Could the Gut Microbiome Hold Clues to Long COVID Relief?

For millions of people living with long COVID, symptoms like brain fog, fatigue, poor sleep and cognitive difficulties can persist for months or even years after the initial infection has passed. Despite the growing number of patients affected worldwide, there are still no widely established treatments for the condition, leaving many searching for answers and effective ways to manage daily symptoms.

Now, new research presented at Digestive Disease Week is exploring a possible new avenue for treatment: the gut microbiome. In a randomized controlled trial, researchers investigated whether a synbiotic called SIM01 — a combination of probiotics and prebiotics — could help rebalance gut bacteria and improve long COVID symptoms. Participants who received the synbiotic experienced changes in their gut microbiota, lower levels of histamine linked to inflammation and improvements in symptoms compared with those taking a placebo.

According to Qi Su, Ph.D., assistant professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, the findings are significant because they suggest that disruptions in gut bacteria caused by COVID-19 may persist long after the virus has cleared. Researchers believe this lingering imbalance in the microbiome could contribute to chronic inflammation and symptoms such as fatigue, memory problems and brain fog.

In an interview with The Educated Patient, Su explains why histamine may play an important role in long COVID symptoms, how synbiotics differ from standard probiotics patients can buy over the counter and what this research could mean for the future of personalized long COVID care. He also discusses how close researchers may be to bringing microbiome-based treatments into routine clinical practice for patients still struggling with persistent symptoms.

For patients with long COVID who have been struggling for months or years without answers, what makes this study significant and why is the gut microbiome an important place to be looking?

Qi Su, Ph.D.: While numerous studies have demonstrated a close relationship between gut microbiota and prolonged COVID-19 symptoms, this study is the first to prove that regulating gut microbiota using probiotics can improve microbiota structure and metabolic function, potentially alleviating various symptoms. Furthermore, although viral infection can be cleared, the gut microbiota dysbiosis it induces can persist for more than a year, thus potentially serving as an inducing factor for prolonged COVID-19 symptoms.

One of the most interesting findings here is that SIM01 significantly reduced histamine levels, and investigators linked that to changes in the gut microbiome. For a patient who has never heard of histamine in this context, can you explain what role it plays in long COVID symptoms like brain fog and fatigue — and why reducing it matters?

QS: High histamine levels frequently cause brain fog, chronic fatigue and cognitive dysfunction. Excess histamine acts as a neuroinflammatory agent, crossing the blood-brain barrier to trigger insomnia, memory issues and exhaustion.

The study used a synbiotic, which combines probiotics and prebiotics. How is that different from the probiotic supplements patients can already pick up at a pharmacy, and why does that distinction matter when it comes to actually shifting the gut microbiome in a meaningful way?

QS: Compared to traditional probiotics, adding prebiotics can significantly improve the colonization and growth efficiency of probiotics. At the same time, prebiotics also provide highly efficient nutrients for some beneficial bacteria already present in the gut, thereby effectively improving the structure and function of the gut microbiota.

The study found that participants’ baseline gut microbiota predicted how successfully SIM01 would colonize their gut. What does that tell us about the future of treating long COVID — and are we moving toward a world where gut microbiome testing becomes a routine part of care for these patients?

QS: The correlation between baseline gut microbiota and probiotic colonization and therapeutic efficacy suggests that different population groups may require different formulations or customized probiotics. While fecal testing can help identify individuals who may achieve clinical benefits, its high cost and potential instability currently make it unsuitable for widespread implementation.

For someone listening to this who has been living with brain fog, fatigue or other persistent symptoms and is wondering whether a probiotic could help them, what is your practical advice — and how close are we to having something clinically available that they can actually ask their doctor about?

QS: The SIM01 formula used in the study is currently available in more than 10 countries and regions. For areas where it is not available, patients may be able to try a similar formula reported in this study to achieve relief.