New genetic research shows a direct link between low vitamin D levels and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component, such as type 2 diabetes. The findings, published in the International Journal of Epidemiology, also helps to settle some of the controversies surrounding the ‘sunshine vitamin’.
The study drew on genetic data for 294 970 participants in the UK Biobank, using Mendelian randomisation to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.
University of South Australia’s Dr Ang Zhou, the study’s lead researcher, said that the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.
“This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation.
“Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”
The study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.
Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, said that these results offer an explanation for some of the controversies in reported associations with vitamin D.
“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen said.
“These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”
Insulin is released just by the sight and smell of a meal, but now, researchers report in Cell Metabolism that this insulin release depends on a short-term inflammatory response that takes place in these circumstances. In overweight individuals, however, this inflammatory response is so excessive that it can impair insulin secretion.
Even the anticipation of a forthcoming meal triggers a series of responses in the body. Insulin is released in this neurally mediated (or cephalic) phase of insulin secretion.
Meal stimulates immune defence
Until now, it was unclear how the sensory perception of a meal generated a signal to the pancreas to ramp up insulin production. Now, researchers from the University of Basel and University Hospital Basel have identified an important piece of the puzzle: an inflammatory factor known as interleukin 1 beta (IL1B), which is also involved in the immune response to pathogens or in tissue damage.
“The fact that this inflammatory factor is responsible for a considerable proportion of normal insulin secretion in healthy individuals is surprising, because it’s also involved in the development of type 2 diabetes,” explained study leader Professor Marc Donath from the Department of Biomedicine and the Clinic of Endocrinology.
Chronic inflammation damaging the insulin-producing cells of the pancreas is one of the causes of type 2 diabetes. This is another situation in which IL1B plays a key role – in this case, it is produced and secreted in excessively large quantities. Thus, researchers are investigating whether inhibiting IL1B could be a treatment for diabetes.
Short-lived inflammatory response
Circumstances are different when it comes to neurally mediated insulin secretion: “The smell and sight of a meal stimulate specific immune cells in the brain known as the microglia,” said study author Dr Sophia Wiedemann, resident physician for internal medicine. “These cells briefly secrete IL1B, which in turn affects the autonomic nervous system via the vagus nerve.” This system then relays the signal to the pancreas.
In the case of morbid obesity, however, this neurally mediated phase of insulin secretion is disrupted. Specifically, by the initial excessive inflammatory response, as explained by doctoral candidate Kelly Trimigliozzi, who carried out the main part of the study in collaboration with Dr Wiedemann.
“Our results indicate that IL1B plays an important role in linking up sensory information such as the sight and smell of a meal with subsequent neurally mediated insulin secretion – and in regulating this connection,” Prof Marc Donath said.
A newly published study has identified a key regulatory mechanism in inflammation that may lead to new targets for resolving that inflammation –and the inflammation of patients with sepsis, cancer and COVID.
In the journal PNAS, scientists reported their discovery of a regulatory pathway for immune response after infection or injury, such as burns. Dysregulation of this pathway could differentiate those who are at risk of fatal sepsis or help identify targets to resolve this unregulated inflammation.
“We are very excited about the findings in this paper and the far-reaching impacts it could have on understanding a key regulatory step in the immune response,” said co-lead author Cindy McReynolds, who holds a doctorate in pharmacology and toxicology.
In a rodent model, the research team found that the metabolites of linoleic acid formed by the enzyme, soluble epoxide hydrolase (sEH), drive damaging inflammation after injury. These metabolites, known as lipid mediators, regulate inflammation, blood pressure and pain. Drugs that inhibit the sEH enzyme and reduce inflammation could lead to better outcomes.
“Our previous work identified that these same lipid mediators were up-regulated in severe COVID infections, and we are now finding that these compounds play a role in modulating the immune response so that the body is unable to fight infection or respond properly to trauma without leading to a potentially fatal overreaction,” said Dr McReynolds.
“This dysregulation has fatal consequences in serious diseases such as COVID, cancer, sepsis, burn, where fatality rates can be as high as 40 percent in severe cases,” she said. “An understanding of these pathways can help identify patients at risk of developing serious disease or identify new therapeutic targets for treatment.”
“The immunological disbalance we see in many cases of severe burn injury, trauma and sepsis pose a huge clinical challenge as we lack the understanding of how to diagnose and treat it,” explained co-lead author Dr Christian Bergmann. “With this work, we reveal an important mechanism how immune cells are functionally disabled by sEH-derived metabolites of linoleic acid.”
