The human immune system changes with age. Immune responses start to become less robust as people get older, which makes them more vulnerable to certain infections and diseases. However, immune system aging looks different from person to person. Research has shown that changes to the composition and diversity of the microorganisms in the gut may explain these differences in immune system aging.
The gut microbiome also helps us to regulate our inflammatory reactions. Inflammation helps the body fight microorganisms that cause disease, and helps repair damaged tissues. However, as the composition of our gut microbiome changes with age, a low level of inflammation can become constant throughout the body. This is called inflammaging.
When inflammaging develops in the gut, it leads to a decrease in immune responses, which puts people at a higher risk for infection and disease.
Let’s take a closer look at the gut microbiome and how it changes with age.
Gut microbiome imbalances in older adults
An overview of the four major gut microbial phyla. (Flore Van Leemput and Narveen Jandu), Author provided (no reuse)
Our gastrointestinal tract can be compared to a densely populated city inhabited by a variety of different bacteria, fungi, archaea and viruses collectively called the gut microbiota. In fact, compared to other parts of the body, the gut microbiome has the largest number of bacteria. In a healthy gut microbiome, there are four dominant families (or phyla) of microorganisms, including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria.
The gut microbiome and immune system work closely together. The microorganisms in the gut send out signals that are detected by immune sensors. This allows the immune system to regulate the beneficial bacteria in the gut, helping maintain immune homeostasis. Through this interaction, the adaptive immune system also receives stimuli from harmful substances called antigens, which trigger an immune reaction.
Over time, the shortage of beneficial bacteria such as Firmicutes in older adults starts to compromise the integrity of their intestinal barrier, causing it to become leaky. This is because the Firmicutes family plays a very important role in keeping the intestinal wall healthy and strong by producing a short-chain fatty acid called butyrate. Short-chain fatty acids such as butyrate help provide nutrients to strengthen the intestinal wall, inform immune responses and lower inflammation.
When the body is exposed to these factors on a regular basis, cellular senescence occurs. Cellular senescence is a state in which cell growth is permanently arrested, which means that cells are no longer able to self-renew. Eventually, this leads to a decrease in immune responses, which are important to prevent foreign substances and pathogens from entering the body.
The microbiome and the human gut work together to maintain health, depicted as a handshake. The green arrows of the inner cycle represent a positive cycle, providing protection to the human gut and allowing it to provide the gut bacteria with a favourable habitat. The red arrows of the outer cycle represent a negative cycle that leads to dysbiosis and reduced immunity. (Flore Van Leemput and Narveen Jandu), Author provided (no reuse)
Maintaining a healthy balance of gut microbiota
There is a common saying that claims “you are what you eat.” Indeed, nutrition and diet play an important role in regulating the number of different microorganisms that live in the gut. This means that diet may also play a key role in the immune function of older adults.
It is clear that the immune system has an intricate relationship with the gut microbiome. A healthy and well-balanced gut microbiome will strengthen the intestinal barrier, which helps to reduce inflammation throughout the body and support the immune system.
To achieve this, it is important to maintain a healthy and well-balanced lifestyle as we grow older. This can include lower intake of dairy products and red meats, and harnessing the benefits of probiotics and prebiotics.
New gene-editing approach to studying immune gene function could improve treatments for cancer, other diseases
Over the past two decades, the immune system has attracted increasing attention for its role in fighting cancer. As researchers have learned more and more about the cancer-immune system interplay, several antitumor immunotherapies have become FDA-approved and are now regularly used to treat multiple cancer types.
Yet despite these advances, much remains unknown about how the immune system fights cancer — and about immunity in general, said Martin LaFleur, a postdoctoral fellow in the laboratory of Arlene Sharpe, chair of the Department of Immunology in the Blavatnik Institute at Harvard Medical School.
CRISPR-based gene editing, in which scientists modify the genome using a tool developed just over a decade ago, has become a mainstay of biological discovery, providing relatively quick insight into the function of individual genes and targets for new therapies.
However, LaFleur said, this approach is not without challenges. Chief among them is that it is hard to modify immune cells without changing their biology, which hampers the ability to study immune cell behavior in its full complexity in a living organism.
Now, LaFleur, Sharpe, and their team have succeeded in bypassing this hurdle by deploying CRISPR in a new way to study the function of immune genes.
Their work, described in two papers — one in Nature Immunologyand one in the Journal of Experimental Medicine — could eventually yield insights about cancer immunology as well as about other diseases driven by immune system dysfunction.
Harvard Medicine News spoke with LaFleur about what this advance means for the future of immunology research.
Harvard Medicine News: Let’s set the stage with a refresher on how CRISPR works.
LaFleur: Programmable CRISPR-based gene editing was developed in 2012 and became such a powerful tool for biologic research that its discoverers won the Nobel Prize in Chemistry in 2020.
The CRISPR gene-editing system uses an enzyme called Cas-9 that acts like a pair of molecular scissors that cuts both strands of DNA and in doing so disrupts or knocks out the function of a gene. To select the gene to knock out, this system uses a complementary piece of RNA that matches the gene and acts as a guide. It’s a very flexible approach for very quickly knocking out and studying the function of almost any gene you want.
HMNews: How is CRISPR used to understand the immune function of genes?
LaFleur: Immune cells interact with a lot of other cell types that can’t be modeled well in petri dishes, so we prefer immune studies to happen inside a living organism like a mouse — a far more reliable way to capture the complexity of cell-to-cell interactions as they occur in the body rather than in a lab dish. CRISPR editing inside the body is difficult, so immune cells typically need to come out and be modified using this tool in a petri dish. The edited cells are then put back into the body.
However, only certain immune cell types can be incorporated efficiently when transferred back into a mouse. Also, the actual process of manipulating immune cells in a dish can change their biology, so you may not be studying what you actually want to study once they’re removed from the body.
