Severe COVID-19 complications linked to gut barrier breakdown

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Severe COVID-19 complications linked to gut barrier breakdown

Post by trader32176 »

Severe COVID-19 complications linked to gut barrier breakdown

11/18/20 ... kdown.aspx

A major focus of research in the current coronavirus disease 2019 (COVID-19) pandemic has been the need to understand the mechanisms operating that cause this potentially lethal disease’s various manifestations and complications.

A new study claims that severe COVID-19 is caused by a positive feedback loop triggered by systemic inflammation and mediated by abnormal gut permeability. This finding could potentially help open up new avenues of treatment.

Disruption of gut microbiome-lung interactions

Earlier research on respiratory infections has shown that lung damage interrupts the ordinary cross-talk between the lung cells and the gut microbiome, triggering systemic inflammation and causing severe disease. Such inflammation causes gut barrier breakdown as well, allowing gut microbes to cross the intestinal epithelium and enter the systemic circulation. This produces further inflammation and worsens lung injury, completing the positive feedback loop.

Viral infection of the gut cells can also occur, leading to direct damage and further disrupting both gut structure and function, as well as gut barrier integrity. These mechanisms are more likely in the elderly or sick, who are more commonly already suffering from gut dysbiosis.

The current study, published as a preprint in the medRxiv* server in November 2020, is based on a systems biology model, used to examine the plasma from 60 patients with COVID-19 but with a range of clinical severity. Their ages ranged from 50 to 65 years.

Inflammation promotes excessive gut permeability

The researchers found a steep increase in the permeability of the gut epithelial tight junctions in severe COVID-19, signaling a loss of the intestinal barrier function. This was accompanied by a steep increase in the protein zonulin, “the only known physiological mediator of tight junction permeability in the digestive tract.” Increased zonulin was a marker for higher mortality in severe COVID-19.

They also measured the level of plasma lipopolysaccharide (LPS) binding protein (LBP), a marker of acute infection or inflammation, which binds to bacterial LPS and triggers the immune system. This reflects increased microbial access to the bloodstream through the leaky gut, and its level was increased in severe COVID-19, compared to milder cases.

There were also elevations in the levels of the fungal marker, β-glucan, and of the tight junction protein occludin, in severe COVID-19. However, the concentration of the intestinal fatty acid-binding protein (I-FABP) was unchanged, ruling out the death of intestinal enterocytes.

Microbial translocation associated with systemic inflammation

As expected, the gut microbial migration across the intestinal barrier was accompanied by signs of myeloid inflammation, with higher levels of neutrophil and monocyte inflammation markers in severe disease, along with cytokines like IL-6 and IL-1β, and the acute-phase reactants CRP and D-dimer.

Immunomodulatory molecules such as lectins also showed markedly raised levels in severely ill patients who eventually succumbed to the infection. The researchers additionally observed an imbalance in the levels of C3a and GDF15, indicators of complement activation and oxidative stress, respectively, in fatal cases.

The researchers comment, “These data support our hypothesis that disruption of intestinal barrier integrity, which results in microbial translocation, is linked to higher systemic inflammation and immune activation during severe COVID-19.”

Gut permeability modulates metabolite levels in severe COVID-19

Abnormal gut permeability not only causes systemic inflammation directly but is linked to alterations in the concentrations of an array of plasma metabolites. These are not only well-known markers of gut dysfunction, but bioactive compounds, associated with inflammatory and immune responses.

For example, several important amino acid pathways are disrupted. These include some like citrulline that are produced only within enterocytes, or others like tryptophan that are catabolized by enterocytes. This results in an increase in amino acids such as citrulline, succinic acid, and in the breakdown products of tryptophan. These disruptions are markers of gut dysbiosis and of dysregulation of immune interactions with the gut microbiome.

These changes were observed to occur in patients with severe disease versus controls or mild COVID-19.

Metabolomic changes associate with dysregulated inflammation

The observed metabolite alterations were associated with inflammatory markers and markers of gut barrier disruption. For instance, low citrulline and high tryptophan metabolite levels were linked to higher IL-6 levels.

Several lipid pathways were also perturbed by the disturbances in amino acid metabolism in severe COVID-19. Of the 16 pathways most significantly affected, those involving glycerophospholipid and choline metabolism were markedly disrupted. Both of these are linked closely to the gut microbiome, and dysbiosis has a negative effect on the breakdown and absorption of these lipids. Thus, severe COVID-19 is associated with systemic disturbances resulting from gut barrier breakdown.

Abnormalities in glycation cause dysregulation of inflammation

Glycans decorate many proteins and antibodies to regulate the immune response. The enzymes that degrade them come from several gut microbes, and the translocation of the latter may lead to a change in the glycosylation profile. This, in turn, can precipitate more inflammation via complement activation.

Such a change in the glycosylation profile of plasma glycoproteins is known to occur in inflammatory bowel disease (IBD). Additionally, fecal microbiota transplantation in order to correct the composition of the gut microbiome affects glycosylation of both IgG and serum.

A loss of galactose, for example, prevents the activation of the anti-inflammatory checkpoint that suppresses complement-mediated inflammation, which is formed by the galactose-mediated linkage of Dectin-1 to FcyRIIB on myeloid cells. This is seen to cause inflammation and complement activation in IBD.

Hospitalization risk score

The researchers used the machine learning algorithm Lasso to select those markers that could best discriminate mild COVID-19 from severe. The results included zonulin, LBP and sCD14, with an AUC of over 99%. They then used this to estimate the risk of hospitalization, and found that it had a sensitivity of around 98% with a specificity of around 95%, for an overall accuracy of 96%. The Kyn-Trp ratio is also capable of robust discrimination. This emphasizes the close link between gut disruption and severe COVID-19.
What are the implications?

