Join the growing number of individuals exploring the benefits of the Keto diet. A low-carb diet can apparently do wonders for inflammation, but it can also do wonders for making you hate all your favorite foods.

A clinical study was conducted to evaluate the effects of a low-carb diet on inflammation. It investigated how a low-carb diet affects inflammation markers. The table shows that the low-carb diet reduces inflammation markers. Especially Interluken-1 beta and TNF-alpha.

The participants all followed this strict diet and reported reduced pain, inflammation, and better quality of life. To understand the data better, we created a table. It shows us info about the trial. The number of people, their ages, the length of the trial, and how much their pain improved.

This study adds to other research showing that the keto diet can do more than help you lose weight. For those suffering from chronic pain or inflammation-related issues like arthritis or IBS, it may bring relief and improve life quality. Research shows that a keto diet can have potential benefits for reducing inflammation.

Moreover, studies suggest that a keto diet has potential benefits in reducing cardiovascular disease, diabetes, and cancer. A pro tip to follow a healthy keto diet is to prioritize nutrient-dense foods like organic meat and vegetables and track macros to maintain a healthy balance of fats, protein, and carbs.

Studies suggest that an anti-inflammatory keto diet can reduce the risk of chronic diseases. High fat, low carbohydrate diets decrease inflammation in the body. This can lower the chance of developing issues such as heart disease, diabetes and certain types of cancer.

Plus, this diet boosts insulin sensitivity and weight loss. This dietary approach focuses on healthy fats like nuts, seeds and avocados instead of processed foods. This keeps insulin levels stable, which stops inflammation. This results in improved health and wellbeing.

Whole foods in an anti-inflammatory keto diet provide nutrients and limit inflammation-causing ingredients. This gives essential vitamins and minerals and helps avoid long-term health issues. To get the most from this diet, work with a healthcare professional or registered dietitian.

Studies suggest that a keto diet can improve cognitive abilities. This dietary approach provides benefits to people looking to boost brain function and quality of life.

The metabolic activities of the keto diet produce ketones which give energy to the brain, improving its productivity. This diet has been seen to increase focus, clarity, and memory retention. Moreover, controlling blood sugar levels reduces inflammation around nerve cells — providing double the prevention against oxidational stress compared to conventional diets.

It is vital to note that this dietary change should not be solely made for cognitive benefits. Seek professional advice before starting any new dietary regimen or changes. The keto diet can bring energy and improved sports performance. It needs careful monitoring and planning for nutrients, fluids, and electrolytes.

But, when done right, the keto diet can boost performance and give health benefits. Maintaining an anti-inflammatory keto diet plan can lead to numerous health benefits.

One unique detail to note is that the keto diet may not be suitable for everyone. Consulting with a healthcare professional before starting any new diet is recommended. Start incorporating these simple steps into your daily routine for a stronger, healthier you.

The Anti-Inflammatory Keto Diet is all about consuming nutrient-rich foods. It eliminates processed foods and refined carbs.

Instead, it recommends whole, unprocessed options. Leafy greens, low carb vegetables, lean meat, oily fish, nuts, seeds, and healthy fats are great anti-inflammatory choices. They boost the immune system and fight inflammation.

This reduces the risk of chronic diseases by supporting gut health and reducing oxidative stress. For an anti-inflammatory keto diet, include beneficial fats and oils!

They promote a healthy heart and brain and reduce inflammation in the body. Opt for olive, avocado or coconut oil instead of vegetable.

Flaxseeds, almonds and chia seeds have omega-3 fatty acids. Eat fatty fish like salmon or sardines too. Get healthy fats from organic eggs. Avocado is great too — it has monounsaturated fat and fiber, potassium, and vitamin K.

When shopping, choose unrefined, organic fats. Remember to switch up your fat sources every week for variety! Processed foods and sugary drinks are big causes of inflammation in the body.

Remember these three key points:. Be aware that natural sweeteners like honey or maple syrup may be healthier than refined sugar, but still use them in moderation on a keto diet.

The Keto diet is linked to potential anti-inflammatory advantages. This lowers blood sugar levels and also decreases insulin production. Research suggests it could decrease inflammatory markers like C-reactive protein CRP.

Also, more wholesome fats such as omega-3 fatty acids and monounsaturated fats , in addition to less processed foods, may bring about a reduction of inflammation in the body.

