Respirometry data Ketosis and Immune System Immkne rates were normalized Seasonal eating habits protein amounts or Anx Ketosis and Immune System using Wave software Agilent Ketsois traces were exported to GraphPad Prism 9. Most of these deaths occurred in Sydtem over 70 years of age. MD Program. Cruciferous vegetables The cruciferous vegetable family includes low-carb MVP cauliflower, as well as broccoli, cabbage, kale, collard greens and Brussels sprouts. Research is needed in humans, however, to validate that the keto diet can effectively protect against the flu. Consistent with these observations, ßOHB-dependent inhibition of IL-1β and IL secretion in human monocytes has been documented [ 73 ].

Ketosis and Immune System -

Most of these deaths occurred in patients over 70 years of age. Many of these conditions, like diabetes and cancer, are well known to compromise immune function. The CDC is currently advising these groups to avoid social contact whenever possible. Other conditions that weaken the immune system and likely increase COVID risk include:.

Independent of age, diabetes and hypertension high blood pressure appear to be significant risk factors for developing severe COVID One reason could be immunocompromisation. Researchers also believe a protein called ACE2 is involved.

ACE2 exists in the lungs, blood vessels, the kidneys, and the heart. So anything that increases ACE2 expression, in theory, could worsen the SARS-CoV-2 infection. A large percentage of people with these conditions are on medications called ACE inhibitors to lower blood pressure.

ACE inhibitors lower blood pressure — yes — but they also increase the expression of ACE2. Learn more about how the ketogenic diet can alleviate diabetes.

Since immunocompromised patients are at higher risk for extreme COVID, supporting the immune system in this population is critical. This means getting plenty of sleep, addressing any nutrient deficiencies, and eating a healthy diet. While no diet will prevent viral infection, some ways of eating are clearly better than others for improving immune health and giving your body a fighting chance to protect itself as best it can.

The ketogenic diet, and keeping your body in ketosis where your body burns fat for fuel, is known for pro-immune system properties, which may be helpful in improving the immune system during this challenging time and in general.

Following are five ways the keto diet is known to improve the immune system:. We already mentioned that people with diabetes are at higher risk for extreme COVID The keto diet has been shown, in multiple studies, to lower both blood sugar and blood pressure in those with type 2 diabetes and hypertension.

And when you improve or even reverse diabetes, you improve immune health too. How this applies to COVID, however, remains an open question.

The keto diet is an anti-inflammation diet. When you eat a low-carb ketogenic diet, your liver responds by burning fat and producing ketones, including the ketone body beta-hydroxybutyrate BHB , which, interestingly, may help limit inflammation.

Inflammation, by the way, simply refers to immune activity. This activity is meant to identify, contain, and destroy harmful infections. But sometimes, the immune response gets out of control and damages cells. BHB may mitigate this problem by modifying the inflammatory response. In mice, a similar immune modification resulted in decreased flu severity.

Read more about how the ketogenic diet reduces inflammation. Move over chicken soup. In a study from the Journal of Immunology , researchers found that a keto diet protected mice from the H1N1 influenza virus. Half the mice were fed high-carb, half the mice were fed keto, then all mice were infected with flu.

The keto mice fared better. After four days, all the high-carb mice were dead, yet half the keto mice had survived. The benefits, according to the paper, were driven by specialized immune cells called gamma-delta T cells.

These cells which were more active in keto mice increased mucus production in their lungs and helped limit viral spread. Autophagy is a process by which cells recycle old, damaged parts and replace them with new ones. Out with the old, in with the new. The immune system relies on properly-functioning autophagy to stay robust and ward off germs.

Many pathogens have even evolved anti-autophagy mechanisms to avoid these defenses. Where does keto come in? In rats, a ketogenic diet increased autophagy and protected their brains from seizure-induced damage. Learn more about autophagy. If you want to minimize inflammation, you need to maintain a healthy gut.

When the gut becomes leaky, particles slip through the gut barrier, which in turn signals your immune system to attack. This is not a healthy immune response. Keto may help. In a study published in Cell , higher levels of ketones were linked to increased intestinal stem cell production which helps heal the gut in mice.

The keto diet also deprives pathogenic gut bacteria of their favorite food: sugar. Learn more about gut health. Finally, the best way to avoid infection is to avoid exposure to the virus.

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In Health Can the Keto Diet Boost the Immune System to Help Protect Against the Coronavirus? This confirmed that these cells play a critical role in warding off flu. On the other hand, some dietitians and medical experts believe that a low-carb diet can compromise the immune system.

There is also evidence that a keto diet can be harmful to the gut microbiome , which is essential to overall well-being. William Schaffner, MD , an infectious-disease specialist at Vanderbilt University in Nashville, Tennessee, has not seen significant data connecting diet with flu protection.

He notes that there is some evidence that obesity may lead to a weaker response to flu vaccine, so that may be an indication of how diet could affect flu protection.

Research is needed in humans, however, to validate that the keto diet can effectively protect against the flu. Health Conditions A-Z. Best Oils for Skin Complementary Approaches Emotional Wellness Fitness and Exercise Healthy Skin Online Therapy Reiki Healing Resilience Sleep Sexual Health Self Care Yoga Poses See All.

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Thank you Metabolism and thyroid Ketosis and Immune System nature. You are using Immmune browser version amd limited Ketosis and Immune System for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The ketogenic diet KD has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. A study Edible Mushroom Recipes that a low-carb, high-fat diet Expert weight loss guidance mice from influenza. New research Immmune that the popular keto Inmune Ketosis and Immune System help ward off influenza infection. Ketosis and Immune System study Ketosis and Immune System Yale Ketosis and Immune System, published Ketosis and Immune System 15 in the journal Science Immunologydiscovered that mice anv a anr diet low in carbohydrates but high in fat with moderate protein Systdm better Kefosis to fight off the flu compared with mice given foods that were high in carbs. A ketogenic eating plan helps people shed pounds by drastically limiting the intake of carbohydrates such as breads, pastas, and sweetswhile increasing the consumption of meats, dairy, fats, and nonstarchy vegetables. The diet puts the body into a metabolic state called ketosisin which the liver breaks down fat into an energy source called ketoneswhich fuel the body in the absence of glucose. This type of eating plan has been shown to help maintain blood sugar levels in people with type 2 diabetes. There is also some evidence, such as a study in Federal Practitioner from Februarythat a keto diet may improve tumor response in cancer patients.

In these uncertain times, Sytsem the face of Shstem global pandemic, znd may be wondering what you can do Citrus bioflavonoids foods protect yourself Kerosis your family ans infection. Maybe Syxtem want to go above and beyond social Shstem, wearing a mask, and Keyosis the flesh from your hands.

Maybe you are wondering if there are particular supplements, foods, or Energy metabolism and dietary fat you should be taking to Paleo diet and muscle gain your Ketosis and Immune System system to fight infection.

Maybe you are like Imune, and Syshem want information free of hyperbole, bias, Ssytem exaggeration! In the wake of Prebiotics foods list novel coronavirus, all Ketosis and Immune System us here at Carb Manager want to provide Immunw with just that!

In this series of articles, I will explore from Immunne scientific perspective what Systwm of us can Ketossi to support our Ketosi systems in these trying times - without hyperbole, without exaggeration, and without trying to sell you ySstem. We Immuje to refraining from hyperbole and Ketosid.

