Summary: New research from the University of Alberta shows that women with long COVID exhibit distinct biological disruptions — including gut inflammation, impaired red blood cell production (anemia), and altered sex hormone levels — that help explain their more severe and persistent symptoms. These conclusions are based on immune profiling, biomarker measurement, and transcriptomic analyses performed about one year after initial SARS-CoV-2 infection.
Hormone imbalances, particularly reduced testosterone in women, were closely associated with ongoing inflammation and common symptoms such as profound fatigue, cognitive impairment (“brain fog”), pain and mood disturbances. The study identifies biological signals that could guide more personalized treatments for people living with long COVID.
Key Facts
- Gut inflammation and barrier dysfunction: Female patients showed biomarkers consistent with increased intestinal permeability, which can allow microbial products into the bloodstream and drive systemic inflammation.
- Hormone disruption: Lower testosterone in women correlated with higher inflammatory markers and worse clinical symptoms; male patients showed alterations in estrogen and both sexes had lower cortisol.
- Anemia and impaired erythropoiesis: Evidence of reduced red blood cell production was observed in women, supporting other reports that anemia may be an important contributor to long COVID symptoms.
Source: University of Alberta
Research published today in Cell Reports Medicine identifies sex-specific biological changes that likely contribute to why women — and those who develop symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) — experience more severe and lingering long COVID than men.
Long COVID, also called post-COVID-19 condition, is defined by the persistence or new onset of neurological, respiratory, or gastrointestinal symptoms three months or more after acute SARS-CoV-2 infection.
Epidemiological data show women are about three times more likely than men to develop long COVID. Until now, the biological mechanisms behind this sex disparity were poorly understood.
This study examined 78 patients with long COVID approximately one year after their acute infection, alongside 62 control participants who had recovered without persistent symptoms. The research team conducted comprehensive blood testing, immune cell profiling, biomarker assays and RNA sequencing to compare male and female patients.
Analysis revealed a clear sex-specific immune signature. Female long COVID patients had signs of myelopoiesis (a shift toward production of myeloid cells), fewer lymphocytes, increased neutrophils and monocytes, and reduced regulatory T cells—findings consistent with ongoing immune activation.
Markers of gut barrier dysfunction were elevated in women, including intestinal fatty acid binding protein, lipopolysaccharide and soluble CD14. These markers indicate increased intestinal permeability, which can allow bacterial components into the circulation and amplify systemic inflammation.
“Our results suggest that, early in infection, the female gut may be more susceptible to viral or microbiome-related disruption, which then contributes to prolonged immune activation,” says principal investigator Shokrollah Elahi, immunology professor in the Mike Petryk School of Dentistry.
Female patients also showed evidence of impaired erythropoiesis. Elevated CD71+ erythroid cells and other signs of disrupted red blood cell production were linked to fatigue and tissue damage, aligning with other recent international studies that identify anemia as an important biological component of long COVID.
Hormonal profiles differed by sex: affected women had lower testosterone, while affected men had lower estradiol; both groups showed reduced cortisol. Because testosterone helps regulate inflammation, reduced levels in women were associated with higher inflammatory markers and with symptoms including cognitive dysfunction, depression, pain and extreme fatigue.
These sex-specific immune, hormonal and transcriptomic patterns partially overlap with but are not identical to idiopathic ME/CFS, which also disproportionately affects women. For example, chronic inflammation is common to both conditions, while anemia appears to be more specific to long COVID in this study.
Elahi and colleagues plan follow-up studies in animal models and aim to secure funding for clinical trials. They propose a precision-medicine strategy tailored to each patient’s biological profile: interventions may include treatments for anemia, targeted anti-inflammatory therapies, and, where appropriate and safe, hormone-based approaches.
The team will also continue investigating the links between long COVID neurological symptoms and neuroimmune changes observed in other chronic viral infections, such as HIV.
Funding: This research was supported by the Canadian Institutes of Health Research and the Li Ka Shing Institute of Virology. Contributors include post-doctoral fellow Shima Shahbaz (CIHR REDI Early Career Transition Award recipient), Mohamed Osman, Jan Willem Cohen Tervaert, Rhonda Rosychuk, Andrew Mason, and Hussain Syed. Some analyses were performed at the University of Alberta’s Flow Cytometry Facility and Advanced Cell Exploration Core.
Elahi, Osman and Mason are affiliated with the Li Ka Shing Institute of Virology, the Women and Children’s Health Research Institute (WCHRI) and the Cancer Research Institute of Northern Alberta (CRINA). Rosychuk is a WCHRI member. Elahi is also affiliated with the Glycomics Institute of Alberta and the Alberta Transplant Institute.
Key Questions Answered:
A: The study found women with long COVID show stronger systemic inflammation, evidence of gut barrier dysfunction, impaired red blood cell production, and sex-hormone disruptions — factors that together are linked to more persistent and severe symptoms.
A: Key markers included elevated inflammatory proteins, indicators of gut leakiness (intestinal fatty acid binding protein, LPS, soluble CD14), signs of disrupted erythropoiesis, and altered sex-hormone and cortisol levels.
A: The findings support a personalized approach: treating anemia where present, addressing persistent inflammation with targeted therapies, and considering hormone modulation when clinically appropriate.
About this Long-COVID research news
Author: Michael Brown
Source: University of Alberta
Contact: Michael Brown – University of Alberta
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS” by Shokrollah Elahi, et al. Cell Reports Medicine
Abstract
Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS
Long COVID (LC) presents notable sex-specific differences, particularly among patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
In this cohort, female LC patients with ME/CFS exhibited a shift toward myelopoiesis, reduced lymphocyte counts, increased neutrophils and monocytes, and lower regulatory T cell numbers—consistent with persistent immune activation. Elevated CD71+ erythroid cells and disturbed erythropoiesis were linked to fatigue and potential tissue injury in affected women.
Cytokine profiles showed a stronger pro-inflammatory response in female patients compared with male patients, alongside biomarkers indicating gut barrier dysfunction.
Hormone assays revealed lower testosterone in affected women and decreased estradiol in affected men; cortisol was reduced in both sexes. Transcriptomic analyses highlighted neuroinflammatory signatures in female patients that may help explain cognitive symptoms.
The study identifies biomarkers that distinguish female and male long COVID patients and that correlate with sex-specific clinical features. Overall, long COVID with ME/CFS is characterized by sex-specific immune, hormonal and transcriptomic alterations, with females showing more pronounced inflammatory changes.
These findings support the development of sex-specific and individualized interventions, including the potential role of hormone-based therapies when appropriate.