Long covid is a complex condition which is still being understood. It appears to be characterised by endothelial damage, chronic inflammation and mitochondrial dysfunction leading to multiple symptoms, the most prevalent of which include; fatigue, brain fog and shortness of breath. Government statistics currently estimate that 2 million people in the UK are affected by long covid. With many people unable to lead their normal lives due to this debilitating condition and few available therapies for long covid recovery, it is important to consider the pathophysiology of long covid and how dysfunctions that contribute to symptoms can be counterbalanced.
This blog looks at the tangled web of dysfunctions that drive each other following covid infection and highlights potential long covid recovery interventions that may be beneficial for supporting individuals who are experiencing long covid.
ACE 2 receptors
SARS-COV-2 has been shown to enter cells in the body via ACE2, an enzyme which is found in the cell membrane of certain cells. The spike proteins of the virus bind to ACE2 and enter cells, in doing so they cause damage to the enzyme, leading to the loss of ACE2 activity.
It is becoming more understood that many of the complications of covid-19 are associated with ACE2 damage. It has been shown to be vitally important to health by protecting blood vessels, heart, brain, lungs, kidneys and bone marrow from damage, inhibiting inflammation and preventing abnormal blood clotting.1
When ACE2 is damaged it leads to resultant inflammation which has been shown to damage mitochondria (the powerhouses responsible for energy production). Both ACE2 deficiency and mitochondrial dysfunction appear to be at the centre of long covid symptoms and this causes a web of further dysfunction which leads to persistent long covid symptoms.
The arms of this web will be described below:1
Long covid: the web of dysfunction
Although initial covid-19 infections target the respiratory tract, it may also be considered a cardiovascular condition, which explains why the symptoms are so widespread, varied and persistent. The virus has a high affinity for endothelial cells which line blood vessels. It can bind to these cells and cause localised inflammation and microscopic blood clots which affect circulation and therefore oxygen delivery to tissues. These are described as:2
This can lead to the loss of capillaries and stiffness in arteries and veins, causing further disruption to normal cardiovascular health and therefore oxygen delivery.1 Poor oxygen delivery can lead to symptoms such as shortness of breath but also reduced delivery of trophic factors to body and brain which will in turn contribute to common symptoms such as fatigue and brain fog.
These tiny blood clots can lead to the blockage of small blood vessels again disrupting oxygen delivery and can also aggravate endothelialitis.1
Restoring ACE2 signalling can be helpful in alleviating both endothelialitis and microthrombosis1– see below.
Also observed following Covid-19 infections is resultant, severe immune dysregulation involving many aspects of the immune system. These could be identified individually, however, this blog will group them together under immune dysregulation.1
- Immune dysregulation1
- Mast cell activation – this is commonly associated with allergies and atopic conditions. Mast cell mediators, such as histamine, can cause constriction (narrowing) or dilation (widening) of blood vessels; they can also make blood vessels and membranes leaky. Therefore, they are associated with pain, swelling, redness, shortness of breath, diarrhoea, and high or low blood pressure. Additionally, they contribute to migraine headaches, asthma, and irritable bowel syndrome.
- Monocyte polarisation – monocytes have a complex life cycle and change their functions through life. Polarisation occurs when the normal life cycle is disrupted to create a disorganised immune response that favours chronic, unrelenting inflammation. Hence, inflammation should be a major target for long covid interventions.
- Autoantibodies – an increase in antibodies which are targeted towards our own body tissues, known as autoantibodies, are associated with autoimmunity and are seen post covid. Most of the covid-induced autoantibodies only become active when there is inflammation and tissue damage. Decreasing inflammation is therefore essential when considering covid-induced autoimmunity.
- T-cell impairment – SARS-CoV-2 can directly invade T-lymphocytes and disable them, making it harder to eliminate the virus from the body. It also increases susceptibility to reinfection and increases the risk of autoantibodies.
- Viral persistence1
Persistence of vital SARS CoV-2 within the body is thought to be a driver of consistent inflammation. It is known that patients with Covid-19 may still shed the virus through their stool for months following an infection. It is thought viral fragments may persist in the lining of the gastrointestinal tract creating inflammation and leading to an imbalance of beneficial digestive flora.2
- Microbiome disruption1
There appears to be a strong correlation between gut dysbiosis and long covid, in fact, research suggests that individuals are more likely to develop long covid if they have a disturbed microbiome prior to infection and tend to have an overgrowth of potentially harmful bacteria. The production of beneficial short-chain fatty acids (such as butyrate) which support the gut lining integrity and is associated with a healthy microflora is also reduced.3 Disruption to the microbiome and the associated increased permeability of the gut lining contributes to inflammation, immune dysregulation, production of autoantibodies and therefore further mitochondrial dysfunction. Hence, supporting both microbiome diversity and gastrointestinal integrity is essential for long covid patients.
