0:00:01 – Announcer

You are listening to the National University Podcast.

0:00:09 – Kimberly King

Hello, I’m Kimberly King. Welcome to the National University Podcast, where we offer an holistic approach to student support, well-being and success: the Whole Human education. We put passion into practice by offering accessible, achievable higher education to lifelong learners. On today’s episode, we’re discussing long COVID. I’m really learning a lot about this on today’s episode, but according to an article on the American Medical Association, a researcher at Yale University, Dr. Iwasaki researcher at Yale University, Dr. Iwasaki she says that we’re now understanding that long COVID is likely not a single disease but rather an umbrella term that encompasses multiple distinct endotypes. That’s triggered by acute SARS-CoV-2 infection. So studies have identified at least four potential root causes persistent viral reservoir in different organs, autoimmune reactions triggered by the infection, tissue damage, and dysfunction, and reactivation of latent herpes viruses like Epstein-Barr virus. There’s going to be a lot more coming up on today’s episode, talking all about long COVID. Stay with us.

On today’s episode we’re discussing long COVID and joining us is Dr. Huda Makhluf. Dr. Makhluf is a professor in the Department of Mathematics and Natural Sciences at National University and the academic program director for the associate degree in science for general education. She earned her PhD in microbiology and immunology from the Medical University of South Carolina and conducted her postdoctoral research at Harvard Medical School in the Department of Orthopedic Surgery before moving to Baylor College of Medicine. At National University, Dr. Makhluf teaches biology and microbiology for pre-allied health majors and collaborates with scientists at the La Jolla Institute for Immunology. She’s a strong advocate for STEM and in 2016, while serving as a department chair of mathematics and natural sciences, she secured an innovation grant from the NU system to pilot next generation learning and strategies to increase inclusive excellence and persistence in math and science. She also tested an artificial intelligent assessment and learning system to improve math and science literacy for students with diverse math and science backgrounds.

Wow, this is impressive. Welcome to the podcast, Dr. Makhluf. How are you?

0:02:38 – Doctor Huda Makhluf

I’m doing great. How are you, Kim?

0:02:40 – Kimberly King

I am well, thank you. Why don’t you fill our audience a little bit on your mission and your work before we get to today’s show topic?

0:02:47 – Doctor Huda Makhluf

My mission. I always strive to provide my students with a world-class education, meaning cutting-edge science and paths to discovery and a commitment to get them excited about science. As a scientist, I try to instill in them the love of science. And, as a lifelong learner myself, I also strive to provide them with high impact opportunities and experiences so that they can make a difference in this world.

0:03:13 – Kimberly King

Oh, I love that, and what a difference they are making with you at the helm there. So thank you for what you’re doing. Today we are talking about long COVID and so, doctor, what is long COVID, and how many people are affected?

0:03:25 – Doctor Huda Makhluf

Long COVID is a term used to encapsulate the post-acute sequelae of SARS-CoV-2 infection that can affect many multiple organ systems. According to the WHO, long COVID can affect anyone who was exposed to SARS-CoV-2, regardless of the severity of the infection or the symptoms. The CDC broadly defines it, for example, as signs, symptoms, and conditions that continue to develop after the initial SARS-CoV-2 infection. These signs and symptoms are present four or five weeks or more after the initial phase of infection. It may be a multi-systemic and may be present with relapsing pattern progressing and worsening over time, with even the possibility of severe life-threatening events even months or years after infection.

You may recall that people suffering from long COVID are called long haulers in reference to the conditions, persistent and lingering symptoms that prevent COVID-19 survivors from returning to their pre-infection selves within 12 weeks of the illness. So five years post-pandemic, almost half a decade later, sars-cov-2 continues to affect many lives across the globe, with an estimated 75 million people suffering from long COVID. In fact, according to the latest data from the CDC, three out of 10 adults who have had COVID reported getting long COVID. And not many people talk about long COVID. There is a lack of awareness when it comes to long COVID. Over a third of Americans are not aware of long COVID or heard of long COVID.