Also, CRISPR had been used only to turn off a single gene at a single time in immune cells. But our cells contain thousands of genes, so what if we want to knock out multiple genes in different cell types at different times in the same animal? This would provide greater insight into the complexities of genes and their interactions in immune cells over time.
HMNews: How does your new study address these challenges?
LaFleur: We decided to take a completely different approach for using CRISPR. Rather than directly modify the immune cells we’re interested in, we modified their precursors, the stem cells found in bone marrow that produce all immune cells. We removed those from mice and used CRISPR to knock out the genes we were interested in, and then replaced these stem cells in mice whose native bone marrow stem cells had been removed. We call this system CHimeric IMmune Editing, or CHIME.
In an earlier study, we used CHIME to knock out a gene called Ptpn2, which has shown some promise for cancer immunotherapy, one of the focuses of the Sharpe Lab. When we deleted that one gene in a subset of immune cells known as CD8+ T cells, they became better cancer fighters.
With our Nature Immunologystudy, we wanted to see if we could modify CHIME and make it both more precise and more versatile. We used it to knock out two genes at once in several different cell types, we deployed it to target genes specifically in a single cell type, we used CRISPR to disrupt genes in modified cells once they were already back inside the animal, and we also used it to knock out two different genes at different points in time.
We used different tactics, such as packaging multiple guide RNAs together and using a trick that disables genes only under certain circumstances, such as when mice receive a drug. We were able to demonstrate that each of these strategies is feasible.
HMNews: What is your ultimate goal with this research?
LaFleur: Our ultimate goal is to better understand the immune system, particularly in its capacity to fight cancer. We want to encourage strong anticancer immunity — meaning we want to optimize how immune cells fight tumors — but also want spare healthy cells and tissues from the immune attack. This requires a very nuanced calibration of the immune system and can be a tricky balance.
Moreover, the benefits could extend beyond cancer and be applied to many other diseases driven by the immune system, including autoimmune conditions.
HMNews: What are your next steps?
LaFleur: We just published a second paper in the Journal of Experimental Medicine that lays out a framework for the field in studies using CRISPR to screen immune gene function in living animals. Central to our framework is adding a genetic “barcode” to CRISPR-edited immune cells so we can track them as they multiply and spread within animals.
We’re hoping that this framework and CHIME will give researchers new tools to study immune cells in cancer or any other disease model of their choice, eventually leading to new immune-centered therapies.
Design by MNT. Photography by sanjeri/Getty Images & CHRISTOPH BURGSTEDT/SCIENCE PHOTO LIBRARY/Getty Images
Researchers are reporting that some early-stage cancer cells activate a gene that helps hide them from the body’s immune response.
They say that identifying this uptick in gene expression among cancer cells could lead to new pathways for early diagnosis and future treatment of colon cancer.
Experts say more research is needed, however, to confirm these findings and explore new potential therapies and treatments.
Early-stage colon cancer cells use special strategies to evade the body’s natural immune responses to become larger tumors, according to a new studyTrusted Source from the Massachusetts Institute of Technology and the Dana-Farber Cancer Institute.
At the most fundamental level, cancer is what happens when cell division runs amok and cells grow uncontrollably.
One of the jobs of the body’s immune system is to recognize and remove these abnormal cells before they proliferate too much.
Identifying where the immune system falters in handling cancerous cells, therefore, is one of the most important areas of study for future cancer treatment and one of the targets of next-generation cancer drugs.
Looking at colon cancer tumors implanted in mice, the researchers found early-stage cancer cells produced and activated a gene called SOX17, which helps hide these cells from the immune system.
In addition, they said SOX17 activation ensures cells will produce fewer molecules called MHC proteins, which are proteins that ensure cancer-associated antigens are visible to the immune system. SOX17 can also stop the production of key receptors that would instruct the immune system to order these cancerous cells to self-destruct.
“Activation of the SOX17 program in the earliest innings of colorectal cancer formation is a critical step that shields precancerous cells from the immune system. If we can inhibit the SOX17 program, we might be better able to prevent colon cancer, particularly in patients that are prone to developing colon polyps,” said Dr, Omer Yilmaz, a study author and an MIT associate professor of biology and a member of MIT’s Koch Institute for Integrative Cancer Research, in a press release.
The scientists also found that as these colon cancer cells grew into larger tumors and metastasized to other organs, the expression of SOX17 was diminished.
“This is a very important study because it provides insight into what triggers early colon cancer to develop and the importance of the protective effect of the immune system,” said Dr. Anton Bilchik, a surgical oncologist and chief of medicine and director of the Gastrointestinal and Hepatobiliary Program at Providence Saint John’s Cancer Institute in California.
“Cancer research is rapidly evolving to improve our understanding of what causes cancer cells to form and then grow,” Bilchik, who wasn’t involved in the study, told Medical News Today. “This is particularly important since most cancers do not have a clear cause and cancer continues to be the second leading causeTrusted Source of death in the U.S. This study provides not only a pathway for cancer development but also potential targets for diagnosis and treatment.”
This research specifically looked at colon cancer cells and is not generalizable to all cancers, which encompass a host of mechanisms of action of uncontrolled cell division.
In some cases, as with leukemia, cancers don’t necessarily produce tumors.
However, this latest research does add to the growing body of knowledge around cancer cell immune evasion and cancer immunotherapy, which is currently used as a target for many cancer therapeutics. More insight into the interaction of the immune system with cancer may help develop novel treatments for future cancers — which could involve helping immune systems remove these previously hidden cancer cells themselves.
“The state of cancer research is rapidly advancing with a strong focus on understanding the molecular mechanisms of cancer development and progression,” said Dr. Wael Harb, a hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast Medical Center in California and vice president of medical affairs at Syneos Health.
