-The ACE1 rs4343 gene is characterized by a genetic deletion/insertion (D/I) polymorphism and is associated with approximately 60% of circulating and tissue concentrations of ACE
- The GG genotype is associated with a higher baseline of the ACE1 enzyme in serum, AG intermediate, and AA low ACE1
- **High ACE1 leads to low ACE2**

- In a twins study, after six weeks of a high saturated fat diet over 37%, circulating ACE concentrations increased by 15%, accompanied by an increased ACE gene expression in adipose tissue.
- **The homozygous carriers (GG) of the variant had higher baseline ACE concentrations and additionally showed a 2-fold increase in ACE concentrations in response to the high saturated fat diet as compared to the AA and AG genotype**
- GG carriers also responded with higher systolic blood pressure as compared to AA and AG carriers

- Women have naturally lower levels of ACE1, and men may have a higher probability of ACE1 expressing higher
- The ACE1/ACE2 imbalance during ACE2 receptor suppression in the presence of SARS-CoV-2 infection is more likely in men and may help explain the differences in severity based on sex

ACE1 inhibition has been demonstrated in research by bilberry, grapes, allicin (raw garlic), cinnamon, and jasmine.

Research for ACE1

- AGTR1 encodes for the Angiotensin-II receptor type 1 enzyme
- The CC genotype was also more prone to high blood pressure from a high fat – especially with excessive carbohydrates – diet
- The NF-kb pathway is a downstream target of AGTR1
> This means that elevated ACE1 and the upregulation of AGTR1 combined puts the body in an inflammatory state, allowing a virus to thrive

- Nitric oxide downregulates AGTR1, balancing out the variant upregulation and blood pressure
- To do this, include nitric oxide precursors like L-arginine, folate, vitamin C, magnesium, vitamin D, DHA, and leafy green vegetables.

Research for AGTR1

- The expression of ACE2 has been detected in nasal epithelial cells, alveolar epithelial type II cells of lungs, and the luminal surface of intestinal epithelial cells
- The nose, lungs, and intestine facilitate viral entry and serve as a potential site of viral invasion
- However, it appears the expression of TMPRSS2 determines the ability of the virus to enter the cells

- Research has suggested that age, sex, and genetic variants in the ACE2 gene can potentially affect ACE2 levels in the body
- Children generally have higher levels of ACE2 than adults. Women have been found to have higher ACE2 levels than men due to the upregulation of ACE2 by estrogen
- This could be the foundational reason men and post-menopausal women are more susceptible to COVID-19

- One study of 534 subjects found that 67% of the variation in circulating ACE2 could be accounted for by genetic factors. Among different polymorphisms, it has been speculated that ACE2 rs2106809 might exhibit primary effects on the ACE2 levels. The circulating ACE2 levels tend to be greater in AA or AG genotype compared with that in the GG genotype.

- How do you increase ACE2 expression? Potassium, vitamin D, and resveratrol. What was interesting about resveratrol is that it mitigated the effect of a high-fat diet by increasing the expression of ACE2 in animal studies. Betulinic acid (chaga mushroom) and oleanolic acid (olive oil) have also been studied as SARS-CoV-2 entry inhibitors.

Research for ACE2

- TMPRSS2 expression is several times higher in the prostate compared with any other tissue, as well as the upper digestive and respiratory tract.
- ESR2 is also found in the prostate, lungs, breast, and the cardiovascular system with implications in blood clotting. TMPRSS2 acts like the shape of the keyhole, while ACE2 is the actual lock. A higher expression of TMPRSS2 means a better keyhole fit for viruses
- In a study looking at the Italian population, expression levels of both ACE2 and TMPRSS2 were assessed. Researchers found no significant evidence that ACE2 is associated with COVID-19 severity or sex bias in the Italian population
> However, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, contributing to the observed epidemiological data among Italian patients. Genes related to higher levels of TMPRSS2 were more frequent in Italians vs. East Asian populations.
- Research has found that the expression of the fusion gene TMPRSS2:ERG, which is thought to be responsible for up to 80% of prostate cancers, is repressed by estrogen receptor beta (ESR2 gene) agonists. Phytoestrogens are agonists known to have up to 30-fold greater affinity for estrogen receptor beta.