Studies suggest that the Keto diet could improve illnesses connected to chronic inflammation, such as arthritis, type 2 diabetes and cancer. As inflammation is a major factor in many chronic diseases, the low-inflammatory nature of the Keto diet might be helpful in fighting these conditions.

This dietary approach not only has weight loss and cognitive advantages, but could be beneficial in battling chronic inflammation, too. A: Many studies suggest that the Keto diet can have anti-inflammatory effects on the body, as it promotes the consumption of healthy fats and limits processed foods and sugar.

A: Some benefits of an anti-inflammatory diet include reduced risk of chronic diseases, improved digestion, clearer skin, and better overall health and well-being.

A: It is possible for some individuals to experience increased inflammation on the Keto diet, particularly if they consume too many processed fats or have an underlying health condition that makes it difficult for their body to process fats effectively.

A: To maintain an anti-inflammatory Keto diet, focus on consuming healthy fats like olive oil, avocados, and nuts, while minimizing processed foods and added sugars. This diet was introduced as an anticonvulsant treatment for drug-refractory epilepsy, and has very low carbohydrate content as a means to induce a metabolic state similar to fasting but without caloric restriction.

In this metabolic state, the liver converts fatty acids to ketone bodies which circulate to be used by other tissues as fuel during reduced availability of glucose; a ketone body-based metabolism should produce fewer free radicals than one based on glucose The KD should reduce inflammation as it enhances various antioxidant mechanisms 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , Indeed, KD treatment reduces reactive oxygen species 17 , 18 , 27 , 28 , 29 , 30 , 31 , 32 , limits oxidative damage to DNA 17 , 20 , 33 , lipids 29 , 34 , 35 , 36 , 37 , and proteins 16 , 20 , 23 , 35 , and modulates immune cell function 28 , Most of these studies did not use a calorie-restricted KD.

In spite of the conceptual overlap among inflammation, pain, oxidative stress, and the KD, there has been very little work on the KD as a treatment for inflammatory pain. Here we tested a KD in a rodent model of experimental inflammatory pain, specifically investigating allodynia and measures of spontaneous pain.

All procedures were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and approved by the Institutional Animal Care and Use Committee of Trinity College A Treatment started at 10—16 week of age rats or 6—8 week mice.

Animals remained on their control diet CD; LabDiet or were switched to a KD BioServ ; all diets were provided ad libitum.

KD was replaced daily. Diet treatment proceeded for three or four weeks before behavioral studies began, and continued through the end of experimentation. Animals were gently handled daily for several days before testing, to reduce handling stress during behavioral studies and to make animals docile for paw volume testing.

All testing occurred during the lights-on period of the daily cycle. All CFA injections were performed in the morning to keep the four h time point well within the light cycle. At various times before and after CFA injection, tactile sensitivity was measured with an electronic von Frey probe IITC, Fig.

The rigid von Frey probe was applied alternately to each hindpaw until the animal either withdrew the paw or allowed it to be lifted by the probe; the maximum force on each trial was recorded. Three trials with no less than a s intertrial interval occurred per hindpaw.

If the animal began to take a step or otherwise shift its position during a trial, that trial was repeated. In rats, spontaneous pain behavior was assessed 48 h prior to and 24 h after CFA injection. Later, videos were watched for indications of spontaneous pain for 60 s every five minutes; videos were watched by two scorers who were independent and blind to dietary treatment and pre- versus post-CFA state.

Epochs with grooming or locomotion were avoided. Position of each hindpaw was placed into the following categories: 0, normal weight bearing; 1, light weight bearing; 2, only paw edge touching floor; 3, paw nearly raised off floor; 4, paw completely raised; 5, licking raised paw, and time spent in each position was recorded.

This test was not used in mice as preliminary experiments indicated that mouse paws were too small to reliably distinguish the categories. In rodents, ongoing painful states interfere with ongoing behavior 40 , 41 , We assessed this effect in mice with marble burying 43 , 44 , 45 at the indicated times Fig.

Photos were taken vertically from above before and after the session and analyzed with Photoshop. This calculation was performed on before and after pictures, with the comparative decrease in the marble percentage compared to before indicating the amount of burying.

Data from two mice that demonstrated very little burying in the baseline test were excluded from analysis. The marble burying test was not used in rats as preliminary experiments indicated that rats did virtually no burying under our conditions.

