Glutamine: why this amino acid matters for gut barrier integrity and the immune system

A study performed at Massachusetts General Hospital in 2021 found the link between intestinal permeability (aka ‘leaky gut’) and COVID-19 complications in children. Although SARS-CoV-2 infection is not serious for most children, there have been some rare cases of a severe post-COVID complication called ‘Multisystem Inflammatory Syndrome in Children’ (MIS-C).

MIS-C followed a prolonged gut infection by the SARS-CoV-2 virus. Children who developed MIS-C had high plasma levels of zonulin, indicating an increased intestinal permeability. They also had the Spike protein detected in the blood circulation, presumably leaking from the gut where the virus was replicating.

MIS-C is typically treated with immunotherapies, such as IVIG and steroids. But those treatments were not enough to get inflammation fully under control in COVID-19 MIS-C patients. Therefore, an investigational drug larazotide was added to the treatment of one severely ill patient under compassionate use authorization. This drug competes with zonulin and restores leaky paracellular junctions in the gut back to their closed state. It was originally developed for celiac patients.

The study reports that after the administration of larazotide, the Spike protein rapidly disappeared from the blood circulation, while systemic inflammation subsided beyond that achieved by IVIG and steroids. This outcome demonstrated the relevance of the leaky gut to the severe form of inflammation observed in MIS-C. 

Plasma markers of disrupted gut permeability are accompanying severe COVID-19 not only in children but also in adults, as reported by this study. Patients described in the study were dealing not only with the viral infection itself but also with bacterial and fungal products that had translocated into the blood via an impaired gut barrier. The authors of the study conclude: "These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity."

Why would gut permeability be induced during an acute viral illness, like COVID-19?  This is likely mediated by the depletion of the amino acid glutamine.  Glutamine is well-recognized as an immuno-nutrient, which is used up by the immune system during its activation.  It is also central to maintaining gut barrier integrity.

When glutamine is depleted through immune activation leading to the leaky gut, what’s leaking into the bloodstream in any given patient would depend on their pre-existing gut microbiome composition. 

Many strains of gut bacteria produce lipopolysaccharide (LPS). Researchers have investigated the properties of LPS from healthy human microbiome samples and found that the majority of the gut bacteria produce LPS that is non-inflammatory.  But there are exceptions. For example, commensal E. coli and Prevotella are known to produce pro-inflammatory LPS. The difference is that a pro-inflammatory form of LPS is fully acylated, whereas non-inflammatory LPS is not.

If you were to obtain LPS from E. coli and incubate it with white blood cells (leukocytes), the latter would start pumping out a lot of pro-inflammatory cytokines, such as IL-6 and IL-1beta. The consequences of having an excessive or constant production of these cytokines would be devastating. And, actually, some of the biological effects of IL-6 are the same as the symptoms of severe COVID-19, as seen HERE.

When people have a diverse microbiome, they are not likely to be at risk of having pro-inflammatory LPS leak through their gut barrier, even if they are transiently depleted of glutamine due to acute illness. That’s because a diverse microbiome produces predominantly non-inflammatory LPS.

But do we really have a diverse microbiome nowadays when we are constantly exposed to glyphosate (Roundup)?  In rats, Roundup was shown to select for the very bacteria (E. coli and Prevotella) that produce pro-inflammatory LPS. And we’ve been exposed to Roundup for generations! 

Now, any impact that results in a leaky gut due to glutamine depletion, be it an infection, vaccination or even physical trauma, may put us at risk of having pro-inflammatory LPS from the gut bacteria reach the immune system in the blood. This endogenous LPS can keep re-stimulating the immune system, getting us stuck in a vicious cycle of chronic inflammation that further depletes glutamine and prevents healing of the gut barrier.   

What can we do to start restoring the microbiome diversity and gut barrier integrity?  First and foremost, we need to reduce, if not eliminate, the exposure to glyphosate and rehabilitate our gut microbiome from overabundance of glyphosate-favored bacteria, which put us at risk of chronic inflammation, back to the microbial diversity of the old days.

Healing the leaky gut will likely heavily depend on having an adequate supply of glutamine, which can be obtained from dietary protein sources and via moderate exercise. Our muscles are a major source of glutamine production in the body. However, over-exertion depletes glutamine and so does physical inactivity. 

Athletes often supplement with glutamine to avoid gut permeability problems. But there’s also an increased need for glutamine during an acute illness. In a small-scale, non-randomized pilot study on COVID-19 outcomes, L-glutamine supplement was found to be beneficial in treating hospitalized adults, essentially eliminating their qSOFA (quick Sequential Organ Failure Assessment) score, the ICU use, and death and reducing overall hospital stay.

Gut barrier integrity and microbiome diversity have always been key to good health, but COVID-19, with its added burden of the Spike protein toxicity and inflammation, has magnified their importance to the degree that can no longer go unnoticed or ignored.

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Disclaimer: This information is for educational purposes only and is not intended as medical advice.

Ready for more Immunology? As immune science educator, I offer a lecture-course Natural Immunity Fundamentals, write a science digest, hold monthly zoom talks and lead weekly science-intensive study groups at Building Bridges in Children’s Health (BBCH Community). Visit BBCH website to become a member.