“Studies like this contribute to our knowledge by identifying new biomarkers and potential therapeutic targets, broadening our understanding of cancer, and opening up new avenues for treatment,” Harb, who wasn’t involved in the study, told Medical News Today.
Experts say this study can potentially help more immediately in the early diagnosis of colon cancers.
“The implications for diagnosis are significant,” Harb said. “By identifying SOX17 up-regulation as a marker for early colorectal cancer, this research could lead to improved screening methods. Early detection of SOX17 could help in identifying patients at risk for more aggressive disease progression.”
Developing treatments will likely take even longer than diagnostics, but this research represents an important step in the process, experts said.
“These findings suggest new therapeutic targets,” Harb noted. “By understanding how SOX17 contributes to immune evasion, researchers can develop strategies to counteract this mechanism, potentially leading to treatments that enhance the immune system’s ability to target cancer cells.”
The researchers pointed out that because of the role of the SOX17 gene, it may be difficult to target for treatment with drugs. The next step is to try to find drugs that might interrupt mechanisms that SOX17 interacts with.
“There are many reasons that immune cells are less effective at controlling tumors,” said Dr. Daniel Landau, an oncologist and hematologist with the Mesothelioma Center at asbestos.com who was not involved in the study.
“I’ve often told patients that our immune system is most adept at destroying things that originated outside of our bodies,” Landau told Medical News Today. “The immune cells recognize antigens and when antigens are ‘foreign,’ the immune cells know to attack. Given that cancer cells originate inside the body, the immune cells don’t recognize them as foreign.”
“This is a very new discovery and confirmatory studies need to be completed, but given the evolution that cancer care has been undergoing, more ways of supporting the immune system will be needed. If a SOX 17 inhibitor could be developed, it could perhaps work similarly to the PD1/PDL1 blockers [for other cancer treatment] that are currently in widespread use,” he added.
Gene-editing strategies that allow stem cells to evade the immune system offer hope for universal cell-replacement therapies
Gene-editing systems, such as CRISPR-Cas9, can be used to give stem cells immune-evasive properties
After decades of development, the dream of regenerative medicine has become a clinical reality — in part. Researchers can now cultivate stem cells in a laboratory, transform them into specialized cell types and then transplant them into people to alleviate disease.
In theory, this strategy promises an endless supply of replacement parts for ailing and ageing bodies: neurons to combat Parkinson’s disease, insulin-producing pancreatic cells to reverse type 1 diabetes, heart muscle cells to enhance cardiac function, and more.
But there’s a catch: therapies derived from stem cells must be customized to the patient — a process that is both slow and expensive. Or they can be made using donor cells. But, because the immune system tends to reject foreign cells, these ‘allogeneic’ off-the-shelf treatments require the concurrent administration of immune-dampening medicines — a strategy that raises the risk of complications such as infection and cancer.
Now, researchers are exploring a third approach — one that could fully realize the vision of mass-produced cell therapies for everyone, without the need for immune suppression.
By harnessing the power of gene-editing techniques, particularly CRISPR–Cas systems, to endow stem cells with immune-evasive properties, researchers can fashion stem cells that circumvent the immune system’s recognition mechanisms. They can also incorporate fail-safe features to ensure that the cells can be eliminated in the event of unforeseen complications. Such ‘stealth’ cells could, in principle, underpin a wide range of cell-replacement therapies, and billions of dollars have been invested in this work over the past five years.
The idea still requires validation. Only a small number of people have so far received any form of cell-replacement therapy derived from immune-edited stem cells, and no clinical results have yet been publicly disclosed. But with more products of this kind slated to enter human testing later this year, researchers are optimistic.
“We know in theory that it will work,” says Torsten Meissner, an immunologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts, who points to the natural precedent of immune evasion to underscore his conviction: “Tumours have figured it out. Viruses have figured it out. Pregnancy is the other example.” Now, he says, biotechnology companies just need to work out how to emulate the same tactics for therapeutic gain.
Incognito mode
Strategies differ, but there are some gene edits that all researchers agree must underpin any universal stem-cell-derived therapy. There is also widespread consensus that the optimal product should incorporate as few edits as possible, both to minimize the potential for unintended genetic consequences and to streamline manufacturing and regulatory approval.
Beyond that, the scientific community is divided. The complexities of the immune system have fuelled spirited debates over the exact genetic manipulations necessary to create a cell therapy that is both capable of bypassing immune defences and delivering meaningful health benefits.
“The immune system is pervasive and persistent,” says Charles Murry, a cardiovascular pathologist at the University of Washington in Seattle and chief executive of StemCardia in Seattle, one of a growing number of biotechnology companies developing gene-editing strategies to overcome immune barriers in regenerative cell treatments.
It might take the immune system a while to find donor cells, Murry notes, “but find them it does. It’s ancient, smart and has lots of tricks up its sleeves.” Researchers must, therefore, be equally crafty when designing cells to evade it.
In most cases, the process starts by disrupting at least one part of the cell’s major histocompatibility complex (MHC), a cluster of proteins that functions like a molecular identity card, displaying unique pieces of cellular information that tell the immune system’s foot soldiers — a group of cells known as T lymphocytes — whether the cell is friend or foe.
“That’s the ‘universal’ element of the universal donor cell,” Murry explains. This edit strips the transplanted cell of its enemy identity, allowing it to seamlessly blend into its new environment and evade T-cell detection.
But the lack of MHC expression also presents a problem. Without the usual distinguishing markers of either ally or adversary, the edited cell becomes susceptible to attack by a different set of immune actors — natural killer (NK) cells, which have evolved to target and eliminate abnormal cells, including those without the proper MHC signatures.
To counteract this vulnerability, some researchers reintroduce genes that encode specific MHC antigens — ones that allow the cell to temper NK cells without inciting T-cell responses. Others are putting in genes that express ‘checkpoint’ proteins, molecules designed to directly curb the activity of NK cells.