0:05:19 – Kimberly King

It’s so interesting talking about this because you’re right, I don’t- You don’t hear enough about long COVID. But I do have a girlfriend and she doesn’t really talk about it ever unless I ask her. But her symptoms are- she still can’t taste food, or she says it tastes like an ashtray, which is so unfortunate when she does taste her food. So what are those common symptoms?

0:05:40 – Doctor Huda Makhluf

Great Kim. Known symptoms include chronic fatigue syndrome, brain fog, cardiovascular issues, autoimmunity, clotting due to inflammation. Also, shortness of breath, palpitations, myalgias, arthralgias, cognitive impairment, headaches, sleep disturbances, anxiety, depression, nausea and diarrhea. Other symptoms may include hair loss- to your point, loss of smell and taste, and low sperm counts are all also observed in long COVID. As you can see, long COVID is not a single disease, but rather a term that encompasses many distinct endotypes or subtypes triggered by acute SARS-CoV-2 infection.

0:06:36 – Kimberly King

It’s so interesting just to see how different people were affected by COVID and when you have now the long COVID, what are the underlying biological causes of long COVID?

0:06:41 – Doctor Huda Makhluf

Now, the precise underlying biological causes of long COVID are still unknown, but there are many proposed hypotheses and theories under investigation. Viral persistence in nerve tissues and other tissues in the body is one of these hypotheses. Some scientists reported the detection of SARS-CoV-2 RNA in plasma, stool, and urine in patients with persistent symptoms after COVID-19. Others established the presence of residual virus in breast tissues and the appendix, and even suggested that the gastrointestinal tract is acting as a viral reservoir of COVID, of SARS-CoV-2.

Third hypothesis is the dysfunction of the immune system that persists post-infection. There is also the reactivation of dormant viruses such as the Epstein-Barr virus and herpes viruses, or impairment of blood flow due to endothelial cell damage. And finally, genetic predispositions leading to production of autoantibodies against type 1 interferons. It’s good to note that these hypotheses are not mutually exclusive and may be sequential. For example, a lingering viral presence can cause chronic inflammation and it triggers blood clot formation. So, when compared to people who either had recovered from COVID or had never contracted the virus or developed the disease, people with long COVID were found to have an elevated level of antibody responses to spike protein. This would suggest a persistent presence of viral antigens stimulating the production of these antibodies. So again, long COVID can be driven by a persistent viral infection, by a reactivation of latent herpes viruses such as EBV and varicella zoster virus, causing inflammation, autoimmune processes, damage to tissues, and hypercoagulation.

0:08:53 – Kimberly King

So there’s not an existing like a blood test or urine test to say oh, you have long COVID. It can be any of these things that would aggravate it or elevate it.

0:08:59 – Doctor Huda Makhluf

Correct, and we’ll be talking about how many organ and organ systems are affected and what are the diagnoses and whether we can use AI.

0:09:14 – Kimberly King

Oh, interesting. So yeah, what are those organ and organ systems that are affected?

0:09:18 – Doctor Huda Makhluf

Well, beyond the immune system, long COVID affects all our organs, most organs and organ systems in the body, including the heart, lungs, brain, kidneys, liver and gut in general, you know, including your spleen, you know, pancreas, as well as the reproductive system.

0:09:40 – Kimberly King

Wow. So, boy, it really does make you feel, think about what we’re putting in our bodies, what you know the environment is who we’re hanging out with, and just you want to make sure that you know we’re checks and balances all times. What are the cardiovascular and gastrointestinal symptoms?

0:10:07 – Doctor Huda Makhluf

So Ziya Dallali’s and his team studied cardiovascular manifestations of long COVID using the national healthcare databases from the US Department of Veterans Affairs. This is to estimate the risks of cardiovascular outcomes in COVID-19 survivors. His team found an increased risk of cardiovascular disease, including heart failure, myocarditis, pericarditis, dithrismias, non-ischemic and ischemic heart disease and thromboembolic disease, even for individuals who are not hospitalized during their acute COVID-19 infection phase.