The researchers sum up, “Our data indicate that severe COVID-19 is associated with a dramatic increase in tight junction permeability and translocation of bacterial and fungal products into the blood. This disrupted intestinal barrier integrity and microbial translocation correlates strongly with increased systemic inflammation, increased immune activation, decreased intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate.”

The researchers also suggest that this may indicate the possibility of long-term sequelae due to the disruption of the gut barrier and perturbed gut function. This may include metabolic dysfunction in COVID-19 ‘long haulers’. Studies to understand this should be a priority, accompanied by research on the most effective ways to ameliorate this. This could appropriate for curbs on the widespread use of antibiotics, which impact the course of the disease, especially in older patients and those with metabolic disease.

Secondly, the study may make it possible eventually to predict severe COVID-19, using the identified rise in multiple biomarkers, including plasma lipids, amino acids and their metabolites, and glycans.

Finally, the study reveals some potential therapeutic targets in severe COVID-19. These include zonulin, which could be successfully inhibited to improve gut barrier integrity, and citrulline. The association between severe COVID-19 and a genetic predisposition to high zonulin production should also be examined further.

Again, lectins and other glycans that modulate inflammation may help prevent the cytokine storm in severe COVID-19. The use of highly glycosylated immune complexes is known to inhibit complement-mediated inflammation, and could be adapted for use in COVID-19.

Overall, therefore, the authors conclude, “Greater understanding of the interaction between the gut, intestinal microbiota, and amino acid metabolism during COVID-19 might inform pharmaceutical and diet approaches to improve COVID-19 outcomes.”
Posts: 1535
Joined: Fri Jun 26, 2020 5:22 am

Re: Severe COVID-19 complications linked to gut barrier breakdown

Post by trader32176 »

Poor gut health may adversely affect COVID-19 prognosis

1/12/21 ... nosis.aspx

People infected with COVID-19 experience a wide range of symptoms and severities, the most commonly reported including high fevers and respiratory problems. However, autopsy and other studies have also revealed that the infection can affect the liver, kidney, heart, spleen--and even the gastrointestinal tract. A sizeable fraction of patients hospitalized with breathing problems also have diarrhea, nausea and vomiting, suggesting that when the virus does get involved in the GI tract it increases the severity of the disease.

In a review published this week in mBio, microbiologist Heenam Stanley Kim, Ph.D, from Korea University's Laboratory for Human-Microbial Interactions, in Seoul, examined emerging evidence suggesting that poor gut health adversely affects COVID-19 prognosis. Based on his analysis, Kim proposed that gut dysfunction--and its associated leaky gut--may exacerbate the severity of infection by enabling the virus to access the surface of the digestive tract and internal organs. These organs are vulnerable to infection because they have widespread ACE2--a protein target of SARS-CoV-2--on the surface.

" There seems to be a clear connection between the altered gut microbiome and severe COVID-19."

- Heenam Stanley Kim, Ph.D., Microbiologist

Studies have demonstrated that people with underlying medical conditions including high blood pressure, diabetes and obesity face a higher risk of severe COVID-19. Risk also increases with age, with older adults most vulnerable to the most serious complications and likelihood of hospitalization. But both of these factors--advanced age and chronic conditions--have a well-known association with an altered gut microbiota. This imbalance can affect gut barrier integrity, Kim noted, which can allow pathogens and pathobionts easier access to cells in the intestinal lining.

So far, the link between gut health and COVID-19 prognosis hasn't been empirically demonstrated, Kim noted. Some researchers have argued, he said, that unhealthy gut microbiomes may be an underlying reason for why some people have such severe infections.

What studies have been done hint at a complicated relationship. A study on symptomatic COVID-19 patients in Singapore, for example, found that about half had a detectable level of the coronavirus in fecal tests--but only about half of those experienced GI symptoms. That study suggests that even if SARS-CoV-2 reaches the GI tract, it may not cause problems. Kim also noted that a person's gut health at the time of infection may be critical for symptom development.

Many recent studies have found reduced bacterial diversity in gut samples collected from COVID-19 patients, compared to samples from healthy people. The disease has also been linked to a depletion of beneficial bacterial species - and the enrichment of pathogenic ones. A similar imbalance has been associated with influenza A infection, though the 2 viruses differ in how they change the overall microbial composition.

The depleted bacterial species associated with COVID-19 infection include some families that are responsible for producing butyrate, a short-chain fatty acid, which plays a pivotal role in gut health by reinforcing gut-barrier function.

Kim said he started analyzing the studies after realizing that wealthy countries with a good medical infrastructure--including the United States and nations in Western Europe--were among the hardest hit by the virus. The "western diet" that's common in these countries is low in fiber, and "a fiber-deficient diet is one of the main causes of altered gut microbiomes," he said, "and such gut microbiome dysbiosis leads to chronic diseases."

The pathogenesis of COVID-19 is still not fully understood. If future studies do show that gut health affects COVID-19 prognosis, Kim argued, then clinicians and researchers should exploit that connection for better strategies aimed at preventing and managing the disease. Eating more fiber, he said, may lower a person's risk of serious disease. And fecal microbiota transplantation might be a treatment worth considering for patients with the worst cases of COVID-19.

The problem with gut health goes beyond COVID-19, though, he said. Once the pandemic passes, the world will still have to reckon with chronic diseases and other problems associated with poor gut health.

"The whole world is suffering from this COVID-19 pandemic," Kim said, "but what people do not realize is that the pandemic of damaged gut microbiomes is far more serious now."


American Society for Microbiology
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