DECREASING THE EXPRESSION OF TMPRSS2
-  Phytoestrogens, curcumin, and lycopene (tomato sauce)
- Research has shown that curcumin binds to receptor-binding domain site of viral S protein and also to the viral attachment sites of ACE2 receptor and downregulates TMPRSS2, demonstrating that curcumin can act as potential inhibitory agent antagonizing the entry of SARS-CoV2 viral protein.
> Variants in the ESR2 gene increase the need for phytoestrogens for prostate and breast health. Post-menopausal women will also benefit from increasing phytoestrogen intake.

Research for TMPRSS2 and ESR2

- Balance ACE1/ACE2 with appropriate fat intake based on gene results, making sure vitamin D is in range, increasing potassium intake from plants, and foods high in resveratrol.
> Foods that have demonstrated ACE1 inhibition including bilberry, grapes, raw garlic, cinnamon, and jasmine.
- For those with variants in ESR2 and the TMPRSS2 gene, and post-menopausal women, increase phytoestrogen, turmeric, and lycopene (tomato sauce) intake
- The best phytoestrogens in research for blood pressure and the ESR2 gene include dark berries (contains resveratrol), beans, rye, hummus, peanuts (contains resveratrol), miso soup, flax seeds (women), tahini sauce, and cruciferous vegetables (broccoli, cabbage, kale, Brussels sprouts)
- Higher levels of TMPRSS2 have been found to upregulate and activate NF-kb creating an inflammatory environment. NF-Kb inhibitors can be both preventative for inflammation and successful with slowing viral aggressiveness.
> These include vitamin C, vitamin D, zinc, selenium, magnesium, resveratrol (red wine, peanuts, pistachios, blueberries, bilberries, cranberries, cacao, and muscadine grapes), triterpenoids (Chaga, reishi, olive oil, holy basil), caffeic acid (coffee, Chaga, red wine, elderberry), and anthocyanins (elderberry, gogi berries, cacao).
- Zinc and copper should be at a 15mg to 1mg balance. A balanced diet of animal and plant foods typically hit this ratio.
> A plant-based diet may be low in zinc and high in copper and can cause sodium cravings.
> High iron levels, malabsorption syndromes, and high amounts of supplemental zinc without copper can push copper too low.
> Copper deficiency can enhance the vulnerability of the heart and blood vessels to damage.

Nutritional Strategies

- The optimal status of specific nutrients is considered crucial to keeping immune components within their normal activity, helping to avoid and overcome infections
- Specifically, the European Food Safety Authority (EFSA) evaluated and deems six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium) to be essential for the normal functioning of the immune system
- an update on the evidence of the contribution of nutritional factors as immune-enhancing aspects, factors that could reduce their bioavailability, and the role of the optimal status of these nutrients within the COVID-19 pandemic context was carried out
- Results from the review approach show the importance of maintaining a correct nutritional status of these 10 nutrients analyzed for the health of the immune system, highlighting the importance of Vitamin D and iron in the context of COVID-19
- the ecological study demonstrates that intake levels of relevant micronutrients-especially Vitamins D, C, B12, and iron-are inversely associated with higher COVID-19 incidence and/or mortality, particularly in populations genetically predisposed to show lower micronutrient status
- Overall, nutrigenetic data provided by joint assessment of 10 essential nutrients for the functioning of the immune system and of the genetic factors that can limit their bioavailability can be a fundamental tool to help strengthen the immune system of individuals and prepare populations to fight against infectious diseases such as COVID-19

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

SUMMARY OF CURRENT INFO
- Research for ACE1
- Research for AGTR1
- Research for ACE2
- Research for TMPRSS2 and ESR2
- Nutritional strategies