It is fundamental that interventions to help ameliorate long covid support the above dysfunction hence the recommendations below aim to support:
- Restoration of ACE2
- Mitochondrial function
- Reduce inflammation
- Support gastrointestinal integrity and microbiome
Long covid recovery: restoring ACE2
Nutrients which restore ACE2 include1
- Spices and herbs can enhance ACE2 activity. The best studied are rosmarinic acid found in rosemary, lemon balm, basil, sage, thyme, oregano, and spearmint as well as curcumin4,5
- Vitamin D – has been shown to increase cellular levels of ACE26
- Curcumin – increases ACE2 activity and has demonstrated protective effects against covid-19. It also enhances brain recovery after injury and may have direct anti-viral activity4,7
- Omega 3 fatty acids (EPA and DHA) – stimulate ACE2 indirectly, by increasing activity of a group of hormones called Apelins, which are potent promoters of ACE2. Omega-3 fats also prevent abnormal blood clotting, alleviate depression, and help brain recovery, enhancing cognitive function8
- CBD (cannabidiol) is another potent apelin enhancer (and therefore potentially an ACE2 enhancer)9,10
- Resveratrol – directly enhances cellular ACE2 activity. Resveratrol has been shown to aid brain recovery after injury and to enhance immunity by stimulating formation of T-effector memory cells. It may also have direct anti-viral and anti-bacterial effects11
- NAC (N-acetylcysteine) – antioxidant which protects ACE2 from the destructive effects of inflammation. NAC has been shown strengthen immune function and can ameliorate symptoms of influenza as well as demonstrating protective effects on lung tissue. It also supports detoxification pathways in the liver12
Nutrients which support energy production by the mitochondria include13,14
- Thiamine (B1) – Cofactor in the essential step which converts pyruvate into acetyl CoA
- Riboflavin (B2) – Also known as FAD, accepts electrons and donates to the electron transport chain (ETC) in order to produce ATP (energy)
- Niacin (B3) – Also known as NADH (similar to FAD) accepts and donates electron to ETC in order to produce ATP. B3 in the form of nicotinamide riboside is the direct precursor to NAD and therefore may be more effective than B3 as niacin
- Pantothenic Acid (B5) – carrier of Coenzyme A, essential for Acetyl CoA and therefore energy production
- CoQ10 – utilised as a carrier in complex II of ETC. CoQ10 also has antioxidant properties and is found to be depleted in patients with Alzheimer’s disease
- Alpha Lipoic Acid – a coenzyme of pyruvate dehydrogenase and a-ketoglutarate; enzymes responsible for reactions involved in the breakdown of fat and carbohydrate within the mitochondria
- Magnesium – binds to ATP and affects its structure making energy more easily available
Long covid recovery: gut health
Diets high in fibre, vegetables, fruits, antioxidants and prebiotics help to create a healthy microbial balance, whereas diets low in fibre, fruits and vegetables and high in sugar, refined carbohydrates, and processed foods create dysbiosis.15,16
Fermented foods such as kimchi, sauerkraut and fermented vegetables are rich in probiotics (friendly bacteria), which can positively influence the metabolic activity of the microbiome.17
Healthy digestive function can be supported by1,14
- maintaining adequate zinc levels; zinc is very important for the production of stomach acid as well as for maintenance of epithelial tissue which lines the digestive system
- eating prebiotic foods such as baked apples, chicory and artichoke
- eating fermented foods such as kefir, sauerkraut and kimchi to support gut flora
- consider taking a multi-strain probiotic
- using digestive enzymes to improve nutrient digestion, if this is impaired
- drinking bone broths – make a broth from meat carcass (ideally organic) – this is high in the amino acid glutamine which supports the repair of the digestive lining
- increasing foods that support the liver such as brassicas, onions, garlic, rocket and watercress
Mediterranean diet and long covid
The Mediterranean diet has long been associated with wellness and longevity as well as the reduced risk of certain chronic diseases, particularly cardiovascular disease, diabetes, and dementia.
Although not conclusive, some research suggests that a Mediterranean style diet may be beneficial for supporting individuals with long covid recovery.
The Mediterranean diet focuses on providing nutrients which are anti-inflammatory, antioxidant and supportive of the gut microflora, so therefore should be considered as these may attenuate many of the driving forces of long covid.18
The main principles of the Mediterranean diet include:
- an abundance of plant foods, including fruits, vegetables, wholegrains, nuts and legumes, which are minimally processed, seasonally fresh, and grown locally
- olive oil as the principal source of fat
- cheese and yogurt, consumed in low amounts
- fish and poultry, consumed in low to moderate amounts a few times a week
- red meat, consumed infrequently and in small amounts
- wine consumed in low to moderate amounts, usually with meals
It is important to note that long covid is a novel and complex condition and therefore each individual will have specific long covid recovery needs. However, the above interventions are low risk and supportive of wellness as well as addressing potential dysfunction that are contributing to long covid symptoms.