And that same team used the same databases to evaluate the risk and burdens of gastrointestinal disorders in long COVID and they reported increases in disorders such as peptic ulcers, pancreatitis, hepatic and biliary disease, motility disorders, stomach pains, indigestion, bloating, and reflux. And you know, interestingly, studies investigated the gut microbiota composition of long COVID patients and found lower levels of good bacteria. An example is fecali bacterium species, fpras for short, and higher levels of bacteroides. Healthful butyrate-producing bacteria such as Bifidobacterium showed an inverse correlation with lung COVID at six months, demonstrating the negative effect of long COVID on the gut microbiome.

0:11:43 – Kimberly King

Wow, we appreciate all of this information, the knowledge and the research that you are all looking into for this, because it’s you know, again, it’s something that you said right at the very beginning of this podcast that people aren’t talking necessarily about those symptoms of long COVID, and it really does- So you talked about cardiovascular, gastrointestinal… You also mentioned neurological. So what do those impairments look like?

0:12:10 – Doctor Huda Makhluf

Right. Great question, Kim. Neurological impairment is a hallmark of long COVID. It includes brain fog, memory loss, loss of taste and smell, dizziness, numbness, tingling, many autonomic dysfunctions. Now, interestingly, scientists found striking similarities between cognitive impairments following cancer treatment- if you’ve heard of chemo brain- and long COVID, typically driven by neuroinflammation and microglial reactivity, which leads to dysregulation of neurogenesis in the hippocampus. Patients suffering from cognitive impairments and deficits due to long COVID had elevated CCL11, it’s a chemokine usually known as eotaxin-1, in their plasma compared to control groups.

So in a mouse model used to investigate the underlying mechanism of these impairments and to understand what’s behind the neuroinflammation caused by this elevated level of CCL11, scientists found that cognitive impairment was linked to, in fact, that microglial activation combined with a loss of myelination and inhibition of neurogenesis. And again, activation of microglia creates a neurotoxic state in the brain and inhibits neurogenesis, potentially leading to these impaired memory formation in the hippocampus. And again, these persistent levels of CCL11 appear to be the culprit. And systemic injection of CCL11 into mice went on to cause the activation of hippocampal microglia. These findings are consistent with results from a cohort of humans with brain fog, but there are promising insights here, right? So this is shedding the light on CCL11 and microglial modulation as maybe a potential therapeutic intervention. Other types may be also involved, but we’re not going to get into that. And what contributes to brain fog.

0:14:29 – Kimberly King

It’s again another really interesting area, especially along with- my mom had Alzheimer’s- and so I don’t know what that looks like in the future of you know, trying to forbid this long COVID to develop into our neurological, like you said, and brain fog and just memory loss. But that’ll be an interesting conversation to have to see what the future looks like, what we can do to prevent that. Were immune deregulation with inflammation and persistent immune activation observed with long COVID, then?

0:15:04 – Doctor Huda Makhluf

Yes, absolutely, Kim. Immune deregulation with inflammation and persistent immune activation were indeed observed with long COVID. Scientists identified key immunological manifestation for long COVID. They saw increases in non-classical monocytes, typically associated with anti-inflammatory responses, activated B-cell, double negative B-cells, often associated with autoimmunity and autoimmune diseases, exhausted T-cells and IL-4, Il-6 secreting T-cells which correlated with antibody reactivity mounted against Epstein-Barr virus or herpes viruses.

Remarkably, long COVID patients showed decreases in cortisol levels compared to their matched control groups. This can negatively impact the immune system by reducing its ability to properly regulate inflammation. They also saw in patients a decrease in type 1 dendritic cells. These are important immune cells. They typically promote cytotoxic CD8 positive T cell differentiation, and other studies pointed out elevated inflammatory cytokines such as interleukin-1, interleukin-6, tnf-alpha, all of which remain deregulated in long COVID and again you can think of the viral persistence in tissues may be driving long COVID and this chronic state of inflammation.