Volumes of rat hindpaws were measured by water volume displacement in 25 ml graduated cylinders 24 h prior to and 50 h after CFA injection. At sacrifice of subjects, glucose and the ketone body β-hydroxybutyrate were measured in tail vein blood with Precision Xtra meters Abbott.

T-tests were used for CD versus KD comparisons, with significance indicated by pound signs. For comparisons of post-CFA time points to baseline time points, multiple Bonferroni comparisons were made, with significance indicated by asterisks. Plantar tactile sensitivity was low in baseline and not different between CD- and KD-fed rats in injected paws CD All rats demonstrated strong allodynia of the injected hindpaw; however the magnitude of this effect was significantly smaller at 4 h post-injection in KD-fed animals Fig.

This difference did not remain significant at the 48 h time point Fig. As expected, plantar tactile sensitivity did not change with diet or time in the uninjected hindpaw Fig. Effects of CFA and diet treatment on tactile allodynia in rats assessed by electronic von Frey probe.

For the injected paw, all 4 h and 48 h groups are significantly different from baseline not indicated.

There were no treatment effects on control paw sensitivity. ketogenic diet. Behaviors indicative of ongoing pain states related to the hindpaws such as licking and avoiding weight bearing were essentially absent pre-CFA, as expected Fig. After injection, such behaviors were present and directed to only the injected hindpaw in all rats; however there was a strong trend toward less such behavior in KD-fed rats Fig.

Effects of CFA and diet treatment on spontaneous expression of pain in rats. The spontaneous pain score was calculated from observations on paw favoring, lifting, and licking before and 24 h after CFA injection.

For the injected paw, spontaneous pain was significantly higher compared to pre-injection for both groups not indicated. However, there was a strong trend for spontaneous pain to be lower in ketogenic diet-treated rats.

There were no effects regarding the uninjected paw. As expected 46 , CFA-induced hindpaw swelling was significantly reduced by KD treatment, measured by change in volume from baseline Fig. The uninjected hindpaw was unaffected Fig.

Effects of dietary treatment on CFA-induced inflammatory paw swelling in rats. Paw volume was expressed as the difference between volume at 50 h after CFA injection and volume at baseline. There was significantly less swelling in rats fed the ketogenic diet.

There was no effect in control paws. Plantar tactile sensitivity was low in baseline and not different between CD- and KD-fed mice in injected paws CD 3. All mice demonstrated robust tactile allodynia of the CFA-injected hindpaw; however, in CD-fed mice significant allodynia remained out to the last time point assessed 7d , whereas in KD-fed mice allodynia was starting to reverse at 2d and tactile sensitivity was no longer different from baseline at 4d Fig.

Effects of CFA and diet treatment on tactile allodynia in mouse assessed by electronic von Frey probe. Injected paws became hypersensitive after CFA injection, but the rate of recovery differed in the groups.

Control diet-fed mice were still strongly hypersensitive at the last examined timepoint, whereas a gradual and complete recovery occurred in ketogenic diet-fed mice. There were no effects in the uninjected paw. Baseline marble burying was not different between CD- and KD-fed mice CD Marble burying in mice was strikingly reduced after CFA injection, likely indicating an ongoing pain state Fig.

Burying behavior slowly recovered in both diet groups; and statistics indicated that there was no diet-related difference in recovery rate. Notably, at 4 and 7 days the KD group is burying at levels above baseline, albeit non-significantly, something not found in the CD group Fig.

Effects of ongoing pain and dietary treatment on marble burying in mice. CFA injection reduced marble burying in all mice, with no effect of dietary treatment. Ketogenic diet treatment strongly elevated blood ketone bodies in both species, reduced blood glucose in mice, and produced a trend for decreased mouse body mass Table 1.

We found that treatment with a KD significantly ameliorated CFA-induced tactile allodynia in two model species, with more modest effects on indices of ongoing spontaneous pain. These results may appear to contradict a large body of literature showing that high-fat diets promote inflammation However, this literature refers to diets such as the Western or standard American diet SAD , high in fat but not low in carbohydrates.

Metabolic syndrome-related allodynia relates to inflammation in the peripheral nervous system 65 , and as diabetic neuropathy is thought also to involve inflammation in the spinal cord 66 , beneficial effects of the KD against pain syndromes involving inflammation could be peripheral, central, or both.