Sana Biotechnology in Seattle, which favours the latter approach, reported last year that just three edits — two to eliminate MHC expression and one to boost expression of a checkpoint protein called CD47 — were sufficient to shield cells of rhesus monkeys (Macaca mulatta) from the animals’ immune systems1. It also showed that human cells, modified in the same manner, could ameliorate diabetes when transplanted into a mouse model2.
In November, Sana announced that it had the go-ahead to begin testing, in people, of donated human pancreatic cells that had been edited in this way. Trials of a stem-cell-derived product are likely to follow.
But not everyone has managed to replicate the findings around CD47. And with conflicting reports about how best to restrain NK-cell activity, stem-cell biologist Audrey Parent at the University of California, San Francisco (UCSF), sees that piece of the immune-evasion puzzle as the primary bottleneck in the field. “The NK cell part is not resolved yet,” she says.
Covert agents
Disagreement around NK-cell inhibition arises, at least in part, from the various methods laboratories use to assess the modified cells’ ability to evade immune detection. Although most research groups evaluate their edited stem cells in engineered mice with human-like immune systems, these ‘humanized’ models cannot faithfully replicate the complete immune response that cell products will face in people’s bodies.
Pancreatic cells could potentially be edited to treat diabetes
Conversely, others generate gene-edited stem cells from monkeys and transplant them into other monkeys, mirroring the clinical scenario with humans. But this strategy is constrained by ethical concerns and the expense of experimentation with primates. Moreover, monkeys, although genetically similar to people, have distinct immune systems that might not faithfully reflect human responses.
Deepta Bhattacharya, an immunologist at the University of Arizona in Tucson, favours a different approach. When it comes to pushing the boundaries of immune evasion, he advocates evaluating universal gene-edited products that are intended for human use in mice with fully intact, natural immune systems. If cell therapies can pass this cross-species test, he reasons, they should be well-suited for transplantation into any human recipient.
Early this year, Bhattacharya and his colleagues reported that human stem cells containing a battery of 12 gene edits could survive in mice for months, with no signs of immune recognition or rejection3.
“A few of [the edits] we don’t think we actually need,” Bhattacharya says. But some edits that he considers crucial for thwarting rejection target a branch of the body’s natural defence mechanism known as the complement system. This system acts as a first line of defence against potential invaders by preparing antibodies to mark and eliminate foreign cells.
“Antibodies are tricky,” says Chad Cowan, co-founder and chief executive of Clade Therapeutics, a Boston-based biotech firm that is developing stem-cell-derived therapies for cancer and autoimmune conditions. (Bhattacharya is also a scientific co-founder.) “I think we’ve solved the cellular side of the equation,” Cowan says. “But antibodies actually turn out to be a bigger barrier than we thought.”
Clade’s solution, currently unpublished, involves engineering cells to secrete an enzyme that degrades and incapacitates nearby antibodies, thereby neutralizing the complement system. Another approach comes from Sonja Schrepfer, head of the hypoimmune platform at Sana who, together with UCSF heart surgeon Tobias Deuse and their colleagues, reported last year that overexpression of a protein that binds and disables antibodies can achieve the same result4.
Neither approach has been vetted in people — and, as molecular endocrinologist Timothy Kieffer at the University of British Columbia in Vancouver points out: “Strategies to thwart the highly evolved immune system are numerous, but are only hypothetical until proven otherwise.”
“The true test can only come in clinical trials,” he says.
Kieffer is also chief scientific officer of Fractyl Health, a metabolic therapeutics company in Lexington, Massachusetts. But two years ago, while serving as chief scientific officer for ViaCyte in San Diego, California, Kieffer played a pivotal part in launching the first clinical study of a stem-cell-derived product that incorporated immune-cloaking edits.
This pioneering product, developed in collaboration with biotech firm CRISPR Therapeutics in Boston, was named VCTX210. Designed to help people with type 1 diabetes to produce their own insulin, the product incorporated a suite of four gene edits collectively intended to enhance immune evasion and bolster cell survival. A subsequent version of this therapy, termed VCTX211, included an additional two edits, each aimed at further enhancing the robustness and functionality of the cells.
Invisibility shield
How effective these therapies were at sidestepping immune detection and improving the control of type 1 diabetes remains unclear. As Nature went to press, no results had been publicly disclosed. And both Vertex (which acquired ViaCyte in 2022, but is now working on separate stem-cell-derived therapies, using gene-editing technologies from CRISPR Therapeutics) and CRISPR Therapeutics (which now wholly owns the VCTX210 and VCTX211 assets) declined to comment on their immune-evasive cell-therapy programmes.
Also unclear is whether any safety concerns emerged in these trials. This matter is of utmost importance to researchers such as Kieffer because, as he explains, “concerns arise with manipulating the genome of cells for therapy, particularly when the goal is to endow them with an invisibility cloak that could be problematic should the cells become dangerous to the recipient”.
In the ViaCyte-CRISPR-Therapeutics trials, the companies took the precautionary step of encapsulating their immune-evasive cells in small, sticking-plaster-sized pouches, which are then implanted beneath the person’s skin. These devices contain pores that allow blood vessels to enter, providing oxygen and nutrients to the metabolically active cells inside, but prevent any therapeutic cells from escaping. If any unanticipated issues arise, they can be swiftly retrieved before rogue cells cause widespread damage.
Another safety measure involves the integration of genetic fail-safe features into the edited cells themselves. These features include drug-inducible suicide genes that can be activated by administration of a relatively benign medication. Researchers are also adorning modified cells with surface proteins that can be targeted with clinically approved antibody drugs, thereby achieving the same goal of cell destruction should any transplants turn cancerous or problematic in other ways.