- Covid-19 enters cells via ACE2 enzymes located across cell membranes and in doing so it inactivates the enzyme leading to both inflammation and mitochondrial dysfunction. This subsequently leads to a tangled web of dysfunction which drives further inflammation, mitochondrial dysfunction and leads to symptoms of long covid
- Interventions for long covid recovery involve restoring ACE2 (with nutrients such as rosmarinic acid, curcumin, vitamin D, omega 3 fatty acids, resveratrol, CBD oil and N-acetyl cysteine) and supporting mitochondrial function (with nutrients including B vitamins, CoQ10, alpha lipoic acid and magnesium)
- Additionally, we see persistent inflammation due to viral persistence and immune dysregulation, so supporting immune and anti-inflammatory pathways is essential. The Mediterranean diet is considered supportive due to it anti-inflammatory and antioxidant properties
- It is demonstrated that viral fragments can particularly persist in the GI tract and that patients with long covid appear to have a dysbiotic microbiome before onset of infection. There is an increase in the permeability of the digestive lining, reduced production of butyrate both of which contribute to further inflammation. Therefore digestive supporting interventions including probiotics, prebiotics and a diversity of fibre from plant-based foods is useful.
- Galland L. LONG COVID: PREVENTION AND TREATMENT. Published online 2023.
- Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146. doi:10.1038/S41579-022-00846-2
- Zuo T, Wu X, Wen W, Lan P. Gut Microbiome Alterations in COVID-19. Genomics Proteomics Bioinformatics. 2021;19(5):679-688. doi:10.1016/J.GPB.2021.09.004
- Junior AG, Tolouei SEL, dos Reis Lívero FA, Gasparotto F, Boeing T, de Souza P. Natural Agents Modulating ACE-2: A Review of Compounds with Potential against SARS-CoV-2 Infections. Curr Pharm Des. 2021;27(13):1588-1596. doi:10.2174/1381612827666210114150607
- Liu Q, Tian J, Xu Y, Li C, Meng X, Fu F. Protective Effect of RA on Myocardial Infarction-Induced Cardiac Fibrosis via AT1R/p38 MAPK Pathway Signaling and Modulation of the ACE2/ACE Ratio. J Agric Food Chem. 2016;64(35):6716-6722. doi:10.1021/ACS.JAFC.6B03001
- Getachew B, Tizabi Y. Vitamin D and COVID-19: Role of ACE2, age, gender, and ethnicity. J Med Virol. 2021;93(9):5285-5294. doi:10.1002/JMV.27075
- Catalano A, Iacopetta D, Ceramella J, et al. Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment? Foods. 2022;11(18). doi:10.3390/FOODS11182884
- Goc A, Niedzwiecki A, Rath M. Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry. Sci Rep. 2021;11(1). doi:10.1038/S41598-021-84850-1
- Corpetti C, Del Re A, Seguella L, et al. Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line. Phytotherapy Research. 2021;35(12):6893-6903. doi:10.1002/ptr.7302
- Pitakbut T, Nguyen GN, Kayser O. Activity of THC, CBD, and CBN on Human ACE2 and SARS-CoV1/2 Main Protease to Understand Antiviral Defense Mechanism. Planta Med. 2022;88(12):1047-1059. doi:10.1055/a-1581-3707
- Horne JR, Vohl MC. Biological plausibility for interactions between dietary fat, resveratrol, ACE2, and SARS-CoV illness severity. Am J Physiol Endocrinol Metab. 2020;318(5):E830-E833. doi:10.1152/AJPENDO.00150.2020
- De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB Journal. 2020;34(10):13185-13193. doi:10.1096/fj.202001807
- Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: Role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006;163(1-2):94-112. doi:10.1016/j.cbi.2006.04.014
- Bland J et al. Textbook of Functional Medicine.; 2008.
- Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. 2017;8(2):172-184. doi:10.1080/19490976.2017.1290756
- Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. 2017;8(2):172-184. doi:10.1080/19490976.2017.1290756
- Rezac S, Kok CR, Heermann M, Hutkins R. Fermented foods as a dietary source of live organisms. Front Microbiol. 2018;9(AUG). doi:10.3389/fmicb.2018.01785
- Angelidi AM, Kokkinos A, Katechaki E, Ros E, Mantzoros CS. Mediterranean diet as a nutritional approach for COVID-19. Metabolism. 2021;114:154407. doi:10.1016/J.METABOL.2020.154407
If you have questions regarding the topics that have been raised, or any other health matters, please do contact our team of Nutritional Therapists.