KD treatment, however, appears not to be equally effective in all neuropathic pain syndromes 67 possibly relating to involvement of inflammation. Clinical work with KD and pain had a very early start, specifically regarding migraine 68 , 69 and this use may be undergoing a resurgence Notably, oxidative stress has been hypothesized to be the trigger of many types of migraines Overall body pain is alleviated in overweight diabetic patients 74 , although it was not specified if the type of pain was neuropathic.

Given the metabolic parallels between KD treatment and fasting, and the established efficacy of fasting against rheumatoid arthritis 75 , 76 , a KD could be particularly useful in this disorder.

Existing studies suggest little clinical benefit 77 , 78 ; however, KD treatment in these studies lasted only seven days to parallel a fasting treatment, which was itself effective. We have found that antinociceptive effects of the KD evolve over days to weeks 79 and others have found a similar pattern in reduced oxidative stress 18 , suggesting that longer treatment durations should be attempted in rheumatoid arthritis.

There were several differences between the results with rats and mice. Mice appeared to be more affected physiologically by ketogenic diet treatment, with lowered glucose and a trend to lower body mass not occurring in rats and a more than two-fold higher elevation in β-hydroxybutyrate than in rats.

These are clearly species related. There were also differences in behavioral outcomes. The ketogenic diet improved tactile allodynia in rats at four hour post-injection, but not later, whereas beneficial effects on tactile allodynia in mice appeared in the two to four day range and persisted thereafter.

Given relative species paw sizes and the currently used doses of CFA, the effective dose in mice is substantially higher, and so either or both dose and species could underlie these differences in diet responsiveness.

Ongoing pain states were unaffected by diet in mice, with a trend to improvement in rats. Species differences, however, led us to use different tests for each species. The mouse marble burying test clearly showed that a state of ongoing pain reduced performance of this behavior.

The lack of a ketogenic diet effect indicates that either that the diet does not improve spontaneous pain in this model in mice, or that marble burying is inappropriate behavior to assess these types of changes.

It is somewhat unclear which of the main metabolic actions of a KD elevated ketone bodies, lowered and less variable glucose leads to limiting inflammation and inflammatory pain.

In fact, acute hyperglycemia elevates circulating cytokines through an oxidative mechanism On the other hand, elevated ketone bodies themselves seem to have beneficial effects: in vivo and in vitro studies show that β-hydroxybutyrate itself moderates the endoplasmic reticulum stress-induced inflammasome 91 , 92 and the NRLP3 inflammasome 49 , 60 , 92 , 93 , 94 in various organs in a manner apparently unrelated to its use as a substrate for the tricarboxylic acid cycle In addition, free fatty acids from a KD might be directly beneficial by reducing mitochondrial production of reactive oxygen species Besides being anti-inflammatory, there are other possible mechanisms for a KD to limit pain Regardless of mechanism, this study and a growing body of evidence suggest that pain be added as a variable in more clinical studies of the KD generally, and specifically that more studies of KD treatment in clinical inflammatory pain syndromes is warranted.

Lugrin, J. et al. The role of oxidative stress during inflammatory processes. Article CAS PubMed Google Scholar. El Assar, M. Frailty as a phenotypic manifestation of underlying oxidative stress.

Free Radic. Article PubMed CAS Google Scholar. Newsholme, P. Oxidative stress pathways in pancreatic beta-cells and insulin-sensitive cells and tissues: Importance to cell metabolism, function, and dysfunction. Cell Physiol. Dinh, Q. Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress.

Aging Albany NY 9 6 , — Article CAS Google Scholar. Oyarce, M. Contribution of oxidative stress and inflammation to the neurogenic hypertension induced by intermittent hypoxia. Article PubMed PubMed Central Google Scholar. Pangrazzi, L. Oxidative stress and immune system dysfunction in autism spectrum disorders.

Puttachary, S. Seizure-induced oxidative stress in temporal lobe epilepsy. Article PubMed PubMed Central CAS Google Scholar. Blesa, J. PubMed PubMed Central Google Scholar.

Abdul-Muneer, P. Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Totsch, S. Effects of a Standard American Diet and an anti-inflammatory diet in male and female mice.

Pain 22 7 , — The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury. Pain 17 , — Article PubMed Google Scholar.

Pain 17 1 , — Veech, R. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: Ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.