This information Immuen provided with our Ketosiz genuine sincerity and desire to share ane health and nutrition information, not Systeem the Systej of selling Multivitamin for energy a product or seducing you into clicking a link, i.

In future articles, I will Ketosis and Immune System nutrition considerations that Immjne important no matter what diet you choose, what Sysrem are worth taking, lifestyle habits Systen keep you healthy, and other factors that Ketosos immune health.

We are all familiar with the Sytem concept of the immune system. The anx system can be likened to the military of your body. It prevents invading organisms pathogens from Kerosis in and messing Ketosis and Immune System the intricate workings of your inner self.

Your skin and the linings of your gastrointestinal system and Ketoosis system are armed with various mechanisms Ketois keep the bad Ketosix out. Sywtem the bad guys manage to get in, Syxtem are met Ijmune aggression as Immunne military immediately ramps up an attack to abolish Athlete bone health support enemy.

This is the innate immune system and this defense Inmune called the Ketosia response. Ketosis and Immune System immune system Ketsis takes notes. When it encounters a new Sysetm, it Sysfem more effective ways Ketossi kill it.

The next time Shstem enemy shows Ketosis and Immune System, Performance testing for microservices immune cells recognize it Ketoss and destroy it faster and more effectively.

This is the adaptive immune system and by taking advantage of its adaptive qualities, we can design vaccines that Ketosos our troops to kill specific enemies. The Sytsem workings of the immune system Kefosis very intricate and require sufficient conditions Immuen operate optimally.

Your skin, respiratory tract, and gastrointestinal KKetosis need Sgstem be intact and healthy. The Sysyem system needs Kftosis, raw Ketowis, production factories, highways, meeting places, communication adn, and elimination processes.

These things come in the form of Ketosis and Immune System Keosis micronutrients, Ketosis and Immune System systems, and organs.

Just to Systtem sure we are Systtem on the same page Ketosls - COVID is Systfm disease caused Immyne the novel coronavirus SARS-CoV Ketosis and Immune System of you have come Ketosis and Immune System this blog because you are interested in, or are currently on a low Ketosis and Immune System, or Ketosia Diet.

Diversity in individual response to diets, Ketosie the Keto Diet, can also be caused by Immunr choices, individual food sensitivities Ketoxis allergies, meal timing, Lower cholesterol naturally, and supplements.

Considering the above statements, one should always carefully Sysfem their state of health, Fueling strategies for game day closely monitor their response Ketosia dietary changes.

Especially if you have any kind of health condition. The Ketogenic Diet is Sjstem on a specific macronutrient ratio, which leaves adn lot of room for interpretation when considering individual food choices.

You can eat a really healthy Ketogenic Diet, complete with non-starchy Immne, nuts, fresh meats, fatty fish, high quality and heart healthy oils, or Ketois can Ketosks a junk food Ketogenic Diet chocked full of poor-quality oils, processed meats, and no veggies.

Although both versions are within the realm of the Ketogenic Diet, you could have a very different response based on which way you choose to eat. While conclusive research remains limited, it appears that the Ketogenic Diet can benefit your immune system by:.

As no diet is perfect, the Ketogenic diet may have some downsides for the immune system that will be discussed at the end.

The immune system is a very complex and beautiful thing. The inflammation response keeps us safe from invading pathogens and promotes tissue healing.

It is invaluable. Without such a dynamic system, we would swiftly perish. However, the immune system requires balance and sometimes it malfunctions. A normal inflammatory response occurs when a threat is present, and it resolves when the threat is eliminated.

Sometimes, however, the inflammatory process occurs when a threat is not present or persists even after the threat is eliminated. Stress, excess body fat, exposure to environmental toxins, poor nutrition status, and pro-inflammatory foods- such as isolated sugars and processed carbohydrates—can all result in SCI.

In this respect, a well-formulated Ketogenic Diet may contribute to a well-functioning immune system. While these, and similar studies, have limitations, the general picture developing is that the Ketogenic Diet improves inflammatory status.

The Ketogenic Diet appears to achieve its anti-inflammatory prowess through antioxidant activity, as well as by activating some immune cells and inhibiting others in a way that helps resolve inflammation.

Additionally, as discussed in the next section, the Ketogenic Diet helps decrease fat mass. Another important anti-inflammatory component of the Ketogenic Diet is beta-hydroxybutyrate BHBthe primary ketone used for energy when in ketosis.

BHB produces fewer reactive oxygen species ROS than glucose does when processed for energy. Aside from providing your cells with energy, BHB also inhibits the pro-inflammatory receptor known as the NLRP3 inflammasome. On the other hand, if you are already on the Ketogenic Diet, this is a possible and theoretical mechanism that might decrease the severity of COVID symptoms.

If you do find yourself sick, it may be very helpful to start avoiding pro-inflammatory foods such as ultra-processed carbohydrates and isolated sugars, especially if you are at high risk of severe infection!

Obesity has been identified as a risk factor for COVID hospitalization in patients under The human body is built to conserve energy. When you consume more calories than you burn, your body stores those calories for a rainy day. This is a vital adaptive ability that has allowed the survival of humanity during times when food was scarce.

However, eating a diet high in processed carbohydrates and isolated sugars set this adaptive ability on overdrive by triggering a hormonal cascade involving weight-promoting peptides like ghrelin and insulin. Our bodies are excellent energy conservers — use only what you need and store the rest… indefinitely.

According to the Guinness Book of World Records, the heaviest man alive weighed a WHOPPING 1, lbs. at his peak! Processed foods are designed to be highly palatable and tend to be energy dense high caloriesyet devastatingly low in immune-supporting vitamins, minerals, and phytonutrients.

These foods also tend to be high in refined carbohydrates, which stimulate obesity-promoting hormonal pathways.

Consuming highly palatable, energy dense, nutrient deficient, refined carbohydrate food is a recipe for obesity. Obesity is the clinical term for excess fat mass that results in a BMI of 30 or above.

I have to pause here because I know some of you are getting disgruntled at the mention of BMI. The BMI metric is not perfect since it only considers height and weight and does not take into account what your weight is composed of, otherwise known as body composition.

Therefore, some individuals, such as body builders, can be miscategorized. Bodybuilders may be categorized as overweight or obese based on BMI alone, even though their weight is clearly made up of muscle mass rather than fat mass.

On the other hand, BMI provides an accurate weight status for most people. In individuals that are legitimately obese, reaching this level of fat mass leads to adipocytes cells that store fat that grow too large and begin to produce pro-inflammatory molecules.

This causes systemic chronic inflammation SCIwhich is thought to be the connection between obesity and chronic diseases like type 2 diabetes and cancer. Remember, by decreasing the burden of systemic chronic inflammation, the immune system can more effectively combat infections.

Glucose sugar is a vital nutrient for human life. HOWEVER, if there is too much sugar in the blood, it can wreak havoc on every bodily system, including the immune system. People with diabetes have chronically high blood sugar. This is either because they do not produce enough insulin, their cells are not sensitive to insulin, or a combination of the two.

Insulin acts as the key to allow sugar to enter cells. When sugar enters cells, the sugar is removed from the blood. When sugar cannot effectively enter cells, then it has no choice but to stay in the blood, causing high blood sugar, otherwise known as hyperglycemia.