0:16:40 – Kimberly King

Okay. So when you are talking about all of these symptoms, can children also develop long COVID, or is it only adults?

0:16:48 – Doctor Huda Makhluf

Now, whether or not children can and do get long COVID has long been discussed in scientific circles. The occurrence of other post-viral syndromes in children, for example those after cytomegalovirus or CMV and Epstein-Barr virus infections, in addition to Guillain-Barre syndrome, and the better understood, though rare multi-system inflammatory syndrome in children complicating a COVID-19 infection, would all support the likelihood that children too can be affected by long COVID. Nevertheless, the prevalence of long COVID in children appears to be lower than in adults, with a prevalence of 4% or less. Risk factors include older age, female sex, allergic diseases and poor pre-COVID health diseases and poor pre-COVID health. Children in the highest risk group for long COVID included, again, girls an incidence of 0.19 versus 0.12 in boys per 100 persons.

Youth, so typically 12 to 17 years old, and those with chronic conditions, again 17 years old, and those with chronic conditions, and prior or previous hospitalizations. So the incidence of long-term COVID was similar across parental education levels, but was six times higher if parents had also had long-term COVID-19. Now, management of children with long COVID continues to evolve according to protocols that are based on expert opinions, protocols that are extrapolated from guidelines in adult medicine and rely on already established approaches used to manage other chronic pediatric conditions like chronic fatigue syndrome, migraines and throbbing headaches, and parent involvement is crucial in managing the stress of a child with long-term COVID. Given a child’s limited ability to communicate or articulate what they feel, perceptive parent can pick up more subtle signs of distress, for example frustration at being unable to complete one’s routine tasks. So definitely an integrated approach that combines physical and mental health is clearly indicated here for children suffering from long COVID.

0:19:22 – Kimberly King

So are pediatricians then starting to ask these questions and really probe more, once the kids go to the doctors, that maybe it’s beyond ADHD or whatever. Kids are dealing with anxiety and all of that, but are they probing now more about long Covid?

0:19:38 – Doctor Huda Makhluf

Yes absolutely. They’re more aware of the long COVID condition Absolutely.

0:19:44 – Kimberly King

So you mentioned this as well the AI Can that be used for diagnostic purposes for long COVID?

0:19:51 – Doctor Huda Makhluf

Wow, yeah, that’s a great question. (Kim: Whole new world, huh?) Yes, absolutely. Leveraging technology here. Yes, many manifestations of long COVID are not measurable using just clinical testing, making a clinical history an important first step in the diagnosis of long COVID. Long COVID is a diagnosis of exclusion, thus known causes of specific symptoms must be ruled out prior to the establishment of long COVID as a diagnosis. Because long COVID manifests across multiple organ systems, differential diagnoses will vary based on symptoms. For example, in addition to what you’ve mentioned, a standard blood and urine testing, patients demonstrating cardiovascular symptoms will receive ECG, echocardiogram, and other cardiovascular evaluations, whereas those with, say, neuropsychiatric manifestations will be evaluated using MRI or other neurologic tests prior to symptoms being attributed to long COVID.

Very recently, data from NIH, from the NIH National Cohort, collaborative and RECOVER programs – RECOVER is an acronym for Researching COVID to Enhance Recovery – so it’s a program launched by the NIH were utilized to identify six long COVID phenotype clusters in over 6,000 long COVID patients using machine learning. Only one cluster, designated Multi-System Plus Lab, largely exhibited lab abnormalities of hyperglycemia, abnormalities of hyperglycemia, hypocalcemia, elevated serum, creatinine, AST, alt and thrombocytopenia. So this cluster was also associated with a worse prognosis. A second cluster, designated pulmonary, exhibited hypoxemia without cardiac palpitations. Two separate clusters designated cardiovascular and multi-system. Plus pain showed palpitations in addition to hypoxemia, wow.