ARTICLES
- Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

Michigan State University

- "Western diets" and saturated fatty acids
- High fiber and balanced diets
- Malnutrition 
- Overnutrition
- Noncommunicable Diseases 
- Vitamin D
- Nutrition Therapy in Critically Ill Patients With Coronavirus Disease 2019
- Eucaloric Ketogenic Diet (EKD)
- Nutritional status of patients with coronavirus disease 2019 (COVID-19)
- Easy-to-prescribe nutrition support in the intensive care in the era of COVID-19
- Anti-inflammatory foods 
- Nutrigenomics
- Epigenetics
- Polyphenols
- Gastrointestinal Manifestations of COVID-19
- Vitamin C
- Maternal and child health

Focuses of Effects of human nutrition in fighting COVID-19

https://nutritiongenome.com/the-latest-nutrigenomic-research-on-covid-19/

The Latest Nutrigenomic Research on COVID-19

A Western Diet is high in saturated fatty acids, refined carbohydrates, and sugars. It is also marked by low consumption of fiber, unsaturated fats, and antioxidants.

Western Diets

Proper nutrition is essential for the body to fight off viral infections. Lack of proper nutrition can not only decrease the immune system's ability to fend off infection, but also increase the likelihood of other comorbidities that increase the fatality of COVID-19.

The effects of malnutrition on fighting COVID-19

Noncommunicable diseases, also known as chronic diseases, are noninfectious and may be caused by an individual's lifestyle, genetics, or environment. There is a direct link between noncommunicable diseases and the severity of viral infections. 

As such, conditions like high blood pressure and diabetes are thought to exacerbate the severity of COVID-19. Researchers propose the best way to combat COVID-19 for individuals with noncommunicable diseases is based in lifestyle changes, with a focus mostly on diet. See: 

- The Mediterranean Diet 
- Vitamins C, D, and E 
- Zinc, Copper, and Fiber 

Noncommunicable Diseases

As therapeutic interventions remain largely experimental, supportive care in the form of nutrition management is integral for critically ill patients.

Nutrition Therapy in Critically Ill Patients With CoronavirusDisease 2019

High fiber and balanced diets are rich in whole grains, cereals, fruits, vegetables and legumes . 

High fiber and balanced diets 

Individual diet plays a significant role in affecting immune response and COVID-19 susceptibility. On the molecular level, certain intake of nutrients can contribute to the activation of certain helper T-cells, B-cells, etc. as well as secretion of signaling molecules like transcription factors that can modulate gene expression. For instance, high consumption of red meat, high glycemic index (GI) food, and high fat often lead to accumulation of visceral fat that causes hormonal imbalances in cytokines secretions. One common effect is chronic expression of pro-inflammatory cytokines like TNFα, IL-1β, and IL-6. Long-term expression of these cytokines triggers increase of Leptin, a downstream cytokine that serves as a positive feedback loop in further enhancing the expression of TNFα, IL-1β, and IL-6. Expression of these cytokines has found to be involved with decreased T-cell population, which explains why this kind of diet increased susceptibility and allergic reactions as well as poor antibody response, particularly in obese populations.
On the microbial level, specific nutrients consumption also play a significant role in shaping the gut microbiome, which can directly influence immune response. Deficiencies in calories, protein, minerals, and vitamins are commonly correlated with suppressed immune surveillance and susceptibility to infection. In the intestinal lumen, various antimicrobial peptides were secreted to impede growth of certain microbe over another. It is evident that to some extent, the gut microbiome has direct interaction with modulating immune homeostasis that finely control pro and anti-inflammatory responses. Microbes play significant roles in fingerprinting microorganism-associated molecular patterns (MAMPs) and pathogen-associated molecular patterns (PAMPs). A typically healthy gut microbiome will contain some of the common bacterial taxonomies like lactobacillus, bacteriodes, and bifidobacteria that secrete certain metabolites and other immune-modulatory signals that often contain short chain fatty acids (SCFA) like acetate and butyrate. These molecules can bind to certain receptors like toll-like receptors of innate cells that can have effect on their metabolism and activity. 