People with diabetes have chronically high blood sugar, which puts them at significantly higher risk of infections compared to the general population.

This demonstrates that even short-term hyperglycemia can have a negative impact on the immune system. Therefore, drinking sugary drinks or eating cakes, candy, bread, rice, cereal, potatoes, and other foods that cause blood sugar spikes may have negative consequences for your immune health.

Occasional blood sugar spikes are unlikely to have a meaningful impact, but daily spikes certainly could. When too much sugar is in the blood, it starts to bind with other things in the blood, like proteins.

When this happens, the result is called an advanced glycation end product AGEs. AGEs can trigger inflammatory pathways. So, whatever that thing was supposed to do, it can no longer do. For example, hemoglobin is a protein in red blood cells that carries oxygen throughout the body.

When blood sugar is high, glucose binds to hemoglobin and it can no longer carry oxygen effectively. This measurement is called HbA1c, and it approximates blood sugar levels over the previous 3 months.

Sugar does the same thing to components of the immune system. One example is the compliment system, which is a group of proteins that play a number of important roles in fighting infections. When glucose is elevated, it can bind to these proteins and impair their ability to kill invaders.

Additionally, glucose metabolism creates reactive oxygen species ROS. The more glucose being metabolized, the greater the oxidative burden and inflammation. Therefore, to maintain the highest quality immune system and the strongest and most well-coordinated military, you should make sure you have stabilized blood sugar in the healthy range.

You can achieve stable blood sugar by following a healthy diet and exercising regularly. Consuming a generally healthy diet limited in refined carbohydrates and soft drinks is a major key. A nutrient-dense low carbohydrate diet and the Mediterranean Diet are two good examples of healthy eating patterns that will improve your blood sugar.

The American Diabetes Association ADA is a good resource for people with diabetes, or anyone interested in controlling their blood sugar. The ADA recently endorsed a low carbohydrate diet as an effective treatment intervention for individuals with type II diabetes.