Prostaglandins Leukot. Fatty Acids 70 , — Kim, D. Ketones prevent oxidative impairment of hippocampal synaptic integrity through K ATP channels.

PLoS ONE 10 , e Nazarewicz, R. Effect of short-term ketogenic diet on redox status of human blood. Rejuvenation Res. Greco, T. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. Blood Flow Metab. Jarrett, S. The ketogenic diet increases mitochondrial glutathione levels.

Milder, J. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Article CAS PubMed PubMed Central Google Scholar. Lu, Y. Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling pathways.

Shimazu, T. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science , — Article ADS CAS PubMed Google Scholar. Elamin, M. Scheibye-Knudsen, M. Kephart, W. The 1-week and 8-month effects of a ketogenic diet or ketone salt supplementation on multi-organ markers of oxidative stress and mitochondrial function in rats.

Nutrients 9 , E Knowles, S. Ketogenic diet regulates the antioxidant catalase via the transcription factor PPARγ 2. Epilepsy Res. Benlloch, M. Satiating effect of a ketogenic diet and its impact on muscle improvement and oxidation state in multiple sclerosis patients.

Nutrients 11 , Article CAS PubMed Central Google Scholar. Nakamura, K. A ketogenic formula prevents tumor progression and cancer cachexia by attenuating systemic inflammation in colon 26 tumor-bearing mice. Nutrients 10 2 Davis, L.

UCP-mediated free fatty acid uncoupling of isolated cortical mitochondria from fasted animals: correlations to dietary modulations. Epilepsia 49 Suppl. Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis.

PLoS ONE 7 , e Article ADS CAS PubMed PubMed Central Google Scholar. Kong, G. Beyond epilepsy, there are yet additional potential uses in neurological disorders because KD appears to have the broad anti-inflammatory and neuroprotective properties. The KD exerts anti-inflammatory action against a variety of experimental models of neurological disorders including multiple sclerosis, Parkinson's disease, pain, and spinal cord injury.

Anti-inflammatory action of KD appears to be mediated by multiple mechanisms.

If you have a family predisposition to these issues, it can happen that much more quickly. What you choose to put into your body in the form of foods has a drastic effect on your inflammation levels. Many people in pain who are suffering from inflammation are looking for alternative approaches.

They can cause serious side effects and become addictive very easily. Being in ketosis helps reduce inflammation, but it can also help you ease pain related to:. The body being in ketosis cause three specific ketone bodies to be released.

Of the three ketones, the most important and the one which allows us to monitor ketosis levels is beta-hydroxybutyrate. Could it all really be so simple?

Could dieting lead us down the road to relief from pain? Studies are starting to show that it can more often than not. There are still discoveries to be made, but science and nutrition are working hand in hand, moving in the right direction.

This is only a scratch on the surface. As these findings continue to come out related to pain and the way it can be treated, we will be sure to keep you updated! Puppala and the staff here would love to help you in any way we can, whether that be an explanation or a procedure.

Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, Sokolove J. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. Article CAS Google Scholar. Chow YY, Chin KY. The role of inflammation in the pathogenesis of osteoarthritis.

Mediat Inflamm. Article Google Scholar. Hu N, Gong X, Yin S, Li Q, Chen H, Li Y, et al. Saxagliptin suppresses degradation of type II collagen and aggrecan in primary human chondrocytes: a therapeutic implication in osteoarthritis.

Artif Cells, Nanomed Biotechnol. Schroder K, Tschopp J. The inflammasomes. McAllister MJ, Chemaly M, Eakin AJ, Gibson DS, McGilligan VE. NLRP3 as a potentially novel biomarker for the management of osteoarthritis.

Osteoarthr Cartil. Cheng F, Yan FF, Liu YP, Cong Y, Sun KF, He XM. Dexmedetomidine inhibits the NF-kappaB pathway and NLRP3 inflammasome to attenuate papain-induced osteoarthritis in rats. Pharm Biol. Ni B, Pei W, Qu Y, Zhang R, Chu X, Wang Y, et al.

MCC, the NLRP3 inhibitor, protects against cartilage degradation in a mouse model of osteoarthritis. Oxidative Med Cell Longev. Google Scholar. Bai H, Yuan R, Zhang Z, Liu L, Wang X, Song X, et al. Intra-articular injection of baicalein inhibits cartilage catabolism and NLRP3 inflammasome signaling in a posttraumatic OA model.