“The natural compounds we are studying in this paper are metabolites of linoleic acid (LA), an essential fatty acid the body needs in very small amounts to survive and is only available through the diet,” Dr McReynolds elaborated. “At lower concentrations, these metabolites are necessary for regulating thermogenesis and heart health but promote inflammation at higher concentrations. LA is more stable and much cheaper than longer chain polyunsaturated fatty acids, so heavily processed foods have higher LA content to increase shelf-life. Additionally, agricultural practices, such as feeding animals corn-based diets, have increased LA in meats and dairy products.”
“As a result, we are consuming the highest amount of linoleic acid and have the highest recorded concentration of LA in our fatty tissue in human history,” McReynolds said. “As our bodies respond to stress or disease, we metabolise LA into the regulatory metabolites that were monitored in this paper. At higher concentrations, the immune system was unable to properly respond to infection, thereby promoting a sustained immune response. These observations are important in inflammatory-driven diseases, such as sepsis and COVID, but could also be important in understanding many of the increased chronic diseases we are seeing in our population.”
Intermittent fasting may not only be a hot dieting trend, but it also has broader health benefits, including helping to fight inflammation, according to a new study. The new research shows thatintermittent fasting raises the levels of galectin-3, a protein tied to inflammatory response.
Intermittent fasting has previously been shown to possibly improve health markers not related to weight.
“Inflammation is associated with higher risk of developing multiple chronic diseases, including diabetes and heart disease. We’re encouraged to see evidence that intermittent fasting is prompting the body to fight inflammation and lowering those risks,” said Benjamin Horne, PhD, principal investigator of the study and director of cardiovascular and genetic epidemiology at the Intermountain Healthcare Heart Institute.
The findings of the study were presented at the American Heart Association’s Scientific Sessions 2021.
These results form part of Intermountain’s WONDERFUL Trial which is studying intermittent fasting. It found that intermittent fasting causes drops in metabolic syndrome score (MSS) and insulin resistance.
This particular study followed 67 patients aged 21 to 70 who all had at least one metabolic syndrome feature or type 2 diabetes, and were also not taking anti-diabetic or statin medication, and had raised LDL cholesterol levels.
Of the 67 patients studied, 36 were prescribed an intermittent fasting schedule: twice a week water-only 24-hour fasting for four weeks, then once a week water-only 24 hour-fasting for 22 weeks. Fasts could not be done on consecutive days. The remaining 31 participants continued their routines.
After 26 weeks, participants’ galectin-3 was measured, and found to be higher in the intermittent fasting group. Lower rates of HOMA-IR (insulin resistance) and MSS (metabolic syndrome) were found, which researchers believe may be similar to the reported effects of SGLT-2 inhibitors.
“In finding higher levels of galectin-3 in patients who fasted, these results provide an interesting mechanism potentially involved in helping reduce the risk of heart failure and diabetes,” said Dr Horne, who added that a few members of the trial team completed the same regime before the study started to make sure that it was doable and not overly onerous for participants.
“Unlike some IF diet plans that are incredibly restrictive and promise magic weight loss, this isn’t a drastic form of fasting. The best routine is one that patients can stick to over the long term, and this study shows that even occasional fasting can have positive health effects,” he added.
The surprise discovery of a new type of cell explains how distress to the skin early in life may prime a person for inflammatory skin disease later, according to a new study in Nature. This finding will likely lead to treatments for autoimmune disorders like scleroderma, and inform understanding of inflammatory disease.
“The results reinforce the idea that what you’re exposed to initially may have lasting ramifications,” said lead researcher Michael Rosenblum, MD, PhD. “It appears that early exposure to inflammation can, through these cells we discovered, imprint an ability for tissues to develop inflammatory disease later in life.”
The team came across this new type of cell while investigating the effects of certain actions known to evoke immune response in mice. One of these actions involved knocking out a group of skin cells that suppress the immune system. Without that regulation, said Dr Rosenblum, a unique cell was observed that seemed to act as a shelter for pathogenic immune cells not typically seen in skin tissues.
“We had to knock out one cell population to see that they were controlling the growth and capacity of these other, unknown cells,” he said, noting that the new cells only became apparent in the tissue exposed to inflammatory triggers. “What normally would be a deserted island on the skin was now inhabited by all these strangers,” he said.
The team dubbed these strangers ‘TIFFs’ (Th2-interacting fascial fibroblasts) after the Th2 immune cells that they help to house. The location of TIFFs in the skin suggests that they belong to a group of cells that make up the fibrous connective tissue that is fascia, said lead author Ian Boothby, a graduate student in Dr Rosenblum’s lab.