In the end, the optimal safety strategy — not to mention the ideal amount of gene editing necessary to tamp down immune responses — can vary with the disease. A ready-to-use cell therapy for cancer does not necessarily need to incorporate the same design features as one tailored for diabetes, for instance, given the differences in the immune system that these cell products will confront and the distinct risk–benefit consideration in each disease. “There is no one catch-all solution,” Meissner says.
Certain parts of the body, including the eye and the brain, also enjoy an ‘immune privileged’ status, meaning that only a limited set of immune cells can enter them. This has led companies such as BlueRock Therapeutics in Cambridge, Massachusetts, which is developing off-the-shelf stem-cell-derived therapies for Parkinson’s disease, to tailor their immune-editing strategies accordingly. “There are some unique opportunities when you’re in the brain,” says BlueRock’s head of immunology, Greg Motz.
Those opportunities won’t be the last word on universal cell therapies, of course. Rather, Murry expects to see incremental advancement in the field, with short-term wins and losses informing long-term editing strategies.
“I would love it to be perfect out of the gates, but that’s not realistic,” Murry says. “This is going to be like peeling an onion.”
A study found that the human body has different immune-system responses to keto and vegan diets.
A new study from researchers at the National Institutes of Health in the United States has found significant immune-system responses to ketogenic and vegan diets.
Participants followed both diets for two weeks each. The keto diet was found to prompt responses associated with pathogen-specific immunity developed through regular exposure and vaccines.
The vegan diet elicited responses rooted in innate immunity, the body’s first line of defense against pathogens.
A new studyTrusted Source from researchers at the National Institutes of Health has found significant immune-system responses to ketogenic and vegan diets.
By performing “a multiomics approach including multidimensional flow cytometry, transcriptomic, proteomic, metabolomic and metagenomic datasets,” the researchers were able to assess how 20 participants’ bodies responded to two weeks each of the ketogenic and vegan dietary regimes.
The ketogenic diet prompted responses associated with adaptive immunityTrusted Source — pathogen-specific immunity that is developed through regular exposure and vaccines — while the vegan diet elicited responses rooted in innate immunityTrusted Source, which is the body’s first line of defense against pathogens.
There were also significant changes in the microbiomes of the participants, specifically the abundance of the gut bacteria associated with each diet. The ketogenic diets seemed to lead to a reduction in amino acid metabolism within their microbiomes, perhaps as a result of the larger amount of amino acids in that diet.
Each participant was allowed to eat as much as they wanted during the two weeks they were adhering to each diet.
When people were on the vegan diet, which contained about 10% fat and 75% carbohydrates, they consumed fewer calories than their counterparts on the keto diet, which was made of about 76% fat and 10% carbohydrates.
Given the random application of the order of the diets and the diversity of the participants in age, race, gender, ethnicity, and body mass index (BMI), the study’s authors point to how these diets can be consistently applied to the body’s pathways with somewhat predictable results.
“Further exploration of functional trade-offs associated with each diet would be an important line of research,” they write in the study.
Kristin Kirkpatrick, MS, a registered dietician at the Cleveland Clinic Department of Department of Wellness & Preventive Medicine in Ohio and a senior fellow at the Meadows Behavioral Healthcare in Wickenburg, Arizona, told Medical News Today that while these varied diets do show effects on overall health, there is a number of other factors that are at play.
“Both dietary patterns varied in their content of fat, fiber, carbohydrate, and protein composition and each approach had variations of change to immune function,” said Kirkpatrick, who wasn’t involved in the study. “Genetics, and specifically, nutrigenomics may help in determining the correct overall dietary pattern for an individual in addition to factors such as personal, religious, and cultural preferences. There is no one-size-fits-all all approach to diet and even though these two diets may appear to some to have extremes on both ends, there appear to be certain factors of each that are impacting immune function. This was also a small study so larger studies may be warranted to further assess results.”
The ketogenic diet, known as keto, focuses on foods that provide a lot of healthy fats, adequate amounts of protein, and few carbohydrates.
By depleting the body’s sugar reserves and getting more calories from fat than from carbs, the diet works by forcing the body to break down fat for energy. This results in the production of molecules called ketones that the body uses for fuel and can stimulate weight loss.
After undergoing the ketogenic diet, participants in the NIH study were found to have an up-regulation of pathways linked to adaptive immunity, including T cell activation and enrichment of B cells and plasma cells. One of those pathways, oxidative phosphorylation, which is associated with T cell activation and memory formation, was improved after the ketogenic diet compared with the aftereffects of a vegan or baseline diet.
Analysis of participants’ proteomesTrusted Source — the entire set of proteins one organism produces — also indicated that the ketogenic diet may have a bigger impact on protein secretion than a vegan diet, with impacted proteins predicted to originate from several tissues, including the blood, brain, and bone marrow. Both diets affected proteins predicted to originate from the liver and secondary lymphoid organs.
The vegan diet eliminates all animal products, including meat, eggs, and dairy.
It has been associated with weight loss, improved heart health, and a reduction in the risk of chronic diseases such as cancer and type 2 diabetes. It is heavy on fruits, vegetables, beans, nuts, and seeds.
The study’s authors reported that the vegan diet resulted in a significant up-regulation of the production of red blood cells (erythropoiesis) and heme metabolism. Heme regulates transcription and protein synthesis during erythropoiesis. And the vegan diet resulted in more dietary iron (also important to erythropoiesis) being ingested in the vegan diet than in the ketogenic diet.
Matthew Carter, a doctoral student at the Sonnenberg Lab in the Department of Microbiology and Immunology at Stanford University in California (which recently published the resultsTrusted Source of a human dietary intervention trial comparing a high-fiber diet to a high-fermented foods diet), told Medical News Today that the vegan diet raised some questions about how it affected the immune system vs the ketogenic protocols.