Liu Z, Liao T, Yang N, Ding L, Li X, Wu P, et al. Front Pharmacol. Yang H, Shan W, Zhu F, Wu J, Wang Q. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms.

Front Neurol. Kong G, Liu J, Li R, Lin J, Huang Z, Yang Z, et al. Ketone metabolite beta-hydroxybutyrate ameliorates inflammation after spinal cord injury by inhibiting the NLRP3 inflammasome.

Neurochem Res. Kong G, Huang Z, Ji W, Wang X, Liu J, Wu X, et al. The ketone metabolite beta-hydroxybutyrate attenuates oxidative stress in spinal cord injury by suppression of class I histone deacetylases.

J Neurotrauma. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. Cheng CW, Biton M, Haber AL, Gunduz N, Eng G, Gaynor LT, et al.

Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al.

Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science New York, NY. Ding J, Xu X, Wu X, Huang Z, Kong G, Liu J, et al. Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats.

Exp Ther Med. Wen ZH, Tang CC, Chang YC, Huang SY, Lin YY, Hsieh SP, et al. Calcitonin attenuates cartilage degeneration and nociception in an experimental rat model of osteoarthritis: role of TGF-beta in chondrocytes. Sci Report. Ji Q, Xu X, Zhang Q, Kang L, Xu Y, Zhang K, et al.

J Mol Med. Wang C, Zeng L, Zhang T, Liu J, Wang W. Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols.

Biomed Pharmacother. Khan NM, Haseeb A, Ansari MY, Devarapalli P, Haynie S, Haqqi TM. Free Radic Biol Med. Griffin TM, Scanzello CR. Innate inflammation and synovial macrophages in osteoarthritis pathophysiology. Clin Exp Rheumatol. PubMed Google Scholar. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.

Cell Metab. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Muller-Fielitz H, et al. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun. Zhang L, Shi J, Du D, Niu N, Liu S, Yang X, et al.

Ketogenesis acts as an endogenous protective programme to restrain inflammatory macrophage activation during acute pancreatitis. Fu SP, Li SN, Wang JF, Li Y, Xie SS, Xue WJ, et al. BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-kappaB activation. Wu X, Huang Z, Wang X, Fu Z, Liu J, Huang Z, et al.

Ketogenic diet compromises both cancellous and cortical bone mass in mice. Calcif Tissue Int. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.

Nat Med. Wu Y, Teng Y, Zhang C, Pan Y, Zhang Q, Zhu X, et al. The ketone body beta-hydroxybutyrate alleviates CoCrMo alloy particles induced osteolysis by regulating NLRP3 inflammasome and osteoclast differentiation.

J Nanobiotechnology. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics.

Nat Rev Immunol. Zhao LR, Xing RL, Wang PM, Zhang NS, Yin SJ, Li XC, et al. Mol Med Rep. CAS PubMed Google Scholar. Zu Y, Mu Y, Li Q, Zhang ST, Yan HJ. Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis.

J Orthop Surg Res. Download references. This study was supported by grants from the National Natural Science Foundation of China , Natural Science Foundation of Guangdong Province A , and Guangzhou Science and Technology plan project Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No.

Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. You can also search for this author in PubMed Google Scholar. Ganggang Kong, Jinyang Wang, Rong Li, and Zhiping Huang performed the experiments. Ganggang Kong designed the study. Le Wang wrote the manuscript.

All authors read and approved the final manuscript. Correspondence to Ganggang Kong or Le Wang. All procedures in this study were conducted in accordance with the protocols approved by the Laboratory Animal Care and Use Committee of Nanfang Hospital, Southern Medical University.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.

The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Reprints and permissions. Kong, G. et al. Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis. Arthritis Res Ther 24 , Download citation. Received : 20 August You are using a browser version with limited support 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.

Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus.

We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines i.

Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.

Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 , the cause of coronavirus disease COVID , has irreversibly impacted human health and life expectancy 1. COVID can lead to heterogeneous symptoms, which span from asymptomatic infections to respiratory failure with systemic toxicity and multi-organ dysfunction 2 , 3 , 4.

Observational studies of COVID revealed that metabolic pro-inflammatory comorbidities such as obesity and diabetes, are associated with disease severity 5 , 6.