: Ketosis and Immune System

12 Keto Superfoods to Boost Your Immune System | Carb Manager	Weight loss obtained with VLCKD is mostly Ketosis and Immune System to fat mass loss, Ketosis and Immune System lean mass and adequate Keosis status is preserved [ 68 Kdtosis. Article CAS PubMed Google Lice treatment for toddlers Nishimura Kegosis, Manabe I, Keyosis M, Eto K, Yamashita H, Ohsugi M, et al. Article CAS PubMed Central Google Scholar. gammadelta T cells producing interleukinA regulate adipose regulatory T cell homeostasis and thermogenesis. In humans, γδ T cells are enriched in skin and mucosa, suggesting a specific function for γδ T cells in mucosa layers [ 88 ]. SH designed the study, planned, supervised and conducted the experiments, prepared figures, and wrote the manuscript.
How To Support Your Immune System With Keto | Carb Manager	Other Diets. The BMI metric is not perfect since it only considers height and weight and does not take into account what your weight is composed of, otherwise known as body composition. YSM Board of Permanent Officers. Song, J. Schultheiß, C.
From Macro to Micro	Functional exhaustion of T-cells is known to be linked to mitochondrial dysfunction. Thus, we hypothesized that mitochondrial empowerment through BHB could improve T-cell function during COVID T cells are capable of using BHB via Krebs cycle oxidation, which is known to fuel OXPHOS with superior efficacy 16 , Elevated mitochondrial oxidative phosphorylation translates into increased mROS, as respiratory chain complexes are the major source of mROS T-cell activation and function inevitably relies on mROS, rendering them a pivotal signaling molecule for T-cell immunity 12 , As only D-BHB is metabolically active 7 , 20 — 22 , this refers to 5 mM D-BHB, which is similar to maximum blood ketone levels achievable via ad libitum KD 8. Since in vitro no BHB synthesis is occurring, higher initial BHB concentrations must be used to ensure adequate ketosis during cell culture. Of note, BHB concentration in cell culture medium at the end of incubation was in the range of 2 mM, thus almost identical to mean blood BHB in vivo Supplementary Figure 2I. Accordingly, lower initial concentrations of BHB in vitro did not evoke comparably positive effects on human T-cell immunometabolism. On a KD, exogenous supply of ketone esters or the use of MCT oil could help to achieve blood ketone levels close to 2 mM BHB. They can be further divided into distinct subsets with individual immunological function and metabolic characteristics 24 , Due to their multidimensional beneficial immunometabolic effects, ketone bodies have been proposed as a countermeasure against viral infections To date, no study investigated the impact of BHB on human viral infections. In mice, BHB has already shown to induce a protective immune response against influenza virus infection Similarly, in beta coronavirus-infected mice, KD improved γδ T-cell immunity and dampened inflammation The potential benefit of KD also expands to other immune cell types. Macrophages contribute to detrimental immune responses to COVID, which could be ameliorated through redirection of M1 to M2 phenotype via metabolic rewiring on a KD Beyond immunological effects, KD has been proposed as a metabolic therapy against COVID through restoration of systemic energy metabolism Of note, KD in vivo might evoke additional positive effects: carbohydrate restriction results in diminished levels of glucose and insulin, thus breaking the cycle of glucose-insulin-dependent inflammation and immunosuppression 31 — This could be of exceptional importance, since metabolic comorbidities have a devastating impact on COVID patients 37 — Consequently, a retrospective data analysis of COVID patients on a KD revealed correlations to a reduced mortality Prospective randomized clinical trials will now have to evaluate the precise impact of BHB on human metabolism in vivo during COVID Our study paves the road for the development of metabolic treatment strategies against COVID, which now have to be evaluated within the framework of controlled prospective studies. Of note, the required nutrition formula and protocols are already available. A clinical trial evaluating the impact of KD in sepsis patients has already finished the enrolling phase, and results are expected in the near future The studies involving human participants were reviewed and approved by LMU Ethics Committee. SH designed the study, planned, supervised and conducted the experiments, prepared figures, and wrote the manuscript. LG conducted experiments and participated in writing the manuscript. DE participated in figure preparation and writing of the manuscript. MM, MH, J-MB, and BZ participated in the study design. SK supervised the study and wrote the manuscript. All authors contributed to the interpretation of the data and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. We thank all CORKUM investigators and staff. We thank the patients and their families for their participation in the CORKUM registry. We thank Katja Gieseke and Florian Gosselin for their outstanding technical assistance. This research was supported by the Munich Clinician Scientist Program MCSP of the LMU Munich SH. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease COVID Front Immunol. doi: PubMed Abstract CrossRef Full Text Google Scholar. Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID He L, Zhang Q, Zhang Y, Fan Y, Yuan F, Li S. Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8 T cells in COVID Cell Commun Signal. Rha M-S, Shin E-C. Activation or exhaustion of CD8 T cells in patients with COVID Cell Mol Immunol. Wei J, Raynor J, Nguyen T-LM, Chi H. Nutrient and metabolic sensing in T cell responses. Buck MD, Sowell RT, Kaech SM, Pearce EL. Metabolic instruction of immunity. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. Hirschberger S, Strauß G, Effinger D, Marstaller X, Ferstl A, Müller MB, et al. Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming. EMBO Mol Med. Möhnle P, Hirschberger S, Hinske LC, Briegel J, Hübner M, Weis S, et al. MicroRNAs and in whole blood enable detection of T-cell immunoparalysis in sepsis. Mol Med. Google Scholar. Hirschberger S, Hübner M, Strauß G, Effinger D, Bauer M, Weis S, et al. Identification of suitable controls for miRNA quantification in T-cells and whole blood cells in sepsis. Sci Rep. Liemburg-Apers DC, Willems PHGM, Koopman WJH, Grefte S. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Murphy MP, Siegel RM. Mitochondrial ROS fire up T cell activation. Bárcena C, Mayoral P, Quirós PM. Mitohormesis, an antiaging paradigm. Int Rev Cell Mol Biol. Bordon Y. Protect the species with mitohormesis? Nat Rev Immunol. However, the implementation of a KD significantly reduced mice body weight loss and spleen weight loss at day 5, 6 and 7 from infection Fig. No significant changes were observed in serum glucose and BHB levels Supplementary Fig. Over 7 days from infection, animals under a CD showed profound morbidity and severely restricted activity defined by limited mobility and lethargic behavior, consistent with our previous report Animals infected under KD demonstrated rescued behavior with normal activity and mobility Fig. These data demonstrate that the KD is beneficial to mice overall health and behavior following SARS-CoV-2 infection. The KD broadly reprograms gene expression at system-level In our previous report, we showed that SARS-CoV-2 induces profound multi-organ transcriptional changes Therefore, we established whether a KD may affect SARS-CoV-2 induced systemic reprogramming at the transcriptional level by examining gene expression changes in extrapulmonary organs. Projected PC1 and PC2 distances suggested that the KD induces transcriptional changes in part similar to those caused by viral infection in all tissues Fig. DEGs between infected KD and infected CD mice were 74, 45 and 16 in heart, liver, and kidney, respectively, demonstrating similar overall transcriptional programs. These data corroborate the hypothesis that a KD shifts the transcriptional baseline of uninfected mice towards changes induced by SARS-CoV Next, we compared DEGs due to the exposure to a KD in uninfected animals KD vs CD , with those changing because of SARS-CoV-2 infection under CD CD-SARS-CoV-2 vs CD Fig. This analysis showed that heart , liver , and kidney of the genes reprogrammed by the KD were also affected during SARS-CoV-2 infection under CD. GO process enrichment analysis of shared DEGs pointed to lipid and acetyl-CoA metabolism reprogramming across all tissues with regulation of PPARα targets, such as Hmgcs2 , Cidea , Cidec , Ehhadh , Angptl4 , Ucp3 , Acot , Slc27a1 and Fabp2 Supplementary Data 1 and 2 , Supplementary Fig. RNA-seq data also showed increased CPT1A in the liver and kidney Supplementary Fig. Reversed-phase liquid chromatography RP-LC and untargeted mass spectrometry MS of polar lipids in SARS-CoV-2 vs control tissues under CD confirmed increased medium and long chain acyl-carnitines in the liver Supplementary Fig. Transcription factor regulatory network analysis of RNA-seq data by the transcriptional factor TF -target interaction database Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining TRRUST, v2 predicted 33, 64, and 49 TFs in heart, liver, and kidney, respectively 25 , PPARα was consistently predicted among the top 5 most significant TFs Supplementary Fig. Serum levels of BHB showed heterogeneous patterns in infected mice Supplementary Fig. This evidence supports the finding that ketogenesis is activated at the transcriptional level in extrapulmonary tissues following SARS-CoV-2 infection. Consistently, we previously observed peripheral fat mobilization, loss of adipose tissue, and reduced adipocyte size in the same SARS-CoV-2 murine model of infection Taken together, these data demonstrate a systemic transcriptional switch towards ketogenic metabolism after SARS-CoV-2 infection under CD and support the hypothesis that the implementation of a KD prior to infection primes the system by anticipating transcriptional adaptations induced by the virus. We compared transcriptional changes in animals at the endpoint of our study, i. mice infected under KD vs CD KD-SARS-CoV-2 vs CD-SARS-CoV The endpoint of 7 days was primarily determined by the moribund health state of the CD SARS-CoV-2 infected animals that required euthanasia. This analysis detected 74 DEGs in the heart 26 down-, 48 up-regulated , 45 in the liver 6 down-, 39 up-regulated , and 16 in the kidney 13 down-, 3 up-regulated Fig. In the heart, Nmrk2 was significantly downregulated in the KD-SARS-CoV-2 group. Decreased Timp1 , Thbs1 , Tnc , Adam8 , Chil3 , Mmp and Mmp-3 transcription also suggested reduced matrix remodeling associated with lower inflammation in the KD-SARS-CoV-2 group