“The authors do speculate that part of these differences might be caused by differences in caloric intake (vegans consumed fewer calories),” Carter said. “So it’s a little hard to see if there was something in particular in the vegan diet that caused these changes, or if something about eating less caused these changes. There are some interesting studies on fasting that have also shown changes to the innate and adaptive immune systems.”
Kirkpatrick noted that while the study’s findings support how powerful a role diet plays in immune function and microbiome health, the rigors of these particular diets can be difficult.
“Many of my patients have benefited from both vegan dietary patterns as well as keto dietary patterns,” Kirkpatrick said. “However, I have also seen challenges with both in terms of long-term sustainability. For example, few of my patients can remain strict keto over 6 months, and many transition to a low to moderate carb approach.”
Summary: Smoking not only affects immune responses in the short term but also leaves a lasting imprint on the body’s defense mechanisms. Through the Milieu Intérieur cohort of 1,000 healthy volunteers, the study identified smoking, alongside latent cytomegalovirus infection and body mass index, as a key factor influencing immune responses.
This groundbreaking research demonstrates that the effects of smoking on adaptive immunity can persist for 10 to 15 years after cessation, attributed to epigenetic changes in DNA methylation that alter gene expression involved in immune cell metabolism. This insight opens new avenues for understanding how lifestyle choices like smoking can have enduring effects on our health.
Key Facts:
Smoking significantly impacts both innate and adaptive immune responses, with some effects persisting for up to 15 years after quitting.
The study used the Milieu Intérieur cohort to demonstrate how smoking, latent cytomegalovirus infection, and body mass index are major factors affecting immunity.
Long-term effects of smoking on immunity are linked to epigenetic changes, specifically DNA methylation, highlighting the durable influence of smoking on the body’s defense systems.
Source: Institut Pasteur
Like other factors such as age, sex and genetics, smoking has a major impact on immune responses.
This is the finding recently made by a team of scientists at the Institut Pasteur using the Milieu Intérieur cohort of 1,000 healthy volunteers, established to understand variability in immune responses.
In addition to its short-term impact on immunity, smoking also has long-term consequences. For many years after they have quit the habit, smokers are left with effects on some of their bodies’ defense mechanisms acquired while smoking.
Basically, the immune system appears to have something resembling a long-term memory of the effects of smoking.
These findings, which for the first time reveal a long-term memory of the effects of smoking on immunity, will be published in the journal Nature on February 14, 2024.
Individuals’ immune systems vary significantly in terms of how effectively they respond to microbial attacks. But how can this variability be explained? What factors cause these differences?
“To answer this key question, we set up the Milieu Intérieur cohort comprising 1,000 healthy individuals aged 20 to 70 in 2011,” comments Darragh Duffy, Head of the Translational Immunology Unit at the Institut Pasteur and last author of the study.
While certain factors such as age, sex and genetics are known to have a significant impact on the immune system, the aim of this new study was to identify which other factors had the most influence.”
The scientists exposed blood samples taken from individuals in the Milieu Intérieur cohort to a wide variety of microbes (viruses, bacteria, etc.) and observed their immune response by measuring levels of secreted cytokines.
Using the large quantities of data gathered for individuals in the cohort, the team then determined which of the 136 investigated variables (body mass index, smoking, number of hours’ sleep, exercise, childhood illnesses, vaccinations, living environment, etc.) had the most influence on the immune responses studied.
Three variables stood out: smoking, latent cytomegalovirus infection and body mass index. “The influence of these three factors on certain immune responses could be equal to that of age, sex or genetics,” points out Darragh Duffy.
As regards smoking, an analysis of the data showed that the inflammatory response, which is immediately triggered by infection with a pathogen, was heightened in smokers, and moreover, the activity of certain cells involved in immune memory was impaired. In other words, this study shows that smoking disrupts not only innate immune mechanisms, but also some adaptive immune mechanisms.
“A comparison of immune responses in smokers and ex-smokers revealed that the inflammatory response returned to normal levels quickly after smoking cessation, while the impact on adaptive immunity persisted for 10 to 15 years,” observes Darragh Duffy.
“This is the first time it has been possible to demonstrate the long-term influence of smoking on immune responses.”
Basically, the immune system appears to have something resembling a long-term memory of the effects of smoking. But how?
“When we realized that the profiles of smokers and ex-smokers were similar, we immediately suspected that epigenetic processes were at play,” says Violaine Saint-André, a bioinformatician in the Institut Pasteur’s Translational Immunology Unit and first author of the study.
“We demonstrated that the long-term effects of smoking on immune responses were linked to differences in DNA methylation – with the potential to modify the expression of genes involved in immune cell metabolism – between smokers, ex-smokers and non-smokers.”
It therefore appears that smoking can induce persistent changes to the immune system through epigenetic mechanisms.
“This is a major discovery elucidating the impact of smoking on healthy individuals’ immunity and also, by comparison, on the immunity of individuals suffering from various diseases,” concludes Violaine Saint-André.
Abstract
Smoking changes adaptive immunity with persistent effects
Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability. However, the variables that drive such differences in cytokine secretion—a crucial component of the host response to immune challenges—remain poorly defined.
Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics.
We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory.
This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism.
Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.
A cigarette habit and previous infection with a common virus both have important effects on the immune system
The immune-system signature of cigarette smoking persists for many years after a person kicks the habit.
The impacts of cigarette smoking on the immune system lingers long after a smoker’s last puff, according to a study of the immune responses of 1,000 people1.
The analysis, published in Nature on 14 February, is part of an effort to determine why immune responses vary so widely from person to person. In addition to cigarette smoking, the study found that having a higher-than-average body mass index and having previously been infected with a typically benign virus called cytomegalovirus also affect the immune response.
“This highlights the importance of considering not only the immediate effects, but also the enduring consequences of lifestyle choices on immune function,” says Yang Luo, a computational immunologist at the University of Oxford, UK, who was not involved in the research.
