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Gut Microbes Control the Body’s Thermostat
Summary: In both healthy people and those with life-threatening infections, the gut microbiome appears to help regulate body temperature.
Source: University of Michigan
What’s considered normal body temperature varies from person to person, yet overall, the average basal temperature of the human body has decreased since the 1860s for unknown reasons. A study points to the gut microbiome as a potential regulator of body temperature, both in health and during life-threatening infections.
The study, led by Robert Dickson, M.D., and his colleagues at U-M Medical School, used health record data from patients hospitalized with sepsis and mouse experiments to examine the interplay between the mix of bacteria residing in the gut, temperature fluctuation, and health outcomes.
Sepsis, the body’s response to a life-threatening infection, can cause drastic changes in body temperature, the trajectory of which is linked to mortality.
Work published in the American Journal of Respiratory and Critical Care Medicine in 2019 has demonstrated that hospitalized patients with sepsis vary widely in their temperature responses, and this variation predicts their survival.
“There’s a reason that temperature is a vital sign,” said Kale Bongers M.D. Ph.D., a clinical instructor in the Department of Internal Medicine and lead author of the study. “It’s both easily measured and tells us important information about the body’s inflammatory and metabolic state.”
Yet the causes of this temperature variation, both in sepsis and in health, have remained unknown.
“We know that temperature response is important in sepsis, because it strongly predicts who lives and who dies,” said Dickson. “But we don’t know what drives this variation and whether it can modified to help patients.”
To try to understand the cause of this variation, the team analyzed rectal swabs from 116 patients admitted to the hospital. The patients’ gut microbiota varied widely, confirming that it is a potential source of variation.
“Arguably, our patients have more variation in their microbiota than they do in their own genetics,” said Bongers. “Any two patients are more than 99% identical in their own genomes, while they may have literally 0% overlap in their gut bacteria.”
The authors found that this variation in gut bacteria was correlated with patient’s temperature trajectories while in the hospital. In particular, common bacteria from the Firmicutes phylum were most strongly associated with increased fever response. These bacteria are common, variable across patients, and are known to produce important metabolites that enter the bloodstream and influence the body’s immune response and metabolism.
To confirm these findings under controlled conditions, the team used mouse models, comparing normal mice with genetically identical mice that lack a microbiome. Experimental sepsis caused dramatic changes in the temperature of conventional mice but had a blunted effect on the temperature response of germ-free mice. Among mice with a microbiome, variation in temperature response was strongly correlated with the same bacterial family (Lachnospiraceae) that was found in humans.
“We found that the same kind of gut bacteria explained temperature variation both in our human subjects and in our laboratory mice,” said Dickson. “This gave us confidence in the validity of our findings and gives us a target for understanding the biology behind this finding.”
Even in health, mice without a microbiome had lower basal body temperatures than conventional mice. Treating normal mice with antibiotics also reduced their body temperature.
The study highlights an underappreciated role of the gut microbiome in body temperature and could explain the reduction in basal body temperature over the past 150 years.
“While we certainly haven’t proven that changes in the microbiome explain the drop in human body temperature, we think it is a reasonable hypothesis,” said Bongers. “Human genetics haven’t meaningfully changed in the last 150 years, but changes in diet, hygiene, and antibiotics have had profound effects on our gut bacteria.”
Further research is needed to understand whether targeting the microbiome to modulate body temperature could help alter the outcome for patients with sepsis.
See also
About this neuroscience research news
Author: Press Office
Source: University of Michigan
Contact: Press Office – University of Michigan
Image: The image is in the public domain
Original Research: Closed access.
“The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health” by Kale S Bongers et al. American Journal of Respiratory and Critical Care Medicine
Abstract
The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health
Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown.
Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature.
Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal lipopolysaccharide in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals.
Measurements and main results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that composition of patients’ gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures when compared to controls. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice.
Conclusions: The gut microbiome is a key modulator of body temperature variation both in health and critical illness, and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.
Important Factors for Regulating the Body’s Immune Response
Summary: Researchers identified differences in isoforms that control Treg cells and how that affects the body’s immune system response.
Source: Indiana University
Researchers at Indiana University School of Medicine are learning more about how special regulatory T cells can impact the immune system’s response and how those cells could be manipulated for potential treatments for food allergies and autoimmune diseases.
In a study recently published in Science Immunology, researchers focused on regulatory T cells, or Treg cells, that regulate immune responses in the body and keep the immune system in order while fighting pathogens.
In some cases, the immune system becomes overly responsive, leading to autoimmune diseases, such as Type 1 diabetes or lupus, food allergies or other issues. Researchers were able to identify the differences in isoforms that control Treg cells and how that affects the body’s immune function.