So, following a prognosis of long COVID through exclusion of other differentials, a review of specific tests may assist in sub-phenotyping and sub-classifying long COVID for the purpose of guiding treatment. And again, a commitment to artificial intelligence, AI, machine learning, and computational science may help to solve the long COVID problem. Long COVID is challenging, both in its diagnosis and treatment. Given its heterogeneous, non-monolithic symptoms coupled with diverse sets of risk factors and outcomes, so leveraging technology and harnessing the power of AI to analyze vast data sets and surface insights on biomarker development, prognosis predictions, and tailored treatment may all bolster genuine efforts toward a full long COVID recovery.

I’ll give you two examples. For example, a machine learning algorithm was deployed to characterize data from patients with long COVID using a specific primary code applied to electronic medical records. Despite the challenges posed by the variation in the quality of the electronic medical records, the algorithm identified different long COVID subtypes with neurological, gastrointestinal, cardiopulmonary, respiratory clustering features, and the insight surfaced here by the researchers was that they’ve discovered the patients who have received this unique code were primarily female.

0:23:50 – Kimberly King

Really.

0:23:51 – Doctor Huda Makhluf

White non-Hispanic individuals, and they were living in areas of low unemployment and poverty Another example using the NIH electronic medical records data repository, extreme gradient boosting, which is a powerful and flexible machine learning algorithm, was used to identify who has long COVID in the USA, and data from about 597 long COVID patients, regardless of their hospitalization status, were used to train three machine learning models to identify long COVID patients amongst COVID-19 patients.

These models identified potential long COVID patients with high precision. It’s a big data play. Long COVID clinical manifestations are complex. They involve a wide range of multi-organs, rendering the sample size crucial when mining various databases. So, with an increased number, unfortunately, of patients with long COVID and the accumulation of more data points, these models can be refined and retrained to evolve the algorithm with additional emergent evidence to solve the long COVID problem.

0:25:10 – Kimberly King

Wow, and that’s just the tip of the iceberg, it sounds like, but that’s so fascinating, wow, interesting. So, again, so many questions I have right now. But, following that diagnosis of long COVID, what are then the preventative, the treatments and the therapeutics that we’re looking into now?

0:25:28 – Doctor Huda Makhluf

Right. So treatment of long COVID addresses both viral and extra viral etheologies. So, following a diagnosis of long COVID, treatment is based on symptoms and lab and clinical findings, right? So given that many people with long COVID have symptoms affecting their nervous, mental, respiratory and cardiovascular system, then you have a team of specialists in cardiology, pulmonary, neurology and mental health deployed to deliver tailored treatment for an individual’s syndrome. So several therapeutics are being investigated. Antiviral drugs- I’m sure you’ve heard of Paxlovid- it’s a viral protease inhibitor and remdesivir, an RNA-dependent RNA polymerase inhibitor. Actually, a remarkable story by a group found that serotonin levels were reduced in people with long COVID and that restoring the levels of circulating serotonin might improve long COVID symptoms. Anti-inflammatory therapies are also under investigation and considered, and these include kinase inhibitors, tnf alpha inhibitors, phosphodiesterase inhibitors.

Kimberly King:

You know, and it is kind of interesting, and this is just my own, I don’t live in your world, so but all um, it seems like during covid we would- After covid we heard a lot about or read a lot about inflammation and it seemed like that really came up into the health world. But you also mentioned the serotonin levels and I am a migraine sufferer as well, and I know that when you don’t have enough serotonin, but also that can lead to depression, which are some of the symptoms you are talking about for COVID, long COVID. So I guess a quick question about, like headaches and brain fog how do we know that that’s long COVID or just another headache or another migraine? Not drinking enough, eating enough, you know, water.

