What is it about?

In 2003, there was an outbreak of SARS-CoV-1, and follow-up data showed that, after several years, in about 40% of the patients, long-term/chronic symptoms persisted, for example, psychiatric illness (post-traumatic stress syndrome, depression, somatoform pain disorder, and panic disorder), chronic fatigue, and reduced pulmonary function (Lam, 2009; Ngai et al., 2010). Recently, similar trends of long-term symptoms have been reported for patients infected with SARS-CoV-2. The definition is still evolving as is the name, for example, long COVID-19, COVID-19 long hauler, post-COVID-19, post-acute COVID-19, and chronic COVID-19 are used to describe symptoms from patients with acute COVID-19 that last longer than 4 or 12 weeks and are not attributable to alternative diagnoses. There is evidence from several studies that SARS-CoV-2 infection leads to changes in the microbiome. These changes can be caused by an infection directly in the gut, as a response to increased inflammation and crosstalk between the oral, lung, and gut microbiome. In case a dysbiosis in the microbiome is established, it can lead to or fuel inflammation, increase intestinal permeability, and change the balance of signalling metabolites. In addition, there is a complex interplay of gene expression regulation via miRNA produced by the host, microbiomes, and SARS-CoV-2 (Hong and Kim, 2021; Omer and Kubra, 2021). Here we postulate that, in a subset of patients, long-term changes (dysbiosis) in the gut microbiota might drive or support some symptoms, especially fatigue, joint pain, diarrhoea, headache, depression, and anxiety, as seen in chronic COVID-19 syndrome. Dysbiosis in the gut microbiome can influence the immune system, lung, and brain via the gut–lung axis and gut-brain axis as well as other organs via miRNA and metabolites produced by the microbiome. The gastrointestinal tract has not just a digestive function but also is responsible for achieving an immune system homeostasis.

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Why is it important?

Infection with SARS-CoV-2, the causative agent for COVID-19, seems to be a rather complex process, at least for patients that are administered to the hospital. It is not "just" affecting the pulmonary system, but also the cardiovascular system, renal system, hepatic system, gastrointestinal system, nervous system, and/or various systems, leading to shock and multi-organ failure. Especially difficult to treat is the overreaction of the immune system in some patients, which is known as a cytokine storm. There is some evidence showing that SARS-CoV-2 infection in the gut leads to changes in the gut microbiome, increases inflammation and weakens the gut mucosal integrity. These can lead to further inflammation, distribution of virus to other organs and increase the chances of bacteremia. Once patients are released from the hospital a large percentage of them, according to a meta-analysis including 47,910 patients, about 80%, developed at least one chronic symptom. The main symptoms were fatigue and/or muscle weakness, joint pain, headache, sleep disturbance, dyspnea, anxiety/depression, hair loss, loss of test/smell, chest pain, and diarrhoea. We found that some of these symptoms are very similar to symptoms described with the dysbiosis of the gut microbiome. In consequence, we postulate that there might be a connection for some of the symptoms. If that is the case, more research is needed, treatment would be possible.

Perspectives

I was quite shocked to hear that about 60-80% of the hospitalized COVID-19 patients remain at least one symptom after weeks/months past discharge from the hospital. Where the symptoms are from a medical perspective mild, they do mean a reduction in quality of life. After what they have been through it's saddening to hear such reports. I noticed that many of these symptoms are similar to symptoms reported in conjunction with gut microbiome dysbiosis. After some research, my colleague and I wrote this opinion paper in the hope that more research is done and maybe an easy treatment can be developed to address dysbiosis in the gut microbiome caused by SARS-CoV-2 and increased gut permeability. That could potentially result in increased life quality for millions of patients. Microbiome research has shown the immense complexity between microbes and humans. In my opinion, we are still at the beginning to understand this complexity and how it is influenced by the microbes as well as the host (humans). There is constant crosstalk not just between the microbes in one place of the body, but also between places for example the gut microbiome crosstalks with the lung microbiome. Various molecules from the microbes will go into the bloodstream and crosstalks to human cells and also to the mitochondria. On the other hand, there is crosstalk from the human cells with the microbes, so the talking is multi-directional. There is no wonder why in many diseases changes in the microbiomes are observed. Seemingly, this is also the case in COVID-19 and it could be an option to reduce the risk of disease severeness and chronic conditions with simple and cheap interventions. In my opinion, worthwhile looking into that more.

Prof Kai Hilpert
St Georges University of London

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This page is a summary of: Is There a Connection Between Gut Microbiome Dysbiosis Occurring in COVID-19 Patients and Post-COVID-19 Symptoms?, Frontiers in Microbiology, September 2021, Frontiers, DOI: 10.3389/fmicb.2021.732838.
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