“There is a particular gene that controls this regulatory group of T cells, which controls immune response,” said Baohua Zhou, PhD, lead author of the study and associate professor of pediatrics for IU School of Medicine Department of Pediatrics.
“Treg cells can help maintain the right balance to help the immune system not respond too strongly or too weakly.”
The human gene FOXP3 produces two major isoforms through alternative splicing—a longer isoform and a shorter isoform.
The two isoforms are naturally expressed in humans, but their differences in controlling regulatory T cell phenotype and functionality has been unclear. In this study, researchers showed patients expressing only the shorter isoform fail to maintain self-tolerance and develop issues like immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome.
They uncovered different functions of the FOXP3 isoforms to regulate Treg cells and immune homeostasis.
“Now that we know the different functions of the isoforms, we hope to study how to change them, which could lead to new treatments for autoimmune diseases and allergies,” Zhou said.
“We could also potentially manipulate them to keep the body from responding improperly to diseases like cancer. If T reg cells are suppressing the antitumor response, can we change that?”
About this immune system research news
Author: Christina Griffiths
Source: Indiana University
Contact: Christina Griffiths – Indiana University
Image: The image is in the public domain
Original Research: Closed access.
“FOXP3 exon 2 controls Treg stability and autoimmunity” by Baohua Zhou et al. Science Immunology
Abstract
See also
FOXP3 exon 2 controls Treg stability and autoimmunity
Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing—a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2).
The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear.
In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.
Mice with Foxp3 exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice.
Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci.
These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Treg stability and immune homeostasis.
Obesity Might Be a Result of Your Body’s Chemistry
Scientists at Clemson University are making progress in understanding the link between specific enzymes that are naturally generated in the body and their involvement in managing obesity and controlling liver diseases.
Scientists are investigating the connections between obesity, age, and body chemistry.
Obesity is described as an abnormal or excessive buildup of fat that poses a health concern. This condition has grown to become widespread across the United States. According to statistics gathered by the Centers for Disease Control and Prevention (CDC) in 2017-18, more than 42 percent of U.S. adults and 19 percent of U.S. youths are obese.
Unfortunately, obesity rates in adults and children continue to rise. From 1975 to 2016, the worldwide prevalence of overweight or obese children and adolescents aged 5–19 years grew more than fourfold, from 4% to 18%. Obesity is generally thought to be caused by eating too much and moving too little, however recent studies suggest other factors may be in play.
A Clemson University research team is making strides in understanding the link between certain enzymes naturally generated in the body and their role in managing obesity and controlling liver diseases.
Three Clemson researchers and Emory University School of Medicine colleagues analyzed male mice lacking the Cyp2b enzyme and how the enzyme’s absence impacted the mice’s metabolism.
According to William Baldwin, a professor and graduate program supervisor at Clemson’s Department of Biological Sciences, the study was prompted in part by a simple observation: male mice without the Cyp2b enzyme were gaining weight. Female Cyp2b-null mice did not show the same effect.
“We noticed that our Cyp2b-null mice were heavier,” said Baldwin, a professor in the department of biological sciences. “They are more prone to obesity — at least, diet-induced obesity — especially in males than are wild-type mice, and we were trying to find out why that is.”
While the observation that tipped off the researchers was pretty straightforward, it turned out that understanding the interactions behind the weight gain would be much more complex.
“It would be nice if there was a nice, simple answer,” Baldwin said, “but there probably isn’t a nice, simple answer.”
Clemson University researcher William Baldwin is studying the connection between obesity, age, and body chemistry. Credit: Clemson University College of Science
Variety of roles
Baldwin noted the complexities of several chemical processes involving the CYP enzyme, which is part of an enzyme superfamily that performs a number of functions in humans. According to him, the Cyp2b enzymes assist in the metabolization of certain toxins and drugs in order to remove them from the body.
But those same CYP enzymes have other jobs, as well. “They metabolize bile acids; they metabolize steroid hormones; they metabolize polyunsaturated fats from our diet,” Baldwin said. “This means that all these things can interact, too. If you have a diet that’s full of fat, that might inhibit your drug metabolism. Of course … drugs might inhibit your fat metabolism, might affect your steroid metabolism, and so on.”
The researchers also looked at the association between “perturbed lipid profiles” and disease.
Disease susceptibility and overall health is greatly affected by changes to the lipidome, the researchers noted. High-fat diets, such as the Western diet, cause obesity and drastically alter the hepatic lipidome, and perturbed lipid profiles are associated with specific liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Impact of age and diet
Baldwin has previously led research examining the link between diet and environmental toxins. The most recent study looked at how aging and diet affect these metabolic processes.