“Because most organs have fascia of some sort, what we’re learning about TIFFs in skin may well be widely applicable to the rest of the body, meaning that these cells may play a role in a huge number of inflammatory diseases,” he said.
Boothby and Dr Rosenblum when skin without regulatory cells receives inflammatory triggers, the TIFFs spread like wildfire and become a sort of holding pen for the Th2 immune cells. Later in life, when there is even a small insult to the skin, Dr Rosenblum said, the TIFFs open their floodgates, unleashing the Th2 cells.
It seems that, through these cells, early exposure to inflammalation can leave a life-long imprint.
“All you need to do is push the immune system just a little bit, with a wound or with stress, to unleash all the pathogenic cells living in these TIFFs and create an exaggerated inflammatory response,” he said.
The researchers hypothesise that the exaggerated response may manifest as the creation of fibroses in the fascia, the driving force behind inflammatory skin diseases such as scleroderma.
To confirm the presence of TIFFs in human skin, the team obtained samples from volunteers with eosinophilic fasciitis (EF), a rare inflammatory disorder in which eosinophils build up in the skin fascia, the fibrous tissue between the skin and the muscles below it.
Comparing the EF samples to those of healthy skin, the researchers found TIFFs in both, but looked completely different. In healthy skin, the fascia forms a thin, spidery network between fat cells, while in the EF skin sample, the cells had expanded to form thick bands of fibrous tissue.
Revealing the mysteries of inflammation TIFFs appear to be present in every organ, said Dr Rosenblum, usually found in the fascia surrounding major organs and serve a role in maintaining structure. They’re also prone to interacting with immune cells. He postulates that TIFFs might have evolved as a sort of emergency brigade in case of injury, able to jump-start repair in the case of internal injury.
“In patients with scleroderma or other fibrosing diseases like EF, that repair program may be kind of co-opted, resulting in this chronic wound-healing response,” said Dr Rosenblum. “If we can understand the biology of these cells, we can come in with drugs that revert them back to what they’re supposed to be doing.”
In children with cystic fibrosis (CF), their lower airways have a higher burden of infection, more inflammation and lower diversity of microorganisms, compared to children with other illnesses who also have lung issues, researchers have found. They noted a clear divergence in these bacterial communities in toddlers, before progressive lung disease manifests in CF patients.
Their findings, published in the journal PLOS ONE, could help providers target specific pathogens earlier, treat them and potentially prevent more severe lung disease.
As lead author Jack O’Connor, at Ann & Robert H. Lurie Children’s Hospital of Chicago explained, “We compared lower airway samples from bronchoscopy in children with CF and disease controls across the age spectrum, and used genetic sequencing to identify microorganisms, finding that a few common cystic fibrosis pathogens begin to dominate at very early ages. Such a clear split from disease controls in this young age group has not been shown before. Our findings deepen our understanding of the disease trajectory in cystic fibrosis and could help improve outcomes through earlier intervention.”
Chronic airway infection and inflammation which leads to progressive, obstructive lung disease is the main cause of illness and death in people with cystic fibrosis.
Researchers tested lower airway samples from 191 patients (63 with cystic fibrosis) aged 0-21 years. The disease controls included patients with diverse conditions, such as cancer, immune deficiency and pneumonia. Using genetic sequencing, researchers were able to identify distinct pathogens that are more dominant at different ages in patients with cystic fibrosis.
“Establishing key age-related differences in lower airway bacterial communities and inflammation in patients with CF, especially during early childhood, may give us a window of opportunity for earlier and more precise treatment,” said senior author Theresa Laguna, MD, MSCS, Division Head of Pulmonary and Sleep Medicine at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If we can prevent worse infections, we could improve the quality of life and potentially expand the life expectancy of patients with CF.”
A study in rats showed that gut microbiomes and antibiotic use could modulate inflammatory pain.
Published in The Journal of Pain, the study examined the impact of antibiotics on the gut microbiome and how antibiotic use can alter inflammatory pain in subjects with or without access to exercise.
According to Glenn Stevenson, Ph.D., professor of psychology within the School of Social and Behavioral Sciences, this is the first publication to assess how antibiotic-induced changes to the gut microbiome impact inflammatory pain distal to the gut (in the limbs, for example).
The study determined the effects of vancomycin on inflammatory pain-stimulated and pain-depressed behaviours in rats, which was induced with formalin. Oral vancomycin administered in drinking water attenuated pain-stimulated behaviour, and prevented formalin pain-depressed wheel running. Faecal microbiota transplantation produced a non-significant trend toward reversal of vancomycin’s effect on pain-stimulated behaviour. Vancomycin depleted Firmicutes and Bacteroidetes gut populations while partially sparing Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut.