Computational biologist Violaine Saint-André at the Pasteur Institute in Paris and her colleagues analysed blood samples and questionnaires collected by the Milieu Intérieur Consortium from 1,000 healthy people who live in Brittany, France. The researchers exposed the blood samples to molecules, microorganisms and viruses known to activate the immune system. They then measured the effect of each molecule or pathogen on the production of proteins called cytokines, which regulate the body’s inflammatory responses.
The authors combined these results with information about 136 personal traits drawn from demographic, environmental and clinical data. They found that three traits stood out as having particularly strong associations with cytokine responses: cigarette smoking, body mass index and previous cytomegalovirus infection.
The data on cigarette consumption were particularly striking: the effect of smoking on cytokine responses was as large as the effects of age, sex and genetics. And these effects lingered for years after participants had given up cigarettes. Saint-André and her team found that these factors correlated with patterns of chemical tags, called methyl groups, that were added to the cells’ DNA in certain regions. The addition of such methyl groups can alter gene activity.
Nature plus nurture
“It is a very important piece of work,” says Vinod Kumar, a geneticist at Radboud University Medical Center in Nijmegen, the Netherlands, not only because of the specific results about smoking, but also because of the overall effort to track sources of variability in immune responses. The study found that individual environmental factors, for example, can affect different cytokines to different degrees. “It makes me wonder how much detail we should consider when we are looking at targeted therapy or personalized medicine,” he says.
But the study still needs to be repeated to ensure that the results are generalizable, says Saint-André. And, in future, it should include a more ethnically and racially diverse group of participants. The team has now expanded their study to include participants from Senegal and Hong Kong, she says. The researchers have also gone back to the original participants, and have collected fresh blood samples from 415 of them 10 years after the original samples were taken.
It would be valuable to learn more about how smoking influences immune cell function, and, in turn, what the body’s responses to infection and vaccination are, says Luo. “That could offer valuable insights into the broader health consequences of smoking.”
Fiber is key to gut health and overall wellness, yet many diets lack sufficient fiber. Balance and variety in fiber sources are important for its full health benefits.
There’s no shortage of advice about what to eat, including hype about the latest superfoods that will help you live to 100, or about the newest restrictive diets that claim to help you lose weight and look beautiful. As a researcher from the Farncombe Family Digestive Health Research Institute, I’m well aware that there is no universal “healthy diet” that will work for everyone.
However, most professionals would agree that a diet should be well balanced between the food groups, and it’s better to include more things like vegetables and fermented foods in your diet than restrict yourself unnecessarily. Eating foods that promote gut health improves your overall health too.
Why is everyone so concerned about fiber?
The importance of fiber has been known for decades. The late great surgeon and fiber researcher Denis Burkitt once said, “If you pass small stools, you have to have large hospitals.” But dietary fiber does more than just help move your bowels. Fiber can be considered a prebiotic nutrient.
Prebiotics aren’t actively digested and absorbed, rather they are selectively used to promote the growth of a beneficial species of microbes in our gut. These microbes then help digest foods for us so we can obtain more nutrients, promote gut barrier integrity, and prevent the growth of harmful bacteria.
Prebiotics aren’t actively digested and absorbed, rather they are selectively used to promote the growth of a beneficial species of microbes in our gut.
Fibers can also have microbe-independent effects on our immune system when they interact directly with receptors expressed by our cells. These beneficial effects may even help teach the immune system to be more tolerant and reduce inflammation.
Good sources of dietary fiber include whole grains, fruits and vegetables, beans and legumes, and nuts and seeds. There is a lot of emphasis on soluble fibers and less on insoluble fibers, but in reality, most foods will contain a mixture of both, and they each have their merits.
High fiber snacks are also gaining popularity. With an estimated global value of US$7 billion in 2022, the value of the prebiotic ingredient market is expected to triple by 2032.
The benefits of dietary fiber
There’s plenty of evidence supporting the benefits of dietary fiber. Fiber isn’t just associated with colon health; it’s associated with overall health and brain health through the gut-brain axis. Diets low in fiber have been associated with gastrointestinal disorders such as irritable bowel syndrome or inflammatory bowel disease.
Fiber is associated with overall health and brain health through the gut-brain axis.
There are some gastrointestinal diseases, like Celiac disease, which are not typically associated with the benefits of dietary fiber. However, there isn’t a consensus to the specific type of fiber and dose that would be beneficial in treating most diseases.
Not all fiber is good fiber
Shockingly, not all fiber is good for you. Fiber is used as an umbrella term for indigestible plant polysaccharides, so there are many different types with varying fermentability, solubility and viscosity in the gut.
To make things more complex, the source matters too. Fiber from one plant isn’t the same as fiber from another plant. Additionally, the old proverb, “too much good is not good” rings true, where overconsumption of fiber supplements can cause symptoms such as constipation, bloating and gas. This is partly due to the differences in gut microbiomes that affect the ability to metabolize fiber to produce beneficial molecules like short-chain fatty acids.
Dietary fiber is an important part of a healthy diet that can promote both gut and overall health. Fiber helps you feel more satisfied after meals and helps to regulate your blood sugar and cholesterol. Do your best to consume fiber as part of your diet, and when needed, take only the dose of supplements as recommended.
Prebiotics promote the growth of gut microbes that can affect gut health and immunity in the context of many different diseases, although not all fibers are created equal. While fiber won’t cure illness, diet is a great addition to medicines and treatment strategies that can improve their efficacy.
Recent research has revealed that neurological damage from acute viral infections, like Zika and COVID-19, is caused by the immune system’s response, particularly by a unique population of T cells. This discovery shifts the focus from the viruses to the immune system, offering new avenues for treatment.
A new study discovered that T cells, not viruses, are responsible for neurological damage in diseases like Zika and COVID-19, suggesting new treatment strategies.
