The gut’s role in viral immunity

An individual patient’s immune response to infection is closely linked to their gut health. Patients with healthy gut microbiomes tend to have an immune system that responds quickly and appropriately to viral attacks. An unhealthy gut is linked to immune activation, mild chronic inflammation, and greater susceptibility to viral infection and more severe illness. During a long viral pandemic, helping patients restore or maintain a healthy gut microbiome and a healthy immune system has never been more consequential.

The Gut-Immune Link

The crosstalk between the gut microbiota and the immune system is constant—and central to mounting an effective immune defense. Between 70 and 80 percent of all immune cells are found in the gut-associated lymphoid tissue (GALT) surrounding the intestines. When the GALT is compromised, the entire immune system is weakened.

The intestinal immune system can distinguish between the wide and ever-changing range of harmless microbes within the gut and pathogens. This constant, delicate immune homeostasis is disrupted when antibiotics, poor diet, lack of exercise, and other harmful factors such as environmental toxins alter the gut bacteria's balance, causing dysbiosis.

In dysbiosis, the GALT is continuously stimulated to produce immune cells and inflammatory response. When dysbiosis continues, the gut epithelial barrier can become permeable—the patient now has a leaky gut syndrome. Bacteria, bacterial metabolic and breakdown byproducts, and large undigested food particles can escape the gut and enter the circulation through tight junctions that open too widely. The result is further immune activation as well as localized and systemic inflammation, usually along with other dysbiosis symptoms such as gas, bloating, diarrhea, and brain fog.

The LPS Effect

The triggering factor for systemic inflammation from increased gut permeability often begins with lipopolysaccharides (LPS) endotoxin from bacteria. An endotoxin is a complex lipopolysaccharide (LPS) found in the outer membrane of gram-negative bacteria such as E. coli and H. pylori. About 65 percent or more of the bacteria in the gut are gram-negative. As some of these bacteria are dying off at any given time, small amounts of LPS are constantly being released.

The gut produces enzymes that neutralize the endotoxin, and any amount of LPS that escapes is easily handled by the immune system. In dysbiosis, however, the gut may have more LPS-producing bacteria than it can handle. If the dysbiosis causes the gut barrier to become permeable, LPS can leak through and trigger endotoxemia, or inflammation throughout the body. Studies also show that LPS damages the blood-brain barrier by making it more permeable.

Leaky gut syndrome and dysbiosis can lead to endotoxemia, but they’re not the only causes. A diet high in saturated fat can kill off gram-negative bacteria, which causes the release of excess LPS into the gut. If the gut barrier is permeable, as it may be from a diet high in bad fats and processed foods, LPS can get through and enter the circulation.

Endotoxemia does its damage by triggering the pro-inflammatory protein complex NLRP3. Activation starts when the LPS component of gram-negative bacteria is detected by Toll-like receptor 4 (TLR4) in the cell membrane, which activates the transcription factors IRF1 and NF-κB.

IRF1 drives the NLRP3 complex to release the proinflammatory cytokine interleukin 1-beta (IL-1β). This inflammatory pathway may be behind a wide range of chronic diseases, including Alzheimer’s disease and type 2 diabetes.

The transcription factor NF-κB is activated by LPS and other harmful stimuli, such as tumor necrosis factor-alpha (TNFα) and IL-6. Once activated, NF-κB enters the cell nucleus. There, it upregulates the genes that tell the immune system’s T cells to get active. It also controls many of the genes involved in inflammation. High levels of NF-κB are associated with chronic inflammatory diseases, such as inflammatory bowel disease, atherosclerosis, and gastritis.

The Viral Link

Modern life puts many adults into a constant state of dysbiosis and low-grade chronic inflammation from immune system activation. Obesity, chronic illness, a poor diet low in fiber and high in sugar, bad fats, processed foods, and a lack of physical activity all promote dysbiosis and gut permeability.

On top of a lifetime of these pro-inflammatory factors, older adults often have an additional source of low-grade chronic inflammation known as “inflammaging.” Among the causes of inflammaging may be a decrease in the overall variety of bacterial species in the gut microbiome, along with an increase in pro-inflammatory species. The dysbiosis this causes leads to greater gut permeability and more immune activation in older adults and adds to any preexisting inflammation from obesity, chronic illness, and lifestyle.