The results indicate that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude. Additionally, results indicated that the antibiotic-induced shift in gut amino acid concentrations may be a causal mechanism for this reduction in pain.
The research for this study took four years to complete, Prof Stevenson said, adding that the link between amino acids and pain reduction is “highly novel.”
Histamine from inflammation dampens serotonin levels and antidepressants’ ability to boost them, according to experiments in mice models.
The findings, published in The Journal of Neuroscience add to mounting evidence that inflammation, and the accompanying release of the molecule histamine, affects serotonin, a key molecule responsible for mood in the brain.
Inflammation triggers the release of histamine in the body, increasing blood flow to affected areas to flood them with immune cells. While these effects help the body fight infections, both long-term and acute inflammation is increasingly linked to depression. There is already strong evidence that patients with both depression and severe inflammation are the ones most likely not to respond to antidepressants.
Dr Parastoo Hashemi, Lead Author, Imperial’s Department of Bioengineering, said: “Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the ‘feel-good molecule’ serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression.”
Chemical messengers Serotonin is a key target for depression-tackling drugs, and selective serotonin reuptake inhibitors (SSRIs) inhibit the re-absorption of serotonin in the brain, allowing it to circulate for longer and improve mood.
However, although SSRIs bring relief to many who take them, an increasing number of people are resistant to it. This could be due to the specific interactions between chemical messengers, or neurotransmitters, including serotonin and histamine.
With this in mind, researchers set out to investigate the relationship between histamine, serotonin, and SSRIs. They created tiny serotonin-measuring microelectrodes and put them into the hippocampus of the brains of live mice, an area known to regulate mood. The technique, known as fast scan cyclic voltammetry (FSCV), allowed them to measure brain serotonin levels in real time..
After placing the microelectrodes, they injected half the mice with lipopolysaccharide (LPS), an inflammation-causing toxin found in some bacteria, and half the mice with a saline solution as a control.
Within minutes of LPS injection, brain serotonin levels dropped, whereas they remained the same in control mice, demonstrating the rapid action of inflammatory responses on the brain and serotonin. Since LPS cannot cross the blood-brain barrier, it could not cause the drop in serotonin. The inflammatory response triggered histamine in the brain which directly inhibited the release of serotonin by attaching to inhibitory receptors.
To counter this, the researchers administered SSRIs to the mice, but they were much less able to boost serotonin levels than in control mice. They posited that this is because the SSRIs directly increased the amount of histamine in the brain, cancelling out its serotonin boosting action.
The researchers then administered histamine reducing drugs alongside the SSRIs to counter histamine’s inhibitory effects, and saw serotonin levels rise back to control levels. This appears to confirm the theory that histamine directly dampens serotonin release in the mouse brain. These histamine reducing drugs cause a whole-body reduction in histamine and are distinct from antihistamines taken for allergies, which block histamine’s effects on neurons.
A new molecule of interest More work is needed before progressing to human studies. However, it is not currently feasible to use microelectrodes to make similar measurements in human brains, so the researchers are now looking at other ways to get a snapshot of the brain by looking at other organs which use serotonin and histamine, like the gut.
A team of researchers has identified how different people respond to the accumulation of dental plaque, helping us understand the vulnerability of some to serious conditions that lead to tooth loss and other problems.
The study was led by University of Washington researchers and recently published in the journal Proceedings of the National Academy of Sciences (PNAS).
Buildup of plaque, the sticky biofilm covering teeth and gums, can induce gingivitis, or gum inflammation if left unchecked. Gingivitis, in turn, can lead to periodontitis, a serious infection that can damage and destroy the gum and bones supporting teeth. As well as causing tooth loss, this chronic inflammation can also trigger heart disease, diabetes, cancer, arthritis, and bowel diseases.
The researchers also discovered a range of inflammatory responses to oral bacterial accumulation. When bacteria build up on tooth surfaces, it generates inflammation as the body responds. Two known major oral inflammation phenotypes were known: a high or strong clinical response and a low clinical response. The team identified a third phenotype, which they dubbed ‘slow’: a delayed strong inflammatory response in the wake of the bacterial buildup.
The study also found that subjects with low clinical response also showed a low inflammatory response for a variety of inflammation signals. “Indeed, this study has revealed a heterogeneity in the inflammatory response to bacterial accumulation that has not been described previously,” said Dr Richard Darveau of the UW School of Dentistry, one of the study’s authors.