0:27:30 – Doctor Huda Makhluf

There are biomarkers for severe cognitive slowing and headaches and the neuro part. Two short web-based cognitive tasks are usually administered to patients with long COVID or patients you know not diagnosed with long COVID to examine cognitive slowing using simple reaction time and number vigilance tests at two clinics in the UK and Germany. Patients with long COVID were aged matched to healthy individuals and then who contracted SARS-CoV-2, but recovered without manifesting long COVID.

In this experiment, two groups were, you know, identified the control in the ones with long COVID, and they did a self-administered psychomotor assessment on their laptops. Patients with long COVID showed about three standard deviations slower reaction times compared to the control. So this is a 30-second psychomotor task. It could be a beneficial test as a diagnostic workup and biomarker to establish a baseline measurement and track the progress and improvements following rehabilitation.

0:28:47 – Kimberly King

Interesting. Wow, yeah, I think that’s the question in all of our health care right now is what are those biomarkers for cancer, for Alzheimer’s, for long COVID, all of this- we all seem to be in this arena of how do we find out? So can another thing we learn about probiotics and bacteriotherapy. I’ve been reading a lot about that as well. Are these effective remedies for managing long COVID?

0:29:13 – Doctor Huda Makhluf

Right. So several studies have suggested that probiotics and bacteriotherapy may be effective remedies for managing long COVID. Probiotics and symbiotics may improve some symptoms of long COVID, especially fatigue, memory loss, and gastrointestinal problems, intestinal upset. However, clinical data and evidence are still limited. More research, of course, is needed and warranted here, but in a randomized, placebo-controlled and double-blind clinical trial, patients with long COVID received either a placebo twice daily for six months or a bacterial powder containing beneficial bacteria with prebiotic compounds, the compounds that probiotics feed on. So researchers found that treatment alleviated the neuropsychiatric symptoms of long COVID, including concentration difficulties and memory loss.

Now the precise mechanisms underlying these improvements warrant research and further investigation. It could be linked to the lack of gut bacteria that produce short-chain fatty acids. These regulate the immune response. But as a follow-up study, they plan to design a single center and a triple-blind randomized, placebo-controlled clinical trial instead of a double-blind. A triple-blind study, and this will aim at evaluating the effectiveness of modifying gut microbiota, boosting immunity and reducing long-term complications and comorbidity in post-COVID conditions. In another study, researchers will evaluate a dietary supplement, omnibiotic Pro, to elucidate the mechanism of post-COVID pulmonary fibrosis and the gut-lung access. This study will measure the microbiome composition using 16S ribosomal RNA sequencing and the changes in TNF-alpha interleukin-1 beta, il-6, il-6 receptor, IL-8. They look at these in the serum over time, with or without the intervention, and other studies will aim at understanding the effect of supplementing an orally ingested lactobacillus on SARS-CoV-2 associated endothelial dysfunction via the reduction in inflammation-related indicators.

0:31:45 – Kimberly King

Wow, so you might have just answered some of this next question about being what are those clinical trials that are researching? Is that sort of what you were kind of gearing up?

0:31:55 – Doctor Huda Makhluf

Right. So again going back to RECOVER, your tax money at work, researching COVID to enhance recovery. This project at NIH- So the project is funded by the National Institute for Health to research long COVID. It uses an innovative platform design and protocol that allows for randomized control trial data collection across multiple sites in the United States. It allows for more efficient strategies to surface insights quickly by enrolling, testing, and introducing new interventions in a coordinated fashion.

So two I’ll mention here RECIVER vital and RECOVER neural trials. They evaluate interventions for viral persistence, reactivation, immune dysfunction and neurocognitive dysfunctions. And one important clinical trial aims to determine the effect of Paxlovid in two dosing durations, one for 15 days and 25 days for the treatment of long COVID, and they test the hypothesis that antiviral therapies may result in viral clearance and reduced inflammation.