In the current novel coronavirus (COVID-19) epidemic, the patients who have experienced the most severe disease and mortality are generally older, or have chronic illnesses, or are obese—or all three. In other words, the sickest patients are also the ones that are the most likely to have already elevated markers of inflammation from disturbances of the gut microbiome/immune system link before they become ill. COVID-19 is associated with increased levels of inflammatory cytokine and chemokine markers such as IL-2, IL-6, IL-7, IL-10, tumor necrosis factor (TNF), and C-reactive protein. When added to preexisting inflammation, the COVID-19 inflammatory response may lead to a cytokine storm and cytokine release syndrome, which is associated with severe illness and high mortality.

Patients who have recovered from the worst of COVID-19 may still have ongoing dysbiosis, ongoing immune activation, and ongoing inflammation. A recent study published in the journal Gut of hospitalized COVID-19 patients after viral clearance showed significant alterations in their gut microbiomes compared to non-COVID-19 individuals. The COVID-19 patients also showed elevated concentrations of inflammatory cytokines and blood markers that corresponded to disease severity.

“Associations between gut microbiota composition, levels of cytokines, and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity, possibly via modulating host immune responses,” the authors concluded. “Furthermore, after disease resolution, gut microbiota dysbiosis could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.”

When their major symptoms have resolved, the disrupted gut/immune crosstalk may still be causing inflammation and lingering “long COVID-19” symptoms, such as fatigue and joint pain. Looking upstream and treating leaky gut syndrome and gut dysbiosis may help resolve these symptoms.

An Integrative Approach

COVID-19 will likely be with us for a long time, even when cases have dropped below epidemic level. A key step to prevention, both now and in the future, will be recognizing and treating dysbiosis and leaky gut syndrome and restoring normal active immunity.

This is particularly important for vulnerable patients, the elderly and those with obesity or chronic illness. Now more than ever, all patients should be encouraged to improve their gut microbiome through a better diet, more exercise, and the use of prebiotic and probiotic supplements to promote a healthy diversity of gut bacteria.

References

d’Hennezel, E., Abubucker, S., Murphy, L., and Cullen, T. (2017) Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling. Host-Microbe Biology. Retrieved from: https://msystems.asm.org/content/2/6/e00046-17

Hirano, T. and Murakami, M. (2020) COVID-19 A New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Immunity. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/32325025/

Hooper, L.V., Littman, D.R., Macpherson, and A.J. (2012) Interactions between the microbiota and the immune system. Science. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22674334/

Levy, M., Kolodziejczyk, A., and Thaiss, C. (2017) Dysbiosis and the immune system. Nature Reviews Immunology. Retrieved from: nature.com/articles/nri.2017.7

Toor, D., Wsson, M.K., and Kumar, P. (2019) Dysbiosis Disrupts Gut Immune Homeostasis and Promotes Gastric Diseases. International Journal of Molecular Sciences. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/31100929/  

Yeoh, Y.K., Zuo, T., Lui, G.C., Zhang, F., Liu, Q., Li, A.Y., Chung, A.C., Cheung, C.P., Tso, E.Y., Fung, K.S., Chan, V., Ling, L., Joynt, G., Hui, D.S., Chow, K.M., Ng, S.S.S., Li, T.C., Ng, R.W., Yip, T.C., Wong, G.L., Chan, F.K., Wong, C.K., Chan, P.K., Ng, S.C. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. Retrieved from: https://gut.bmj.com/content/early/2021/01/04/gutjnl-2020-323020

About the Author 

Robert G. Silverman, DC, DACBN, DCBCN, MS, CCN, CNS, CSCS, CIISN, CKTP, CES, HKC, FAKTR

Robert Silverman is a chiropractic doctor, clinical nutritionist, international speaker, author of bestseller Inside-Out Health, and founder and CEO of Westchester Integrative Health Center. He graduated magna cum laude from the University of Bridgeport College of Chiropractic and has a master’s degree in human nutrition. The ACA Sports Council named Silverman Sports Chiropractor of the Year in 2015. Silverman is on the advisory board for the Functional Medicine University and is a seasoned health and wellness expert on both the speaking circuits and the media. A frequently published author in peer-reviewed journals and other mainstream publications, Silverman is a thought leader in his field and practice. Silverman was the principal investigator on a Level 1 laser U.S. Food and Drug Administration study. Silverman’s new book, Superhighway to Health, is expected to be published in June 2021.

Editor's note: Photo courtesy of Freepik/katemangostar.