“What does a poor diet do to us? What does age do to us? That’s kind of the idea here,” Baldwin said of the latest research. “We’re looking at these enzymes; what might happen over time to our profiles in this mouse model compared to just a wild-type mouse. What might happen over time with a high-fat diet, what might happen as we age, and how does it differ between this one mouse model, which doesn’t have these enzymes, compared to one that does have these enzymes.”
Simply put, Baldwin said, “One of the things that we saw, and not surprisingly, is that getting older is bad. It’s tougher for the mice to regulate body weight. They gain weight. The weight that they have is more white adipose tissue [connective tissue mainly comprising fat cells]. … And some of these things were a little bit worse in the mice that lacked the Cyp2b enzymes. They were a little bit heavier. They had a little more fat than their counterparts. Their livers were a little bit bigger and a little bit less healthy. So they had a lot of those things that we associate with age going on.”
Diet also had an impact on the mice’s health.
“Of course, diet didn’t help, as well,” Baldwin continued. “It’s the same case: Eating a poor diet caused weight gain, and it was a little worse with these [Cyp2b-null] mice, probably because of poor metabolism.”
He said the exact mechanism by which the Cyp2b enzyme works is not completely understood.
“You take away an enzyme that helps metabolize these, but I don’t think it is really important that it helps get rid of the fat, but that it lets the body know the fat is there. It probably produces signaling molecules that say ‘Hey, we need to decide what we’re going to do with this fat; we need to distribute this fat.’ That kind of information. That’s just an educated guess at this time, but I think that’s probably what’s happening.”
Differences in humans
Baldwin said his current research takes a closer look at the mechanisms that are in play and how they differ in a human model from the mouse studies.
He said the research, which will be a part of an as-yet-unpublished paper, indicates that the mouse and the human enzymes probably don’t work the same. “The human enzyme seems to cause us to keep some of the fat in the liver, and the mouse enzyme seems to drive that to the white adipose tissue. There are hints here in this paper that that’s the case,” Baldwin said.
A National Institutes of Health grant supported the research.
Reference: “Age- and Diet-Dependent Changes in Hepatic Lipidomic Profiles of Phospholipids in Male Mice: Age Acceleration in Cyp2b-Null Mice” by Melissa M. Heintz, Ramiya Kumar, Kristal M. Maner-Smith, Eric A. Ortlund and William S. Baldwin, 29 March 2022, Journal of Lipids.
DOI: 10.1155/2022/7122738
New cancer treatment uses body’s cellular waste disposal to flag harmful proteins | Cancer research
Scientists are perfecting a new anti-cancer treatment that exploits the body’s own cellular waste disposal system. Some drugs are already producing promising results, and the number of new medicines is expected to rise in the near future with the opening of a British centre dedicated to using the technique.
Fifteen researchers will work at the Centre for Protein Degradation which has been set up through a £9m donation to the Institute of Cancer Research, in London, by philanthropists David and Ruth Hill.
Many modern cancer drugs work by blocking the function of harmful proteins, said Professor Ian Collins, head of the new centre. However, this technique is different, he added. It wipes them out completely.
“Our cells have evolved a highly efficient technique for removing harmful proteins. It’s part of the everyday business of life. However, our cells’ protein degradation processes only recognise a specific number of proteins.
“Science has now found a way to add to that number – to put flags on to new proteins that the cell wouldn’t otherwise touch but which we now realise are harmful and involved in tumour development.
“We are saying to our cells: please can you add this harmful protein to the trash that you are taking out?” An early example of this approach is provided by the protein degradation drug lenalidomide, which is used to treat the blood cancer myeloma, and which has been shown to improve patients’ quality of life.
“I’d never even heard the word myeloma,” said Cecelia Brunott, 45, from Farnham in Surrey, who was diagnosed in 2020. “Today it is working to keep my condition stable and keep my myeloma in check for longer.”
Collins said drugs like lenalidomide could pinpoint a molecule that would otherwise continue to carry out its function in promoting cancer. “Essentially, it makes it visible to the cell’s waste disposal machinery. It flags it up for disposal and ensures it is shredded and destroyed.”
A similar type of drug has also been found to target breast cancer. Known as a selective oestrogen receptor degrader, it degrades a protein that is an important driver of breast cancer.
“At present, much effort is concentrating on using protein degradation to develop new cancer drugs,” added Collins.
“However, we hope that in future this technique will be used to develop medicines for tackling other types of disease. It has powerful potential and promise.”