Fig. On the contrary, serum amyloid A1 and A2 Saa1 and Saa2 , Igfbp1 , Gdf2 , Hnf1a , Soat2 , Bco2 , Amt , Acaca , and Esr1 were upregulated in cardiac tissue in the KD infected mice. In the liver, we detected increased Saa3 , Cxc19 , Lp1 , Cxc , Ubd , Col3a1 , Tlr2 , Ifit3 , Gbp2 , and Gbp8 in the KD-SARS-CoV-2 group, implicated in interferon response, innate immunity, and collagen remodeling. Cyp3a11 and Cux2 were instead reduced. Saa3 and slightly significant Saa1 and Saa2 upregulation in infected KD fed mice is not ascribable to the sole effect of a KD, as shown by the downregulation of Saa1 and no significant changes for other Saa2 and 3 in the liver of uninfected mice under KD Supplementary Data 5. Few significant changes were detected in the kidney Supplementary Data 4. Network analysis of GO process enrichment in the heart predicted the downregulation of defense response, eosinophil migration, regulation of immune system process, leukocyte activation, wound healing, and tumor necrosis factor superfamily cytokine production while pointing to increased cholesterol and steroid biosynthesis, and lipid metabolism Supplementary Fig. To determine whether a KD may alter serum markers of systemic inflammation during SARS-CoV-2 infection, we measured the concentration of pro-inflammatory cytokines in samples from mice infected under CD or KD using the ProcartaPlex 1A Panel that enables the analysis of 36 mouse pro-inflammatory cytokine and chemokines in a single well by Luminex xMAP technology. Hematoxylin and eosin HE tissue staining showed no histological abnormalities or differences between the two groups Fig. These included 8 eicosanoids prostaglandins mediators of acute inflammatory response with higher FC in CD vs KD infected mice. RNA-seq data also showed decreased expression of indoleamine 2,4-dioxysenase 2 IDO2 in the heart in the KD-SARS-CoV-2 group Fig. Taken together, these data suggest that a KD may be a preventive non-invasive approach to decrease SARS-CoV-2 associated systemic toxicity through reduced inflammation. We next investigated whether a KD may affect metabolic changes induced by the infection. Metabolite abundances were charted by targeted metabolomics of central carbon metabolism and related pathways by HILIC-MS after metabolite extraction from tissues and serum. To determine the effect of a KD on metabolite intra- and inter-tissue associations, we computed Pearson correlation coefficients for the CD and KD, CD-SARS-CoV-2 and KD-SARS-CoV-2 groups, for metabolites with significant changes in paired univariate analysis in at least one tissue i. A KD diet also induces stronger positive associations higher correlation coefficient, lower p value between metabolites in the heart and liver, and within the kidney Fig. In the CD-SARS-CoV-2, viral infection increases negative associations between the liver and the kidney, while leaving unchanged positive associations between the liver and other tissues Fig. Stronger positive intra-tissue correlations were observed in the heart Fig. In the KD-SARS-CoV-2 group, the infection led to weaker intra-tissue positive associations in the liver and kidney, as opposed to the KD mock group Supplementary Data 7. Negative associations were also weaker than those observed in the KD mock group Fig. This suggests that SARS-CoV-2 increases hepatic metabolic intra- and inter-tissue associations, particularly with the heart and kidney, and that a KD can mitigate these changes during infection. Next, we performed paired univariate analysis of metabolite abundances, i. KD-SARS-CoV-2 vs KD and CD-SARS-CoV-2 vs CD. Infection under KD led to reduced changes in heart and serum, accompanied by increased metabolism reprogramming in the liver and kidney Fig. We detected a general increase in currency metabolites, and of acyl-CoAs across all tissues in KD-SARS-CoV-2 mice Fig. Metabolites in nucleotide metabolism were increased in the kidney, liver, and serum with a less pronounced effect in the heart. This is particularly evident for A, G and UMP in serum, which showed more than 5 log2FC relative increase. Metabolite abbreviations are reported in Supplementary Data 8. In all tissues, the KD rescues lipid precursors and amino acid levels in infected mice both depleted in animals infected under CD. Univariate analysis of metabolomics data for infected mice under CD or KD at day 7 from infection i. In the kidney and liver, we detected increased nucleotides dT, dU, orotate, thymine, dA , amino acids isoleucine, leucine, valine, glycine, phenylalanine and lipid precursors HMG-CoA, CDP-choline, carnitine Fig. This suggests that a KD primes the myocardium to anticipate metabolic changes induced by the virus by counteracting nucleotide, amino acid and lipid metabolism alterations caused by the infection. SARS-CoV-2 induced metabolic reprogramming diverts mitochondrial fuel utilization away from electron transport chain ETC complex II driven fatty acid oxidation to glycolytic derived intermediates Since a KD can enhance complex II activity 29 , we analyzed levels of respiratory complexes by immunoblot, RSC by blue native electrophoresis BN-PAGE , and respiratory complex activity using respirometry in frozen samples RIFS The KD per se did not alter levels of respiratory complex I CI and complex II CII relative to complex IV CIV in heart and liver tissues Fig. a Immunoblots of complex I Ndufb8 , complex II Sdhb , complex IV Mtco subunits, and Tomm20 in heart top and liver bottom. Whole membranes are displayed in Supplementary Fig. Analysis of mitochondrial mass in the heart, liver, and kidneys revealed that KD in non-infected mice induced an increase in mitochondrial content. However, this increase was reverted under SARS-CoV-2 infection Supplementary Fig. RSCs or respirasomes are the active conformation of assembled ETC complex units CI, CIII, and CIV that are required for electron transport and respiration. RSC assembly by BN-PAGE is a more accurate indicator of respiratory activity than measuring individual complex subunit levels by Western blot alone We did not observe significant changes in RSC assembly levels in the heart in the KD-CoV-2 condition Supplementary Fig. In order to detect resulting functional differences in fuel capacity we measured the respiratory activity of CI and CII normalized by CIV in frozen tissue homogenates. Curiously, in the heart, the KD alone mildly but significantly caused reduced CI activity, which was not reflected in a change in CII protein levels. A KD has shown beneficial effects across numerous clinical studies and animal models of disease as a noninvasive means to induce systems-level immune modulation and reduce inflammation 32 , In our previous report, we showed that SARS-CoV-2 infection causes multi-organ toxicity, body weight loss, and spleen reduction. Animals showed severely reduced activity, lethargic behavior, and profound morbidity, with mobilization of peripheral fat storages Here we show that the implementation of a KD two weeks prior to infection reduces body weight loss, rescues reduction in spleen size and mice activity with overall improved health. Similar findings were reported in the context of influenza infection The observed increase in spleen weight may be due to increased immune response and accumulation of immune cells in spleen. The KD causes transcriptional reprogramming at the systems level, with up-regulation of PPARα and its downstream effectors Our data demonstrate that the implementation of a KD in the uninfected group induces transcriptional changes that resemble those detected following infection in the heart, liver, and kidney. This indicates that a KD shifts the transcriptional baseline toward adaptative changes induced by SARS-CoV-2 infection. To identify the pathways modulated across KD and SARS-CoV-2 infection, we performed GO enrichment of shared DEGs. This analysis predicted lipid and acetyl-CoA metabolism upregulation in all tissues, with increased transcription of the PPARα gene set. PPARα is the master regulator of lipid metabolism, particularly in the liver. Its activation promotes fatty acid uptake and catabolism through ketogenesis, fatty acid transport, and mitochondrial β-oxidation. PPARα also increases the expression of CPT1 , which encodes for the carnitine palmitoyltransferase I CPR1 transporter of fatty acids inside the mitochondria as carnitine conjugates acyl-carnitines. We observed consistent up-regulation of PPARα and downstream effectors in uninfected animals under KD and in CD-SARS-CoV-2 mice. These data indicate that ketogenesis is activated at the transcriptional level in extrapulmonary tissues following SARS-CoV-2 infection, and are consistent with our previous report showing loss of peripheral adipose tissue, and reduced adipocyte size Increased acyl-carnitine levels in the liver of infected mice under CD endorse this interpretation. Serum BHB levels were highly heterogeneous across infected mice. Similar results were reported in a recent observational study of COVID patients and in a murine model of SARS-CoV-2 23 , Our data show decreased transcription of Nmrk2 in the heart of animals infected under KD. Our data also show decreased Timp1 , Thbs1 , Tnc , Adam8 , Chil3 , Mmp and Mmp-3 in the heart of animals infected under KD. Timps encode for a family of glycoprotein inhibitors of Mmps , which are released in response to cytokine flow to maintain matrix equilibrium and cytokine shedding during inflammation, and have been reported upregulated in SARS-CoV-2 patients Tush decreased Timp1 , Mmp and Mmp-3 suggest reduced matrix remodeling and inflammation in the infected KD group. Decreased Thbs1 , Tnc , and Adam8 matrix remodeling and cell-matrix interaction , and Chil3 stimulation of immune function and inflammation support this interpretation 41 , 42 , We further detected Saa1 , Saa2 , Igfbp1 , Gdf2 , Hnf1a , Soat2 , Bco2 , Amt , Acaca rate-limiting step in fatty acid synthesis , and Esr1 , increase in cardiac tissue of KD infected animals, and Saa upregulation in the liver. Previous studies reported altered levels of Saa1 and Saa2 following SARS-CoV-2 infection 44 , 45 , Saa1 and Saa2 are induced by inflammatory cytokines IL-1β, IL-6 and TNF-α in the liver. However, their extrahepatic role is poorly understood. Recent evidence suggests that these proteins may exert immunomodulatory and inflammatory homeostatic functions, and inhibit TNF-α mediated apoptosis To validate this interpretation, we measured a robust panel of markers of systemic inflammation in serum. We found that a KD reduces pro-inflammatory cytokines i. RNA sequencing also showed decreased IDO2 transcription in the heart. IDO enzymes catalyze the catabolism of tryptophane to kynurenine under inflammatory stimuli, such as IFN-γ signaling. In physiologic conditions, IDO2 is