Inflamed Gut May Explain Prolonged Post-COVID Fatigue

Researchers have discovered that gut problems before and after COVID-19 may be linked to persistent chronic fatigue, known as Post-COVID Syndrome. The study shows that changes in the immune system and intestinal inflammation may play a role in this prolonged fatigue. Monitoring digestive symptoms could help predict who is at greatest risk and improve diagnosis and treatment.

COVID-19, caused by the SARS-CoV-2 virus, was initially identified as a respiratory infection, but over time, scientists have realized that its effects extend far beyond the lungs. Many patients have reported persistent symptoms even after recovering from the acute infection, a condition known as Post-COVID Syndrome (PCS).

One of the most common problems among these patients is intense and long-lasting fatigue, which in some cases resembles a condition called Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS). Both syndromes share symptoms such as extreme tiredness, cognitive difficulties, and malaise after simple exertion.

However, as there are no definitive laboratory tests for these conditions, diagnosis is still based on symptoms described by patients, making case estimation a challenge.

Studies show that approximately 1% to 10% of people infected with SARS-CoV-2 may develop symptoms similar to those of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome, which indicates that the numbers of this syndrome may double in the coming years.

As with Chronic Fatigue Syndrome, Myalgic Encephalomyelitis often begins after viral infections. Researchers believe that these conditions involve changes in the immune system, intestinal dysfunction and problems with the functioning of mitochondria (the “power plants” of cells).

In particular, a dysregulated immune system can lead to the exaggerated production of inflammatory substances called cytokines, which interfere with the normal functioning of the body.

Although it is a respiratory disease, COVID-19 also affects other organs, especially the intestine. The virus can directly damage the cells that line the digestive tract or cause this damage through inflammation triggered by the immune system.

This damage affects the intestinal barrier, an essential structure that prevents microorganisms and toxins from entering the bloodstream. When this barrier is compromised, as has been observed in severe cases of COVID-19, substances such as proteins from the zonulin family and fragments of bacterial DNA can be detected in the blood, suggesting intestinal inflammation.

Research shows that COVID-19 can alter the composition of the intestinal microbiota (the beneficial bacteria that live in the intestine), which affects the immune system and intestinal protection.

In addition, the enzyme ACE-2, which the virus uses to enter cells, is highly present in the intestine, suggesting that the gastrointestinal tract can serve as a viral reservoir even after the acute infection has passed. A meta-analysis found that 22% of patients with Chronic Fatigue Syndrome report gastrointestinal symptoms, reinforcing the idea that the intestine plays a central role in this condition.

In this study, researchers from the Medical University of Vienna, Austria, analyzed patients with persistent fatigue after COVID-19, comparing their symptoms and medical history with biological samples such as blood, saliva and stool.

The goal was to better understand how the virus affects the body in the long term and to identify risk factors and possible markers that could help predict who might develop Chronic Fatigue Syndrome.

The results showed that people with gut problems before infection were more likely to develop post-COVID fatigue. These patients showed changes in specific inflammatory markers, such as increased levels of IL-6 (a pro-inflammatory cytokine), reduced levels of IL-33, and an imbalance between the molecules LBP and sCD14, which indicate inflammation and immune system activation.

Based on these findings, scientists propose that COVID-19 may cause chronic fatigue through persistent intestinal inflammation and compromised gut barrier. This allows unwanted substances to enter the bloodstream, triggering reactions throughout the body.

Monitoring gut symptoms before and after infection may help identify people at risk of developing Chronic Fatigue Syndrome early. With this knowledge, doctors will be able to develop better diagnostic, treatment, and prevention methods, offering a better quality of life to affected patients.

This schematic figure shows how COVID-19 can cause a type of extreme and long-lasting fatigue called Post-COVID Syndrome (or long COVID), especially when the gut is involved. When a person becomes infected with the SARS-CoV-2 virus, it can damage the protective barrier of the gut, allowing substances and microorganisms to escape into the body, triggering inflammation. This can cause symptoms such as intense fatigue. The study also found that people who already had gut problems before COVID-19 appeared to be more likely to develop this fatigue. To investigate this, the researchers analyzed blood, saliva and stool samples from four groups: people with post-COVID fatigue, people who recovered from COVID without fatigue, people with post-Epstein-Barr fatigue and healthy people. The results showed changes in inflammatory substances in the blood (such as IL-6 and IL-33), especially in people with fatigue who already had gut complaints before infection. This suggests that taking care of your gut health may be important for preventing or treating post-COVID-19 fatigue.

READ MORE:

Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients

Johanna Rohrhofer, Viktoria Wolflehner, Johannes Schweighardt, Larissa Koidl, Michael Stingl, Sonja Zehetmayer, Joana Séneca, Petra Pjevac, Eva Untersmayr

Allergy. 15 May 2025 

https://doi.org/10.1111/all.16593

Abstract:

Post-COVID Syndrome (PCS) is the term for a condition with persistent symptoms in a proportion of COVID-19 patients after asymptomatic, mild, or severe disease courses. Numbers vary, but the current estimate is that after COVID-19 approximately 10% develop PCS. The aim of our study was to evaluate the impact of SARS-CoV-2 infection on the gastrointestinal (GI) tract and associations with the development of PCS with fatigue, post-exertional malaise (PEM), orthostatic dysregulation, autonomous dysregulation, and/or neurocognitive dysregulation. By combining medical record data from a prospective observational study with symptom analysis before, during, and after SARS-CoV-2 infection, we aimed to identify potential risk factors and predictive markers for PCS. Additionally, we analyzed blood, saliva, and stool samples from this well-characterized PCS patient cohort to biologically validate our findings. We identified significant associations between pre-existing GI complaints and the development of PCS Fatigue. PCS patients showed higher LBP/sCD14 ratios, lower IL-33 levels, and higher IL-6 levels compared to control groups. Our results highlight the critical role of the GI tract in PCS development of post-viral Fatigue. We propose that the viral infection disrupts pathways related to the innate immune response and GI barrier function, evidenced by intestinal low-grade inflammation and GI barrier leakage. Monitoring GI symptoms and markers before, during, and after SARS-CoV-2 infection is crucial for identifying predictive clinical phenotypes in PCS. Understanding the interaction between viral infections, immune responses, and gut integrity could lead to more effective diagnostic and treatment strategies, ultimately reducing the burden on PCS patients.