Effects of Nutrition and Gut Microbiome on Immune Response to COVID-19

Vitamin D is a nutrient that is both endogenously synthesized in the skin and consumed dietarily.  Its biologically active form [1,25-(OH)2D] is a known negative regulator of the Renin-Angiotensin System (RAS).  1,25-(OH)2D has been shown to increase ACE2 expression and suppress the inflammatory outcomes caused by angiotensin II (Ang II).  Additionally, vitamin D can modulate the immune system by inhibiting B-cell and T-cell proliferation as well as inducing T-regulatory cells, which suppress pro-inflammatory cytokines and increase anti-inflammatory cytokines.  These processes may make vitamin D a useful molecule in treating or preventing a SARS-CoV-2 infection.

Using Vitamin D to Mitigate COVID-19

An imbalanced nutritional status resulting from excessive intake of nutrients generated by an energy imbalance between food consumption and energy expenditure leading to disorders such as obesity.

Overnutrition

Compounds in plants that can have healing and therapeutic properties for treating illnesses or injuries. 


Phytomedicines 

The eucaloric ketogenic diet is a diet consisting of mainly fat and minimal amounts of carbohydrates. It provides the body with sufficient calories while it stabilizes blood glucose levels and reduces oxidative stress.

Eucaloric Ketogenic Diet (EKD)

Among 50 (mean age 52.2, SD 20.7) hospitalized patients with COVID-19, 76% were deficient in vitamin D and 42% in selenium. Among the nutrients zinc, B1, B6, B12, folate, vitamin D, selenium, all the 12 patients with severe respiratory distress and advanced stage of the disease had a deficiency in more than one nutrient .

Nutritional status of patients with coronavirus disease 2019 (COVID-19)

Due to the large influx of Covid-19 ICU patients, a new protocol has been developed to provide easier and simplified nutritional distribution. At the end of the pandemic wave, the protocol was evaluated in the form of questionnaires and surveys. 122 physicians on the ICU medical team received the protocol and a great majority of the medical team as well as the participants assessed it as a useful tool for nutritional therapy.

Easy-to-prescribe nutrition support in the intensive care in the era of COVID-19

Foods used to treat chronic illnesses have shown to improve the health of patients who have COVID-19 as well. Some examples of these foods are:

-Vegetables: Broccoli, kale, Brussels sprouts, cabbage, cauliflower, etc.


-Fruit: Especially deeply colored berries like grapes and cherries


-High-fat fruits: Avocados and olives


-Healthy fats: Olive oil and coconut oil


-Fatty fish: Salmon, sardines, herring, mackerel, and anchovies


-Nuts: Almonds and other nuts


-Peppers: Bell peppers and chili peppers


-Chocolate: Dark chocolate


-Spices: Turmeric, fenugreek, cinnamon, etc.


-Tea: Green tea


-Red wine: Up to 5 ounces (140 ml) of red wine per day for women and 10 ounces (280 ml) per day for men

Anti-inflammatory Foods

Nutrigenomics

ARTICLES RESEARCHED
- Can Vitamins, as Epigenetic Modifiers, Enhance Immunity in COVID-19 Patients with Non-communicable Disease?
- Epigenetic Diet to Modulate Immune Response against SARS-CoV-2
- The epigenetic implication in coronavirus infection and therapy

Epigenetics

Polyphenols is from plant based food and a potential use for against COVID-19. 

Polyphenols

Even though COVID-19 is primarily viewed as a reparatory illness, it has also been found to affect the gastrointestinal system. Therefore, there is an increasing need for a focus on gastroenterology to establish proper nutrition therapies. To develop these nutrition therapies, a better understanding of preexisting gastrointestinal diseases is vital, as well as consideration of the challenges and obstacles of nutrition therapy.

Gastrointestinal Manifestations of COVID-19: Impact on Nutrition Practices

Vitamin C, ascorbic acid, is a required nutrient for humans that humans are unable to endogenously synthesize.  Therefore, humans are dependent of food and other external sources for sources of vitamin C.
A deficiency of vitamin C has been found to be linked with respiratory infections, and current evidence suggests that 2-8 g/day of oral vitamin C may reduce the incidence and duration of these respiratory infections, including COVID-19.  

Using Vitamin C to mitigate Covid-19

- COVID-19 pandemic and mitigation strategies: implications for maternal and child health and nutrition

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