Inside every one of us is an army of immune cells. Within that army exists a multitude of actors. While you often hear about the “fighter” immune cells that attack dangerous invaders, the little-known “regulator” immune cells that tell the army when to cease fire are rarely discussed. Human health is contingent on having an appropriate balance of fighter and regulator immune cells. The health challenges that increasingly confront us – including the rapidly rising rates of autoimmune disease, allergies, cancer, RSV and COVID-19 – can be influenced by a disruption of this delicate balance.
One of the mysterious things about COVID is its varying degrees of severity. Though there are certain obvious drivers of severity like age and medical comorbidities, an emerging, less obvious and perhaps overlooked driver may be an imbalance among one’s immune cells. A systematic review published in the Journal of Medical Virology synthesizing data from 18 studies found that patients with severe COVID tended to have decreased levels of “regulatory T cells,” also known as “Tregs.”
Tregs are a special type of immune cell that tell the body when the fight is over and ensure that, when appropriate, the army retreats. The lung damage that can result from COVID is the product of an immune system that sent in too many troops and fired more shots than necessary. Hence, it’s not surprising that the amount of Tregs in a patient’s lungs have been found to correlate with the amount of time spent on a ventilator. One case report even showed improvements in ICU patients after the infusion of donor Tregs harvested from umbilical cord blood.
Tregs also ensure that the army doesn’t become confused about what it is actually fighting. This, the hallmark of all autoimmune disease, has been found to be part of the etiology of long COVID.
So, the question then becomes why do some people have more Tregs than others? And is there anything we can do about it?
The immune system is dynamic. It constantly trains new recruits based on the body’s needs. The training centre for immune cells exists largely in the gut, where 70 per cent of the body’s immune cells reside within the wall of the intestines. This location is ideal for receiving signals from the bacteria (also known as the microbiome) that live inside the intestines. These bacteria act like drill sergeants and send signals to direct T cell maturity. The signals sent by these bacteria dictate whether a recruit becomes a fighter immune cell or a regulator immune cell.
Every time you eat, you’re not just feeding you, you’re also feeding the trillions of bacteria that live inside of you.
The signals sent by these bacteria are influenced by what they eat, which is determined by what you eat. Because every time you eat, you’re not just feeding you, you’re also feeding the trillions of bacteria that live inside of you. This is why diet can affect the immune system. A study of patients with rheumatoid arthritis demonstrated that a higher intake of fiber resulted in a higher number of Tregs. The unique thing about fiber is that it was long considered an anti-nutrient because humans don’t derive any vitamins, minerals or energy from it. However, its nutritional value is indirect. The two pounds of bacteria that live inside us ferment fiber, resulting in the production of chemical by-products (known as short-chain fatty acids) that are absorbed across the gut wall. Upon arriving on the other side, these short-chain fatty acids greet the naïve immune cells residing there and in doing so direct the growth and development of Tregs.
This may explain why a cohort study of more than 500,000 people conducted at Harvard and King’s College London demonstrated that diet quality is a risk factor for COVID-19 incidence and severity. The study specifically identified that diets higher in plant-derived foods, namely fruits, vegetables, whole grains, nuts and legumes, were protective against COVID-19. This makes sense because these foods are the richest dietary sources of fiber, unlike dairy products, animal-derived foods and processed foods that lack fiber. Furthermore, 95 per cent of people don’t eat enough fiber. In fact, the average person only eats about 16 grams of fiber per day, far less than the 25g recommended for adult women and 38g recommended for adult men.
Fiber isn’t the only nutrient that influences Tregs. A systematic review showed that supplemental vitamin D increased Tregs both in healthy people and those with an autoimmune/inflammatory condition. This is because vitamin D induces the high commanders (what scientists call transcription factors) that dictate how to train naïve immune cells. Vitamin D deficiency is rampant in northern latitudes like ours where adequate exposure to the sun – which is necessary for vitamin D synthesis via the skin – is impossible to obtain for months of the year. Animal and cell culture studies also suggest that vitamin A (and its precursor beta-carotene) may play a role in Treg development, however, this is yet to be demonstrated in humans. Nevertheless, this is another reason eating more dark-green leafy vegetables, pumpkin, squash and carrots is unlikely to be anything but a benefit.
While diet is an important director of Tregs development, it is not the only lifestyle factor with potential influence. Everything that affects the microbiome can theoretically affect Tregs because bacteria are the drill sergeants that direct Treg development. Not surprisingly, research has found that significant gut microbiome alterations also correlate with COVID-19 severity.
The most obvious threat to the microbiome is antibiotics. Just a seven-day course of clindamycin causes microbiome changes that can persist for more than two years. Other commonly prescribed medications that negatively affect the microbiome include antidepressants (namely SSRIs), metformin, proton pump inhibitors (PPIs) and laxatives. Furthermore, having had your gallbladder and/or appendix removed, being born via caesarean section and not having been breastfed can also negatively impact the microbiome.
Recognizing that the factors that disrupt Treg development are hallmarks of modern civilization, it’s no wonder that health conditions influenced by Tregs are on the rise. Addressing Treg dysfunction may be a crucial avenue for preventing and treating the unprecedented health challenges that increasingly stem from an immune system that inadvertently damages the body it intended to protect. Where infectious diseases were once the greatest threat to human survival, today it is not necessarily the infection itself but rather the immune system’s response to the infection that dictates the survival of the fittest.
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