Another one aims to test interventions that could potentially ameliorate deficits and declines in cognition, executive function, say attention, and they use actually cognitively stimulating activities like puzzles and games that engage and adapt and challenge every participant. Brain HQ is one of those brain training programs that they are testing to leverage the principle of neuroplasticity. These brain HQ training programs will be used to gauge improvements into processing speed, attention and memory. Another intervention I believe will use transcranial direct current stimulation. It’s a non-invasive and safe brain stimulation technique. It will be tested using a home-based device that delivers a weak electric current to target the prefrontal cortex region of the brain.

0:34:13 – Kimberly King

I’m thinking we should all be doing that as we age anyway, right? Okay, and we talked a little bit about this too, but nutrition and personalized nutritional interventions, can they alleviate some of these long COVID symptoms?

0:34:28 – Doctor Huda Makhluf

Uh, During the 2020 global pandemic, Sars-cov-2 disproportionately affected racial minorities in the US. Significant disparities were documented, if you recall, primarily among Latino individuals and African Americans with high mortality rates than other individuals. This could include the frequency of type 2 diabetes as an underlying comorbid health condition. So again, we go back to the gut microbiome. It plays a significant role in the pathogenesis of obesity and obesity-related metabolic dysfunctions. Unhealthy diets could change the composition of the microbiome, causing an increase in inflammation and definitely resulting in the glucose intolerance and insulin resistance typically observed in type 2 diabetes.

Rob Knight and his team actually demonstrated that the association between a healthful Mediterranean diet and the prevalence of diabetes in US Latino populations is strongly modified by the profile of an individual gut microbiome. In essence, loss of species diversity and disturbances in the composition of a gut microbiome could definitely result in dire consequences on human health. Now, while further research is needed to elucidate that underlying mechanism between nutrition and disease, adherence to a Mediterranean diet may help improve long-term health outcomes regarding long COVID comorbidities, serving as a possible starting point in addressing the weight of racial disparities in long COVID health outcomes.

Also, if you’re wondering about keto diet and vegan diet, not just the Mediterranean diet, in a randomized cross-clinical trial, researchers investigated the impact of nutrition, specifically ketogenic and vegan diets, on both the peripheral immune response and the body’s microbiome composition. So 20 participants were divided into two groups, group A and B. So we had two groups, and both remained on site for the entire four-week period. They stayed at the Metabolic Clinical Research Unit at the NIH Clinical Center to ensure good controls of the dietary interventions. So each group compromised, both males and females, and boasted a diversity of ethnicity, race, age, and body mass index.

Each participant ate a keto or a vegan diet for two weeks, then switched to a keto or vegan diet for another successive two successive weeks. The vegan diet was a low-fat diet and the keto diet was low in carbs, carbohydrates, and, using a multiomics approach comprising metagenomic, metabolomic, proteomic, and transcriptomic data sets, researchers found that a vegan diet had a substantial impact on the innate immune system and antiviral immunity, while the ketogenic diet had a significant impact on adaptive immunity. Researchers suggested that it may be possible to personally tailor one’s diet towards disease prevention and treatment, since the immune system responds swiftly to nutritional interventions. This is the first type of multi-omics studies to investigate the impact of diet in humans. It is ushering in a whole new era in precision in nutrition and a deeper understanding of diet-based therapeutics for the treatment and mitigation of disease.

This was a small study with 10 participants in the treatment group, so it would be beneficial to pilot these interventions for long COVID treatment. Again, shedding light on the nutrition and its impact on restoring the gut microbiota is beneficial, since we know that short chain fatty acids released from dietary fibers by the gut microbiome play a critical role in modulating the immune system and our overall health maintenance. Again, the nutritional supplements such as antioxidants and essential fatty acids could alleviate and manage long COVID symptoms. We know deficiencies in vitamin B, vitamin C, coenzyme Q, magnesium, zinc, folic acid, essential fatty acids all contribute to the progression and severity of chronic fatigue syndrome. So a balance and a healthy diet with sufficient supplements and antioxidant could help alleviate long COVID fatigue syndrome.