The interplay between metabolism and the immune-inflammatory response can significantly impact patient health during viral infection 7 , 8 , 9 , 10 , 11 , In particular, the implementation of a ketogenic diet KD can be harnessed to improve immunity and protect from inflammatory damage The KD regimen has shown effective in enhancing immunity across independent studies and in activating protective γδ T cells 14 , 15 , Consequently, systemic reprogramming induced by the KD may alter COVID multi-organ toxicity 17 , The ketogenic diet KD entails the intake of high-fat, low-carbohydrate foods that activate the production of ketone bodies i.

In ketogenesis, lipids and proteins are used to support cellular energy demands by providing metabolic intermediates ketone bodies that function as fuel in lieu of glucose 20 , Similarly to starvation and fasting, under KD peripheral fat is mobilized towards the liver for ketogenic catabolism of fatty acids via β-oxidation to acetyl-CoA, later converted in BHB, ACA, AC.

These are distributed to the peripheral tissues and central organs to sustain energy demands while bypassing glucose oxidation Supplementary Fig. In our recent study, we demonstrated that SARS-CoV-2 induces severe systemic extrapulmonary toxicity and metabolic reprogramming of vital organs in a murine model within 7 days of infection Mice expressing the hACE2 transgene via adenoviral delivery and infected with SARS-CoV-2 showed suppression of oxidative phosphorylation OXPHOS and of the tricarboxylic acid cycle TCA at the transcriptional level, accompanied by severe myocardial toxicity decreased heart rate, myocardial edema, and myofibrillar disarray.

Key metabolites of the TCA cycle showed directional decrease consistent with the transcriptional response This phenotype was associated with profound weight loss, massive peripheral fat mobilization, and morbidity within 7 days from infection, which led us to hypothesize that ketogenesis may affect the systemic response to SARS-CoV Here we sought to determine whether a KD may improve mice health by reducing extrapulmonary systemic toxicity and inflammation induced by infection with SARS-CoV First, we developed a murine model susceptible to viral infection that recapitulates metabolic and transcriptional changes of systemic ketosis.

Next, we monitored mice health over one week from infection under KD or control chow diet CD and performed multi-organ transcriptional and metabolic profiling Fig. Our data indicate that a KD attenuates systemic toxicity following SARS-CoV-2 infection.

Reduced multi-organ transcriptional reprogramming suggests that a KD anticipates adaptive systemic changes induced by viral infection. We observed reduced metalloproteases and increased inflammatory homeostatic gene transcription in the heart and liver.

Further analysis performed on mice serum revealed decreased pro-inflammatory cytokines i. Metabolomics profiling also indicated decreased metabolism rewiring in the heart and rescued amino acid, nucleotide, energy currency metabolites, acyl-Coenzyme A pool acyl-CoAs , and lipid precursors in all tissues of KD fed mice.

Created with BioRender. Taken together our observations provide a solid rationale to investigate the efficacy of targeted dietary and metabolic interventions for improved COVID acute and potentially chronic long COVID disease outcomes. We set out to determine whether a KD may mitigate SARS-CoV-2 induced systemic toxicity and overall animal health.

We used a murine model of SARS-CoV-2 systemic toxicity we have recently described To determine the role of ketogenesis in affecting systemic toxicity, animals were placed on a KD or CD ad libitum for 2 weeks.

CD and KD composition by weight and energy values kcal are reported in Fig. Serum BHB increased after two weeks of KD in hACE2-AAV-9 mice, while glucose levels remained unchanged Supplementary Fig. Prior to SARS-CoV-2 infection, both mice on CD and KD maintained steady body weight Supplementary Fig.

Genes involved in ketogenesis, lipid β-oxidation and other PPARα targets were upregulated in the liver, while genes involved in lipid synthesis Fas, Scd-1, Srebp-1c were suppressed Supplementary Fig. Gene Ontology GO process pathway enrichment analysis of differentially regulated genes DEGs confirmed the upregulation of lipid catabolism, β-oxidation, and oxygen transport Supplementary Fig.

These data demonstrate robust ketogenesis in animals following 2 week administration of KD versus CD. Mice on a KD showed reduced food intake but similar calorie intake over one week from infection, an observation consistent with the different caloric content of the CD and KD pellets 6.

With the progression of time from infection, both CD and KD groups showed a significant decrease in food and calorie intake. 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.