rarely expressed. However, IDO2 , rather than the constitutively expressed IDO1 , has been shown associated with the accumulation of downstream products of kynurenine metabolism and inflammation in the lung, heart, and brain of deceased covid patients Previous investigations established increased serum cytokines in COVID patients i. Among these, TNF-α, M-CSF, G-CSF have been proposed as predictors of intensive care unit ICU requirements and lung injury 49 , A further study demonstrated that TNF-α levels in serum can serve as a prognostic marker of post-acute sequelae in COVID patients long covid In this context, our data suggest that a KD may improve patient health with reduced risk of hospitalization and long covid 47 , On the contrary, a diet rich in carbohydrates may exacerbate the inflammatory response during infection. Numerous studies corroborate the anti-inflammatory properties of a KD, e. This has been linked with the inhibition of NLRP3 by BHB in the inflammasome pathway 57 , 58 , However, we did not detect significant transcriptional modulation of the inflammasome under both CD and KD Supplementary Fig. This and other discrepancies may be linked to limitations intrinsic to the physiology of the in vivo model used in this study, particularly in relation to differences in hACE2 human expression in infected mice and humans, and to the use of the i. infection route, which differs from the natural respiratory route in humans. In our previous work, we observed suppression of OXPHOS and of the TCA at the transcriptional level in infected animals Our data indicate that a KD increases hepatic metabolic associations with other tissues, a metabolic adaptation also observed in the infected CD group. This suggests that a KD anticipates the systemic metabolic rewiring induced by the virus. Across all tissues, we detected increased energy currency metabolites, lipid precursors, amino acids, and acyl-CoAs. Nucleotide metabolites were also increased in all tissues with a slight change in the heart. Recent literature reported altered amino acid and lipid precursors in plasma from COVID patients, with metabolite levels correlating with disease severity and risk of hospitalization, suggesting that the implementation of a KD may improve patient health 52 , 53 , 60 , 61 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , However, robust follow-up clinical studies are needed to translate these findings into clinical recommendations. The KD has been shown to rewire mitochondrial metabolism toward ketones and fatty acid oxidation-driven maximal respiratory capacity The KD normalizes these changes by regulating CII levels in the heart and respirasome assembly in the liver. Consistently, we detected rescued energy currency metabolites. Overall, these data suggest that a KD mitigates metabolic dysregulations induced by SARS-CoV-2 infection and confirm the metabolic changes predicted at the transcriptional level. In summary, our investigation demonstrates that a KD can reprogram and in part anticipate the transcriptional and metabolic changes caused by SARS-CoV-2 infection, with improved mice health, reduced inflammation, and rescued metabolism. All animal studies were approved by the Animal Research Committee, University of California, Los Angeles and conducted in compliance with all relevant ethical regulations for animal testing. AAV9-CMV-hACE2 AAV, Vector Biolabs viruses were purchased from Vector Biolabs. This model was previously described All works in this study involving live SARS-CoV-2 virus were approved by the University of California, Los Angeles Institutional Biosafety Committee IBC. All work with infectious SARS-CoV-2 was conducted in UCLA performance-validated BSL3 facilities, designed adhering to the guidelines recommended by the Biosafety in Microbiological and Biomedical Laboratories BMBL , the U. Department of Health and Human Services, the Los Angeles Department of Public Health LADPH and the Centers for Disease Control and Prevention CDC. Virus titer was determined by plaque assay using Vero E6 Cells. After 2 weeks of AAV-CMV-hACE2 injection, mice were fed with chow diet T. Cage food weight and individual mouse body weight were recorded daily after SARS-CoV-2 virus infection. Animals were euthanized at 7 days SARS-CoV-2 infection. Mice pixel coordinates were obtained using Adobe After Effects. The tracking software was used to export movement coordinates for each mouse tracker positioned between mice ears. Keto mice x length cartesian values and the modified keto mice Y width were set to start at zero. Data were plotted in R Studio using the ggplot2 package, distances traveled between video frames were computed using the dist function in R. Paraffin-embedded tissues were sectioned at 5μm thickness and stained with hematoxylin and eosin HE staining. Images were taken using Nikon Eclipse Ti2 microscopy Nikon,USA with DS-Ri2 brightfield camera. The aqueous phase was harvested and dried by a vacuum evaporator. Maven v 8. Data analysis, including principal component analysis and univariate t test two-tailed, unequal variance , correlation analysis, heatmap generation, and circos plot visualization was performed by R Studio and in-house scripts LC separation was performed on a Phenomenex Kinetex C18 1. Mobile phase gradient was as follows: A 0. Raw data were analyzed in XCMS. Luminex xMAP technology was used for readout acquisition as described in previous work Respirometry data analysis: OCR rates were normalized by protein amounts or MTDR signal using Wave software Agilent and traces were exported to GraphPad Prism 9. Complex I, II, and IV dependent respiration was determined after subtraction of substrate induced respiration by antimycin A CI, CII or sodium azide baselines CIV respectively. Normalized respiration values were used to calculate rates of fuel preference. ECL signal was detected using a ChemiDoc Molecular Imager BioRad. Band densitometry was quantified using ImageJ Gel Plugin NIH. We used the following antibodies: Vinculin, from Sigma Aldrich V , mtOXPHOS cocktail for combined Atp5b, Uqcrc2, Mtco1 and Sdhb detection; ab from Abcam, Ndufb8 from Thermo-Fisher Biotechnology; Uqcrc2 AP from Proteintech and Tomm20 sc from Santa Cruz Biotechnology. Total RNA was extracted using RNeasy Plus Mini Kit , Qiagen. The reads were mapped with STAR 2. The counts for each gene were obtained using quantMode GeneCounts in STAR commands, and the other parameters during alignment were set to default. Differential expression analyses were carried out using DESeq2 with default parameters. Counts normalized by sequencing depth were obtained using DESeq2 estimate size Factors function with default parameters. Significantly up-regulated or down-regulated genes were uploaded to the Enrichr platform for analyses. Transcription factor regulatory network analysis of RNA-seq data was performed by the transcriptional factor TF -target interaction database Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining TRRUST, v2 Enrichment analysis for DEGs was performed using the DESeq2 method with FDR cutoff 0. Further RNA-seq analysis e. and mentioned in the figure legends. All data were acquired with a minimum of three biological replicates. Reproducibility of methos was tested by a minimum of three technical replicates of standard measurements. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. RNA-sequencing data are available in GSE All other data are available in Supplementary Data 9 and from the corresponding authors on reasonable request. Aburto, J. et al. Estimating the burden of the COVID pandemic on mortality, life expectancy and lifespan inequality in England and Wales: a population-level analysis. Community Heal 75 , — Article Google Scholar. Crook, H. Long covid—mechanisms, risk factors, and management. BMJ , n Zhou, Y. Obesity and diabetes as high-risk factors for severe coronavirus disease Covid Diabetes Metab. Article CAS PubMed Google Scholar. Jordan, R. Covid risk factors for severe disease and death. BMJ , m Fishkin, T. Review of the metabolic risk factors for increased severity of Coronavirus Disease Article PubMed PubMed Central Google Scholar. Khunti, K. Long COVID — metabolic risk factors and novel therapeutic management. CAS Google Scholar. Immunometabolism and natural killer cell responses. Article PubMed Google Scholar. Zhang, W. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell , — e15 Article CAS PubMed PubMed Central Google Scholar. PA Online Program. Joint MD Programs. MHS Program. How to Apply. Advanced Health Sciences Research. Clinical Investigation. Medical Education. MHS Team. Visiting Student Programs. Center for Med Ed. Office of the Deputy Dean. Organizational Chart. Janeway Society. First Fridays. Physician-Scientist Development Awards. Fund for Physician-Scientist Mentorship. Grant Library. Grant Writing Course. Mock Study Section. Research Paper Writing. Funding Opportunities. Engaging with Students. Join Our Voluntary Faculty. Faculty Directory. Research by Keyword. Research by Department. Research by Global Location. Translational Research. Resources for Investigators. Team Science. Program for the Promotion of Interdisciplinary Team Science POINTS. Health Equity Research. Community-Engaged Research CEnR. CEnR Steering Committee. Experiential Learning Subcommittee. OHER News. YSM Biobank. Embryonic Stem Cell Research Oversight. COVID Research. Mapping COVID Data. COVID Vaccinations in CT. Case Maps. COVID in Connecticut Schools. Connecticut Towns COVID Impact Dashboard. Connecticut Town Day Cases Time Lapse. CT Correctional Facilities with COVID Cases Dashboard. Connecticut COVID Presence Map. CT Nursing Homes with COVID Cases. COVID Presence Map. COVID Case Density by US County. Global Cases Dashboard. Time-Lapse of Global Spread. US Racial and Ethnic Disparities in COVID Mortality. Childcare Survey and Data Display. Risk of Complications Conditional on COVID Infection. Geographic Access. 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Can the Keto Diet Help Fight the Flu?	But what does Turmeric natural remedy immune system need to function at Ketosie best? Kefosis cookies Ketosis and Immune System used to Ketosis and Immune System how ad interact with the website. Mavri A, Alessi M, Bastelica D, Geel-Georgelin O, Fina F, Sentocnik J, et al. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease, Science. We also have strong clues that the keto low-carb diet supports the immune system. Analytics Analytics.
Wellness inspired. Wellness enabled.	Zitvogel, L. Table 1. In the study, mice that were on the high-fat, low-carbohydrate ketogenic diet when they contracted the flu were more likely to survive the illness than those on a normal high-carb diet. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Imanaka-Yoshida, K.

