People who remained sick long after their COVID-19 infection often had alterations in their intestinal bacteria
Some COVID patients still had poor lung function three months after admission to Norwegian hospitals. These patients also had alterations in their intestinal flora and possible evidence of a leaky gut, a new study shows.
Researchers have long suspected that the gut may play a role in COVID-19.
Some studies have documented that viruses are not only found in the faeces, but in tissues from different parts of the intestinal tract, as was shown in this study from 2021.
Other studies have shown that the intestinal flora in COVID-19 patients is different than in healthy people, and that some people experience gastrointestinal problems in connection with the disease.
Now a new Norwegian study has linked the intestine to COVID-19 related lung problems.
Large drug test
The Norwegian effort started as part of an international study.
In 2020, the World Health Organization (WHO) initiated a large study to investigate whether the drugs Remdesivir and hydroxychloroquine could slow the course of disease in patients admitted to hospital with COVID-19.
Twenty-nine Norwegian hospitals participated.
But Norwegian researchers decided to go a step further, says Marius Trøseid, a professor and infection specialist at Oslo University Hospital.
“We collected biobank material at admission and followed up with the patients three months after their discharge. Then we tested their lung function and took stool samples,” he said.
Gold mine of data
The results from the original WHO study from February last year, including the Norwegian part, was published in the journal Annals of Internal Medicine and proved to be disappointing.
“They were unable to find that the medication made any difference in mortality, virus clearance or degree of respiratory failure,” said Beate Vestad, a postdoctoral fellow and researcher at Oslo University Hospital.
“But all the data that was collected is a gold mine,” she said.
Analyses of these data show that the patients who had reduced lung function three months after discharge also had alterations in their intestinal flora, Vestad said.
The diversity of the gut bacteria in these individuals had been reduced. There were fewer bacteria from 20 different bacterial groups.
At the same time, numbers for five other bacterial groups had increased. Among them was Veillonella, a bacterium previously linked to both COVID-19 and the development of pulmonary fibrosis, which causes scar tissue in the lungs.
These changes in the composition of the intestinal flora did not appear to be due to the use of antibiotics during hospitalization.
“This is an important study,” said Gülen Arslan Lied, a professor at the Centre for Nutrition at the University of Bergen and Haukeland University Hospital.
Her research group is also studying the intestinal flora of COVID-19 patients, but she did not participate in this study.
“This is the first study that potentially links lung function to intestinal flora changes in COVID-19. It will be exciting to see whether the bacterial group Veillonella plays a role in the development of pulmonary fibrosis,” Lied wrote to sciencenorway.no.
She believes the data collected are valuable and interesting, but points out some weaknesses in the survey.
For example, the researchers could only take stool samples at the check-up, three months after admission.
“We thus do not know which intestinal flora profile the patient had when they were diagnosed with COVID-19 or were admitted to hospital. Intestinal flora can be affected by a number of factors, including what you eat, various diets, use of probiotics and antibiotics,” Lied wrote.
Changes in bacterial flora were not the only association between COVID-19 and the gut in the patients in the study. The results also showed a clear link between breathing problems and a substance in the blood called lipopolysaccharide binding protein (LBP).
LBP is a substance made by the immune system. It binds to the harmful substance lipopolysaccharide (LPS).
LPS is typically produced by the bacteria in the intestinal flora. Normally, the intestinal walls stop this toxic substance so that it does not enter the bloodstream.
But if the intestinal wall leaks more than normal, LPS will still be able to move through the gut and trigger an increase in LBP production. As a result, the levels of LBP in the blood can be a measure of how much the intestines are leaking.
May be a sign of persistent leakage
The new study shows that patients with respiratory failure during hospitalization had clearly higher levels of LBP than the other patients. In this situation, however, LBP levels may also reflect a general immune response to the infection.
However, in some patients the levels of LPB were still elevated three months later, while other typical immune substances, such as CRP, had gone down.
The researchers believe this may be an indication of persistent leakage in the intestines of these patients.
“At the same time, results in the research literature related to methods and markers as sa way to assess the intestinal barrier and leakage are controversial, when it comes to including LBP,” Lied from the University of Bergen wrote.
“There’s quite a bit of discussion over which methods and markers are accurate and most appropriate,” she wrote.
Don’t know what leads to what
The results show that alterations in the intestinal flora and evidence of intestinal leakage can be associated with long-term lung disease after a COVID-19 infection.
But for now, it’s difficult to say for certain what this means.
For example, the condition of the intestine may determine how sick you become. But it is also possible that the disease itself causes alterations in the intestinal flora and increased permeability in the intestinal walls.
Or none of these things.
Perhaps the connection is due to an underlying factor, such as a poor diet, which leads to both intestinal problems and more serious lung disease from a COVID-19 infection.
“We don’t yet know this,” Vestad said.
Likely that the illness leaves an effect
“This is first and foremost a study to generate hypotheses,” she says.
In other words, the researchers can use their results to form hypotheses about the mechanisms behind them, such as that a certain intestinal flora gives a higher risk of serious Covid-19 disease.
Trøseid, who led the study, believes it is most likely that very severe disease leaves its mark in several organs, including the intestinal flora, and that this can linger for a long time.
However, the hypotheses are not mutually exclusive. For example, it is conceivable that serious illness alters the intestinal flora, but that these alterations in turn aid in prolonging complications after the disease.
To find answers, the hypotheses have to be examined in other, larger studies.
“I think that in the first instance you have to reproduce our results and then follow up in other cohorts where a stool sample has also been taken at admission,” Trøseid said.
Vestad believes there are good reasons to do more research on this.
“Our results provide fertile ground for examining the connection between the intestine and lung in more detail, also in connection with long COVID. There is much more we do not know,” she said.
Bergen study of the intestines and COVID-19
Lied also believes more research is needed.
“This is exciting, and further studies are definitely needed in greater numbers to reproduce the results and better understand the interaction between the intestinal and lungs,” she wrote to sciencenorway.no.
Her research group at the University of Bergen is conducting a study on people with confirmed COVID-19. The researchers will survey the participants' intestinal flora after one and six months, and compare the results with healthy people.
“It is also desirable to determine whether COVID-19 can cause post-infectious low-grade inflammation in subgroups of patients,” Lied wrote.
“This can lead to irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), sleep disorders and anxiety and depression,” she wrote.
“The giardia epidemic in Bergen in 2004 caused post-infectious IBS in more than a thousand patients who had reduced quality of life and chronic fatigue ten years after infection,” the professor wrote.
Translated by Nancy Bazilchuk
Beate Vestad et.al.: Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Journal of Internal Medicine, 2022.
Read the Norwegian version of this article at forskning.no