For years, there has been a long-held belief that acute viral infections like Zika or COVID-19 are directly responsible for neurological damage, but researchers from McMaster University have now discovered that it’s the immune system’s response that is behind it.
The research, published today (February 5, 2024) in Nature Communications, was led by Elizabeth Balint, a PhD student at McMaster, and Ali Ashkar, a professor with the Department of Medicine and the Canada Research Chair in Natural Immunity and NK Cell Function.
The Role of T Cells in Neurological Diseases
“We were interested in trying to understand why so many viral infections are associated with neurological diseases,” says Balint. “Our evidence suggests that it’s not the virus itself that causes the damage, but a unique population of T cells, which are part of the immune system, that are actually responsible for the damage.”
To come to this conclusion, the McMaster team focused on Zika virus. During laboratory testing, researchers, as expected, found T cells that were specific for Zika and designed to eliminate infected cells. They found something else, too.
“What was interesting in our study is that although we did find some T cells specific for Zika, we identified cells that weren’t functioning like a normal T cell and were killing lots of cells that weren’t infected with Zika.”
These cells are called NKG2D+CD8+ T cells and researchers say their aggressive response is responsible for neurological damage suffered from infections beyond just Zika, like COVID-19 and even septic shock.
Immune Response and Potential Treatments
The aggressive response is the result of the body producing large amounts of inflammatory proteins called cytokines, which in moderation help to coordinate the body’s response in battling an infection or injury by telling immune cells where to go and what to do when they arrive.
“If our body’s immune cells overreact and overproduce inflammatory cytokines, this condition will lead to non-specific activation of our immune cells which in turn leads to collateral damage. This can have severe consequences if it happens in the brain,” Ashkar says.
The discovery offers researchers and scientists a new target for treatments of neurological diseases sparked by acute viral infections. In fact, Balint has already found a treatment that holds promise.
“Elizabeth has experimented with an antibody that can completely block and treat devastating neurotoxicity in the animal model, which is already in clinical trials for different uses in humans,” says Ashkar.
Balint hopes to continue her work towards finding a treatment that would be effective in humans.
“There are a few different other viruses we’re interested in studying, which will aid us in creating the best treatment options,” Balint says.
New findings from the National Institutes of Health (NIH) researchers showed that people who switched to a vegan or ketogenic diet showed rapid and distinct changes in their immune system.
The small study, reported in the journal Nature Medicine, closely monitored the biological responses of people who sequentially ate vegan and ketogenic diets in random order. Those on the vegan diet showed responses that are linked to innate immunity, while the people on the ketogenic diet showed changes in their adaptive immunity, the pathogen-specific immunity that is built via exposures to our daily life and vaccines.
In addition, “both diets significantly and differentially impacted the microbiome and host-associated amino acid metabolism, with a strong downregulation of most microbial pathways following ketogenic diet compared with baseline and vegan diet,” the researchers wrote.
The distinct changes noted in the study related to both diets were observed consistently across the diversity of the participants demonstrating that the dietary changes consistently affect widespread and interconnected pathways in the body.
The investigators noted that nutrition affects all the processes that regulate the human immune system, and that a better understanding of the link between nutrition and host immunity provides an untapped opportunity to develop personalized, diet-based approaches to treating a range of human diseases including inflammatory disorders and cancer. Further, prior research has well established the association between a low-fat vegetarian or vegan diet with decreased inflammation, a reduced risk for cardiovascular disease, and a reduction in overall mortality.
However, the NIH investigators noted that given what is already known about the impact of diet on wellness and the development of disease, there is a significant lack of data on how nutritional interventions impact the human immune system. Further, studies in this area have only explored responses to only one diet at a time. This lack of data hampers the development of meaningful, proven nutritional interventions.
“Based on the highly variable responses of individuals to nutritional interventions and the high number of diets consumed, addressing how individuals respond to different diets remains an important line of research,” the NIH investigators stated in their published research.
The new study was conducted by a team in the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the Metabolic Clinical Research Unit in the NIH Clinical Center. The small, 20-person study represented diverse ethnicity, race, gender, body mass index (BMI), and age. During the four-week study period, the participants ate as much as they wanted of one diet—either vegan or ketogenic—for the first two weeks, followed by as much as they wanted in the following two of the other diet.
People on the vegan diet which comprised roughly 10% fat and 75% carbohydrates chose to consume fewer calories than when they were on the ketogenic diet (76% fat, 10% carbohydrates).
Blood, urine, and stool samples were collected for analysis, which used a multi-omics approach to show the body’s biochemical, metabolic, cellular, and immune responses to the diets. The team also analyzed participants’ microbiome. All 20 people remained on-site for the duration of the study to allow for careful control of the participants’ diets.
Specifically, the vegan diet’s effects to the innate immune system included antiviral responses. The ketogenic diet affected biochemical and cellular processes associated with T cells and B cells, which play roles in adaptive immunity. The ketogenic diets affected the levels of a broader range of proteins in the blood plasma, as well as the proteins in range of other tissues including those in the brain and bone marrow. The ketogenic diet was also associated with changes in amino acid metabolism—an increase in human metabolic pathways for the production and degradation of amino acids and a reduction in microbial pathways for these processes—which might reflect the higher amounts of protein consumed by people on this diet.
The vegan diet promoted more pathways that are linked to red blood cells, such as the heme metabolism, which could be related to the higher iron content of the diet.
The investigators said the data obtained from the study demonstrates how rapidly the immune system responds to nutritional changes and while more research is needed to provide a more detailed understanding of how these dietary changes affect the interconnected pathways in the human body, the results, nonetheless, point to the potential of tailoring diets to either prevent disease development or to complement disease treatments, by slowing processes associated with cancer progression or neurodegenerative disorders.
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