance that may help develop new treatments for several diseases.

The human digestive system houses thousands of different strains of bacteria, many of which are beneficial, while some have been linked to metabolic disorders and inflammatory bowel diseases for over a decade.

To know more about how these microbes changed in individuals over time, the researchers at MIT, in the US collected stool samples from about 90 people from an area, for up to 2 years.

Results from the data set (BIO-ML) should help in understanding the way in which microbial populations change in the human gut, researchers said.

This may also help scientists develop new treatments for a variety of diseases, said a Prof. of biological engineering and of civil and environmental engineering at MIT.

There's a lot of excitement in the microbiome field because there are associations between thesee bacteria and health and disease. But we're lacking in being able to develop to understand why that is, what's the mechanism, and what are the functions of those bacteria that are causing them to associate with the disease, she said.

More than ever before, modern techniques allow us to isolate previously uncultured human gut bacteria. Exloring this genetic and functional diversity is fascinating-- everywhere we look, we discover new things, said one of the lead authors.

I'm convinced that enriching biobanks with a large diversity of strains from individuals living diverse lifestyles is essential for future advancements in human microbiome research, she added. This is the first time we're getting a glimpse of these really different dynamics, she said.

In a case, the researchers found 3 related strains of Bacteroides vulgatus coexisting within a single person, all of which appeared to have diverged from one ancestor strain within the host.

In another case, the study noted one strain of Turicibacter snaguinis completely replacing a related strain of the same species nearly overnight.

For the most part of the research, the team focused on microbes found in about a dozen individuals who had provided samples over an extended period.

That was a unique opportunity, and we thought that would be a great set of individuals to really try to dig down and characterise the microbial populations more thoroughly, she said.

To date, there hadn't been a tonne of longitudinal studies, and we wanted to make that a key focus of our study, so we could understand what the variation is day-to-day , she said.

The team was able to isolate a total of 7,758 strains from the 6 major phyla of bacteria that mostly make up the human GI tract, and for 3,632 of these, they sequenced the full genomes.

For the remaining strains, they sequenced partial genomes. They also measured the quantities of different metabolites found in the stool samples, revealing that, within a single person, changes in amino acid levels were closely linked with changes in microbial populations over time.
However, when looking at the differences in the composition of microbial populations across people, the variations were closely associated with changes in the levels of bile acids that help in digestion.

The researchers don't know exactly procedures these differences, but say they could be influenced by diet-- a link they hope to study in the future. Comprehensive and high-resolution collections of bacterial isolates open the mechanistically investigate how our lifestyle shapes out gut microbiome, metabolism and inflammation. 

We aim to provide such a resource to the research community worldwide, including to lower-income research community worldwide, including to lower-income research institutions, said MIT research associate.

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I inflammatory bowel disease linked to prostate cancer

Inflammatory bowel disease increases the risk of prostate cancer by four-to-five times, according to a study. The findings appear in the journal European Urology. The 20-year study is the first report to show men with inflammatory bowel disease have higher than average PSA (prostate-specific antigen) values, and this group also has a significantly higher risk of potentially dangerous prostate cancer.

Inflammatory bowel disease is a common chronic condition that includes Crohn's disease and ulcerative colitis. "These patients may need to be screened more carefully than a man without inflammatory bowel disease," said lead study author. "If a man with inflammatory bowel disease has an elevated PSA, it may be an indicator of prostate cancer."

In his practice, the Dr. sees many men with inflammatory bowel disease who have elevated PSA tests "Many doctors think their PSA is elevated just because they have an inflammatory condition," he added. "There is no data to guide how we should treat these men."

For the extensive study, researchers looked at 1,033 men with inflammatory bowel disease and a control group of 9,306 men without the disease. They followed the two groups of men for 18 years and found those with inflammatory bowel disease were much more likely to have prostate cancer and higher PSA levels. 

THIS IS ONLY FOR INFORMATION, ALWAYS CONSULT YOU PHYSICIAN BEFORE HAVING ANY PARTICULAR FOOD/ MEDICATION/EXERCISE/OTHER REMEDIES.                                                                                                                                                                                                                                                                                        PS- THOSE INTERESTED IN RECIPES ARE FREE TO  VIEW MY BLOG-                                                                                           https://gseasyrecipes.blogspot.com/                                                                                                                                                                             FOR INFO ABOUT KNEE REPLACEMENT, YOU CAN VIEW MY BLOG-                                                                                                                             https:// kneereplacement-stickclub.blogspot.com/                                                                                       FOR CROCHET DESIGNS                                                                                                                                                                                                                                 https://gscrochetdesigns.blogspot.com