Microbiome: COVID-19's hidden factor?
Pre-pandemic microbiome composition influences severe disease outcomes years later in a population study.
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11/06/2025
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by Kerri Miller
In a population-based cohort of 5,084 patients, baseline gut microbiota composition was associated with the risk of future COVID-19 hospitalization or death, with higher relative abundances of butyrate-producing bacteria linked to a lower risk, according to lead study author Robert F.J. Kullberg, MD, of Amsterdam University Medical Center, and colleagues.
Fecal samples collected between May 2011 and November 2015 in the Healthy Life in an Urban Setting (HELIUS) study were analyzed using 16S rRNA gene sequencing (V4 region) and ANOVA (Bray-Curtis) to assess overall community differences. During the first 2 years of the COVID-19 pandemic, 73 patients developed severe disease, defined as hospitalization or mortality. Baseline microbiota composition differed between those who later developed severe COVID-19 and those who did not. Cox proportional-hazards models then quantified associations between individual genera or features and severe outcomes.
Greater abundances of the anaerobic gut symbiont Enterocloster were linked to an increased risk, while Oscillospirales species—many of which produce butyrate—were linked to reduced risk of developing severe COVID-19. An abundance of butyrate-producing bacteria showed a protective association both when modeled as a continuous variable and when comparing the highest vs the lowest tertile.
These associations remained statistically significant after adjustment for age, sex, ethnicity, body mass index, time from inclusion to January 1, 2020, and comorbidities, including hypertension, diabetes, cancer, and cardiovascular, pulmonary, and gastrointestinal disease. Findings were consistent in analyses controlling for antibiotic use, vaccination status, and time frame. Three sensitivity analyses yielded similar results: adding recent antibiotic exposure (within 3 months of sampling) as a confounder, restricting outcomes to 2020, and censoring at the first SARS-CoV-2 vaccination.
Among 934 patients with confirmed SARS-CoV-2 infection during follow-up, microbiota composition differed between those with and without severe COVID-19, and butyrate-producer abundance was lower in severe cases.
Patients who developed severe disease were older (median 57 vs 52 years), had higher body mass index (median 31 vs 27), and more comorbidities than those without severe disease. Common diseases included hypertension (49% vs 26%), diabetes (31% vs 11%), cardiovascular disease (23% vs 10%), and pulmonary disease (26% vs 10%). Only 3% of the severe group were of Dutch ethnicity vs 30% among nonsevere cases; 37% were South-Asian Surinamese vs 16%, 15% were Turkish vs 9%,3% were Ghanaian or identified as other vs 10%, while relatively 12% of both severe and nonsevere groups were Moroccan.
Preclinical studies suggest that butyrate enhances epithelial barrier integrity and modulates systemic and pulmonary immune responses—for example, via G protein-coupled receptor signaling and histone deacetylase inhibition—supporting more effective CD8+ T cell antiviral activity and reduced airway neutrophilia. Murine studies showed Faecalibacterium prausnitzii and other Oscillospiraceae improved pneumonia outcomes.
The researchers emphasize that while infection acquisition is largely exposure-driven, baseline gut microbiota may relate primarily to severity given infection, not to infection risk per se.
"Combined with the preclinical evidence, our findings suggest that microbiome-directed therapies aimed at increasing intestinal abundances of butyrate-producers might limit the risk of future severe viral pneumonia," the researchers wrote. "Butyrate-producing gut microbiota may represent a novel therapeutic target for the prevention of viral pneumonia."
A key limitation is the long interval between stool collection and pandemic outcomes; while adult microbiota can be relatively stable over years, changes over time could attenuate associations. Also, the relative abundance of butyrate-producers is a proxy measure—actual butyrate production varies by strain and environmental context, which were not directly measured.
Funding included an Amsterdam University Medical Center PhD scholarship, a Niels Stensen Fellowship, the Dutch Heart Foundation, ZonMw/NWO, the European Union FP-7 program, and the European Fund for the Integration of non-EU immigrants. One author reported being a co-founder and member of the Scientific Advisory Board of Caelus Pharmaceuticals and Advanced Microbiota Therapeutics. Another author reported grants from ZonMw/NWO and the EU outside the submitted work.
Summary content
7 Key Takeaways
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Developed a paper-based colorimetric sensor array for chemical threat detection.
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Can detect 12 chemical agents, including industrial toxins.
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Production cost is under 20 cents per chip.
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Utilizes dye-loaded silica particles on self-adhesive paper.
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Provides rapid, simultaneous identification through image analysis.
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Inspired by the mammalian olfactory system for pattern recognition.
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Future developments include a machine learning-enabled reader device.
The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.