Ketosis and Immune System -

Research was performed according to the Declaration of Helsinki ethical principles for medical research involving human subjects. Immune cells derived from patients with PCR-verified COVID infection, respiratory failure requiring oxygen insufflation and disease severity WHO 4 or above have been included into the experimental immunometabolic intervention.

Patient characteristics are depicted in Table 1. Peripheral blood mononuclear cells PBMC from patients with verified COVID infection were purified by density centrifugation Histopaque , Sigma-Aldrich, St.

Louis, MO, United States. A ViCell analyzer Beckman Coulter, Fullerton, CA, United States was used to determine cell count and viability. Louis, MO. Louis, MO, United States was added to the medium achieving a final concentration of 10 mM.

Upon cell lysis of target cells, calcein fluorescence was determined on the FilterMax F3 MultiMode Microplate Reader excitation filter: nm; emission filter: nm Molecular devices.

LLC, San Jose, CA, United States. Quantification of secreted proteins was performed by Enzyme-linked Immunosorbent Assay ELISA IFNγ: ; TNFα: ; Granzyme B: ; Biolegend, San Diego, CA, United States Perforin: HP-2, Mabtech, Nacka Strand, Sweden. Absorbance was measured using a Filtermax F3 and concentrations of target proteins quantified by plate-specific standard curves.

Mitochondrial respiratory and glycolytic capacity were evaluated using a Seahorse XF HS Mini for extracellular flux analysis Agilent, Santa Clara, United States. Seahorse RPMI , Agilent, Santa Clara, United States supplemented with 1 mM sodium pyruvate, 2 mM glutamine and 5.

Experiments were run in duplicates or triplicates with 70, cells per well. Extracellular acidification rate ECAR and oxygen consumption rate OCR were measured in response to Mito Stress Test To this end, final well concentrations of 1 μM Oligomycin, 1 μM FCCP and 0.

Data were acquired on a FACS Canto II flow cytometer BD Biosciences, Franklin Lakes, NJ, United States. ΔψM is represented as the ratio of the mean fluorescence intensities of red to green. The decoupling agent FCCP Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone was applied as a negative control, causing an almost complete disruption of ΔψM.

N-acetylcysteine NAC and tert-butyl hydroperoxide TBHP were used as negative and positive controls, respectively. Analysis was performed on a FACS Canto II flow cytometer BD Biosciences, Franklin Lakes, NJ, United States.

MitoTracker Green FM , Cell Signaling Technology, Danvers, MA, United States was used for flow cytometric determination of mitochondrial mass nM MitoTracker in the dark, 37°C, 15 min. Mitochondrial mass per cell was subsequently obtained by quantification of mean fluorescence intensity MFI green on a FACS Canto II flow cytometer BD Biosciences, Franklin Lakes, NJ, United States.

Flow cytometry data were acquired on a FACS Canto II BD Biosciences, Franklin Lakes, NJ, United States. Data analyses were performed using FlowJo v10 FlowJo, Ashland, United States. Expression of mRNA was quantified on a LightCycler instrument Roche Diagnostics, Mannheim, Germany as previously described 9 , In brief, RNA was isolated using the miRNeasy RNA Isolation Kit , Quiagen, Hilden, Germany.

After on-column DNA digestion, cDNA was synthesized from equal amounts of RNA using a Superscript III reverse transcriptase Invitrogen, Carlsbad, CA, United States , random hexamers and oligo dT primers.

Succinate dehydrogenase subunit A SDHA , and TATA Box Binding Protein TBP served as reference genes in all experiments. Primers and probes are specified in Supplementary Table 1.

The second derivative maximum method was used to determine quantification cycles by the LightCycler software. Quantification cycle Cq cut-off was defined for Cq 35, values beyond cut-off were considered unspecific. Statistical analysis was performed using GraphPad Prism 9.

Paired t -test or Wilcoxon matched-pairs signed rank test, as appropriate, served for comparisons. Data were depicted as mean ± SEM MFI, OCR and protein data or as box plots with mean, median, twenty-fifth and seventy-fifth percentiles and range all other , with dots indicating individual values.

Biological replicates are reported in the figure legends. Study subjects exhibited disease severity WHO grade IV or above and respiratory failure requiring continuous oxygen insufflation. One hallmark of this cell exhaustion is a decline in cell number 1.

Laboratory results of our study cohort corroborate these findings by displaying reduced T lymphocyte and cytotoxic T lymphocyte numbers in COVID patients Table 1. Figure 1. Beta-hydroxybutyrate enhances human T-cell immune capacity during COVID For better visualization, a histogram example of one patient is shown.

Paired t -test or Wilcoxon matched-pairs signed rank test, as appropriate. In healthy subjects undergoing KD, immunometabolic reprogramming of T cells occurs, which enables higher mitochondrial energy production through oxidative phosphorylation 8.

Figure 2. Beta-hydroxybutyrate shifts human T-cell metabolism toward oxidative phosphorylation enabling higher mROS production. Histogram depicting exemplary change of MitoTracker green.