And interestingly, researchers at the Salk Institute investigated the effects of caloric restriction on the aging process in a rat animal model by building a single-cell transcriptomic atlas with a particular focus on immune cells. But the findings are phenomenal. They revealed that excessive inflammation can be reversed by caloric restriction. In humans, prolonged caloric restriction decreases fasting insulin levels and body temperature. And in a small study of long COVID patients, long-term fasting was considered to be an effective intervention for managing and treating long COVID. 

And if you think about it, it’s basically nutritional ketosis, because nutritional ketosis will initiate when the body switches to burning fat as a primary energy source. And actually, scientists look into it and they showed that ketone bodies are essential fuels in supporting CD8 positive T cell metabolism and their effective effector function. So ketolysis is a metabolic and epigenetic driver of optimizing T-cell, specifically the CD8 positive T-cell effector response. Now you can say these experiments were performed using a mouse model, so murine T-cells. The extent to which these findings can be extrapolated to humans remains to be elucidated, but nonetheless we know nutritional approaches that lead to a decrease in inflammation and oxidative stress may be beneficial.

0:41:24 – Kimberly King

And that’s everything that we’re kind of reading about now too. And you mentioned the Mediterranean diet. I wonder if there’s been a study of the people that have exclusively been eating the Mediterranean diet, because that’s the area that they live in. So I’m doing a long COVID study on those people, or you know I’m talking. You know if you grew up with that as your diet or a carnivore diet or something I don’t know, but it’s so interesting. And then you do read about a lot of that fasting too, so I like what I’m hearing on that. So, as we wrap up this podcast, again I have tons of questions, but what are some of the public health implications?

0:42:02 – Doctor Huda Makhluf

Long COVID is already being addressed as a significant public health crisis. It is possible that certain individuals may not recognize that they are experiencing long COVID and may not be aware that they have long COVID. There is no one size fits all, Kim. It’s not the approach to long COVID. Many factors complicate the understanding and treatment of long COVID. These include genetic predispositions, prior infections with Epstein-Barr virus or other herpes viruses, individual BMI differences, that’s body mass index, microbiome composition, your baseline inflammation, your gender, your age, your fitness advantage, viral load coupled, say, with the uniqueness of the variant that you contracted during the infection, with the corresponding, if you want to be geeky, at the molecular level, you can look at the corresponding amino acid changes and the prolonged stage between exposure, infection and long COVID onset. So a treatment regimen that could be helpful to one patient might cause adverse effects in another.

Despite many studies, trials and interventions, the underlying mechanisms behind the conditions are still under investigation. Current treatments are limited to managing individual symptoms with a focus on recovering a good quality of life despite the condition. Due to the chronic nature of long COVID, as well as the sheer number of symptoms, current treatments can also seem insufficient, inconvenient, and even ineffective for many individuals. Certain cases of long COVID are debilitating enough to be individually categorized as legal disabilities, greatly hampering productivity in the workplace and leading to negative economic outcomes for individuals and their families. So long COVID characterization and research are still in their early stages and more is yet to be discovered. Given the complexity of long COVID and the sheer millions impacted by long COVID, managing and alleviating long COVID symptoms should be a top priority and imperative for public health.

0:44:25 – Kimberly King

Well, we appreciate all the research that is being done. We appreciate that conversation about long COVID because, again at the beginning, I don’t think people really talk about it enough. So this is a very interesting conversation, and we appreciate you sharing your knowledge. If you want more information, you can visit National University’s website, it’s nu.edu, and doctor, thank you so much for your time.

0:44:48 – Doctor Huda Makhluf

Absolutely. Thank you for having me, Kim. Thank you so. Stay safe, stay healthy, exercise, eat your fruits and veggies, remember that what you eat, you feed your microbial zoo, your microbiome, and get a good night’s sleep to strengthen your immune system and, lastly, wash your hands.

0:45:08 – Kimberly King

I love it. Thank you. You’ve been listening to the National University Podcast. For updates on future or past guests, visit us at nu.edu. You can also follow us on social media. Thanks for listening.