Study co-author Dr Jeffrey McLean said, “We found a particular group of people that have a slower development of plaque as well as a distinct microbial community makeup prior to the start of the study.” The authors wrote that understanding the variations in gum inflammation could help screen for higher periodontitis risk. In addition, it is possible that this variation in the inflammatory response among the human population may be related to the susceptibility to other chronic bacterial-associated inflammatory conditions such as inflammatory bowel disease.
Additionally, the researchers found a novel protective response by the body, triggered by plaque accumulation, that can save tissue and bone during inflammation. This mechanism, which was apparent among all three phenotypes, utilises white blood cells known as neutrophils. In the mouth, they act something like cops on the beat, patrolling and regulating the bacterial population to maintain a stable condition known as healthy homeostasis.
In this instance, plaque is not a villain. To the contrary, the researchers said that the proper amount and makeup of plaque supports normal tissue function. Studies in mice have also shown that plaque also provides a pathway for neutrophils to migrate from the bloodstream through the gum tissue and into the crevice between the teeth and gums.
When healthy homeostasis exists and everything is working right, the neutrophils promote colonization resistance, a low-level protective inflammatory response that helps the mouth fend off an excess of unhealthy bacteria and resist infection. At the same time, the neutrophils help ensure the proper microbial composition for normal periodontal bone and tissue function.
The researchers’ findings underscore why dentists preach the virtues of regular brushing and flossing, which prevent too much plaque buildup. “The idea of oral hygiene is to in fact recolonise the tooth surface with appropriate bacteria that participate with the host inflammatory response to keep unwanted bacteria out,” Dr Darveau explained. The bacteria start repopulating the mouth’s surfaces spontaneously and almost immediately afterward, Dr Darveau said.
Researchers have discovered that the pituitary gland in mice ages due to an age-related form of chronic inflammation — which raises the possibility of slowing or even partially repairing this process.
The pituitary gland is a small, globular gland located underneath the brain that plays a major role in the hormonal system, explained Professor Hugo Vankelecom, a stem cell biologist from the Department of Development and Regeneration at KU Leuven. “My research group discovered that the pituitary gland ages as a result of a form of chronic inflammation that affects tissue and even the organism as a whole,” he said. “This natural process usually goes unnoticed and is referred to as ‘inflammaging’ — a contraction of inflammation and ageing. Inflammaging has previously been linked to the ageing of other organs.”
Because of the pituitary’s pivotal role in the body, its ageing may contribute to the reduction of hormonal processes and hormone levels in our body – such as in menopause.
The study also provides significant insight into the stem cells in the ageing pituitary gland. In 2012, Prof Vankelecom and colleagues showed that a prompt reaction of these stem cells to injury in the gland leads to repair of the tissue, even in adult animals.
“As a result of this new study, we now know that stem cells in the pituitary do not lose this regenerative capacity when the organism ages. In fact, the stem cells are only unable to do their job because, over time, the pituitary becomes an ‘inflammatory environment’ as a result of the chronic inflammation. But as soon as the stem cells are taken out of this environment, they show the same properties as stem cells from a young pituitary.”
Could damage be repaired?
This insight opens up a number of potential therapeutic avenues: would it be possible to reactivate the pituitary? This wouldn’t just involve slowing down hormonal ageing processes, but also repairing the damage caused by a tumour in the pituitary, for example.
“No fewer than one in every 1000 people is faced with this kind of tumour — which causes damage to the surrounding tissue — at some point.
“The quality of life of many of these patients would be drastically improved if we could repair this damage. We may be able to do so by activating the stem cells already present — for which our present study also provides new indications — or even by transplanting cells. That said, these new treatment options are not quite around the corner just yet, as the step from fundamental research to an actual therapy can take years to complete. For the time being, our study sets out a potential direction for further research.”
The study also brings up another interesting approach: using anti-inflammatory drugs to slow down pituitary ageing or even rejuvenate an ageing pituitary. “Several studies have shown that anti-inflammatory drugs may have a positive impact on some ageing organs. No research has yet been performed on this effect in relation to the pituitary.”
From mice to humans
Since Prof Vankelecom and colleagues studied the pituitary of mice, further research is required to demonstrate whether their findings also apply to humans. Prof Vankelecom cautioned, however: “Mice have a much greater regeneration capacity than humans.
“They can repair damaged teeth, for instance, while humans have lost this ability over the course of their evolution. Regardless, there are plenty of signs suggesting that pituitary processes in mice and humans are similar, and we have recent evidence to hand that gene expression in the pituitaries of humans and mice is very similar. As such, it is highly likely that the insights we gained will equally apply to humans.”
Source: KU Leuven
Journal information: Vennekens, A., et al. (2021) Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2100052118.
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