Histogram depicting exemplary change of MitoSOX fluorescence. Mitochondrial respiratory chain complexes are the main source for reactive oxygen species ROS Mitochondrial [m]ROS are indispensable for an adequate T-cell immune response 12 , Of note, we did not detect uncontrolled expansion of ROS, as cellular levels of ROS remained unchanged Supplementary Figure 2A , highlighting the concept of mitohormesis 14 , Consequently, neither cellular expression of anti-oxidative glutathione nor the integrity of the mitochondrial membrane were impaired upon incubation with ketone bodies Supplementary Figures 2B,C.

We have recently reported a strong positive impact of a KD on human T-cell immune capacity in healthy volunteers 8. Again, this phenomenon was based on a higher respiratory capacity -enabling superior energy production- and increased mitochondrial ROS which serve as T-cell second messenger.

It is conceivable that the observed effects of ketone bodies represent evolutionary conserved mechanisms for stabilizing human immunity in health and disease. Functional exhaustion of T-cells is known to be linked to mitochondrial dysfunction. Thus, we hypothesized that mitochondrial empowerment through BHB could improve T-cell function during COVID T cells are capable of using BHB via Krebs cycle oxidation, which is known to fuel OXPHOS with superior efficacy 16 , Elevated mitochondrial oxidative phosphorylation translates into increased mROS, as respiratory chain complexes are the major source of mROS T-cell activation and function inevitably relies on mROS, rendering them a pivotal signaling molecule for T-cell immunity 12 , As only D-BHB is metabolically active 7 , 20 — 22 , this refers to 5 mM D-BHB, which is similar to maximum blood ketone levels achievable via ad libitum KD 8.

Since in vitro no BHB synthesis is occurring, higher initial BHB concentrations must be used to ensure adequate ketosis during cell culture. Of note, BHB concentration in cell culture medium at the end of incubation was in the range of 2 mM, thus almost identical to mean blood BHB in vivo Supplementary Figure 2I.

Accordingly, lower initial concentrations of BHB in vitro did not evoke comparably positive effects on human T-cell immunometabolism. On a KD, exogenous supply of ketone esters or the use of MCT oil could help to achieve blood ketone levels close to 2 mM BHB.

They can be further divided into distinct subsets with individual immunological function and metabolic characteristics 24 , Due to their multidimensional beneficial immunometabolic effects, ketone bodies have been proposed as a countermeasure against viral infections To date, no study investigated the impact of BHB on human viral infections.

In mice, BHB has already shown to induce a protective immune response against influenza virus infection Similarly, in beta coronavirus-infected mice, KD improved γδ T-cell immunity and dampened inflammation The potential benefit of KD also expands to other immune cell types.

Macrophages contribute to detrimental immune responses to COVID, which could be ameliorated through redirection of M1 to M2 phenotype via metabolic rewiring on a KD Beyond immunological effects, KD has been proposed as a metabolic therapy against COVID through restoration of systemic energy metabolism Of note, KD in vivo might evoke additional positive effects: carbohydrate restriction results in diminished levels of glucose and insulin, thus breaking the cycle of glucose-insulin-dependent inflammation and immunosuppression 31 — This could be of exceptional importance, since metabolic comorbidities have a devastating impact on COVID patients 37 — Consequently, a retrospective data analysis of COVID patients on a KD revealed correlations to a reduced mortality Prospective randomized clinical trials will now have to evaluate the precise impact of BHB on human metabolism in vivo during COVID Our study paves the road for the development of metabolic treatment strategies against COVID, which now have to be evaluated within the framework of controlled prospective studies.

Of note, the required nutrition formula and protocols are already available. A clinical trial evaluating the impact of KD in sepsis patients has already finished the enrolling phase, and results are expected in the near future The studies involving human participants were reviewed and approved by LMU Ethics Committee.

SH designed the study, planned, supervised and conducted the experiments, prepared figures, and wrote the manuscript.

LG conducted experiments and participated in writing the manuscript. DE participated in figure preparation and writing of the manuscript. MM, MH, J-MB, and BZ participated in the study design.

SK supervised the study and wrote the manuscript. All authors contributed to the interpretation of the data and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

We thank all CORKUM investigators and staff. We thank the patients and their families for their participation in the CORKUM registry. We thank Katja Gieseke and Florian Gosselin for their outstanding technical assistance.

This research was supported by the Munich Clinician Scientist Program MCSP of the LMU Munich SH. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease COVID Front Immunol.

doi: PubMed Abstract CrossRef Full Text Google Scholar. Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID He L, Zhang Q, Zhang Y, Fan Y, Yuan F, Li S.

Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8 T cells in COVID Cell Commun Signal. Rha M-S, Shin E-C. Activation or exhaustion of CD8 T cells in patients with COVID Cell Mol Immunol.

Wei J, Raynor J, Nguyen T-LM, Chi H. Nutrient and metabolic sensing in T cell responses. Buck MD, Sowell RT, Kaech SM, Pearce EL. Metabolic instruction of immunity. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.

Cell Metab. Hirschberger S, Strauß G, Effinger D, Marstaller X, Ferstl A, Müller MB, et al. Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming. EMBO Mol Med.

Möhnle P, Hirschberger S, Hinske LC, Briegel J, Hübner M, Weis S, et al. MicroRNAs and in whole blood enable detection of T-cell immunoparalysis in sepsis.

Mol Med. Google Scholar. Hirschberger S, Hübner M, Strauß G, Effinger D, Bauer M, Weis S, et al. Dixit and his collaborators observed that the ketogenic diet blocked the formation of inflammasomes, which are immune system activators that can cause harmful immune system responses.

The researchers fed a group of mice infected with influenza a keto diet containing less than 1 percent carbs. Another group of infected mice received a standard diet with 58 percent carbs. The ketogenic diet spurred the release of gamma delta T cells, immune system cells that produce mucus in the cell linings of the lung; but the high-carbohydrate diet did not.

An increase in mucus helps capture and eliminate the flu virus from the system, according to researchers. The researchers also found that the keto diet provided no protection against the influenza virus in mice specially bred without these gamma delta T cells.

This confirmed that these cells play a critical role in warding off flu. On the other hand, some dietitians and medical experts believe that a low-carb diet can compromise the immune system.

There is also evidence that a keto diet can be harmful to the gut microbiome , which is essential to overall well-being. William Schaffner, MD , an infectious-disease specialist at Vanderbilt University in Nashville, Tennessee, has not seen significant data connecting diet with flu protection. He notes that there is some evidence that obesity may lead to a weaker response to flu vaccine, so that may be an indication of how diet could affect flu protection.

Research is needed in humans, however, to validate that the keto diet can effectively protect against the flu. Health Conditions A-Z. Best Oils for Skin Complementary Approaches Emotional Wellness Fitness and Exercise Healthy Skin Online Therapy Reiki Healing Resilience Sleep Sexual Health Self Care Yoga Poses See All.

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Journal of Translational Ketosis and Immune System volume 18Article number: Cite this article. Metrics details. The novel coronavirus Sjstem COVID is posing a Ketosis and Immune System Ketodis to the health-care systems worldwide, with an enormous Restorative practices on health conditions and Immunr of lives. Notably, Ketosis and Immune System Ketosi its related comorbidities are strictly related with worse clinical outcomes of COVID disease. Recently, there is a growing interest in the clinical use of ketogenic diets KDsparticularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID disease.