Pharmacological and non-pharmacological management of long COVID

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a major global health burden in terms of acute infection and long-term consequences. Approximately 10% of infected experience autonomic dysfunction, cardiovascular complications, and neurological impairments. While immune dysregulation, persistent viral reservoirs, chronic inflammation, gut dysbiosis, and vascular dysfunction are implicated, the exact pathophysiological mechanisms of Long COVID remain unclear. Additionally, treatment options are limited and challenging to prescribe due to symptom heterogeneity. Non-pharmacological interventions such as increased salt intake, elimination diets for gastrointestinal symptoms, and cognitive pacing for fatigue may not be sufficient for severe symptoms. Moreover, pharmacological interventions such as β-blockers, calcium channel blockers, pyridostigmine, antihistamines, and low-dose naltrexone can improve tachycardia, fatigue, and brain fog but there are no standardized guidelines. In light of evidence supporting a strong association of Long COVID with gut dysbiosis, probiotics have emerged as a promising intervention. Clinical studies have shown that Bacillus coagulans, Bacillus subtilis, Lactobacillus acidophilus, and Bifidobacterium species can improve fatigue, gastrointestinal health, and overall physical and mental well-being in Long COVID patients. Large-scale randomized controlled trials are warranted to validate probiotic efficacy in Long COVID and reduce burden on individual health and healthcare institutions.

Introduction

The first reports of COVID-19 were associated with symptoms of fever, dry cough, pneumonia, dyspnea, and fatigue, providing evidence of a highly transmissible viral infection attributable to SARS-CoV-2. COVID-19 has evolved into a long-term health concern and as of March 3, 2025 there have been over 770 million acute infections and 7 million deaths. COVID-19 health impacts extend beyond the acute infection [1]. Many recovered patients continue to experience multisystem symptoms with adverse outcomes. It may also cause new cardiac, renal, respiratory, musculoskeletal, and neurological conditions [2]. This condition, known as Long COVID or the post-acute sequelae of COVID-19 (PASC), is a multisystem syndrome following SARS-CoV-2 infection.

Long COVID is reported to take place in 10% of SARS-CoV-2 infections [3]. This equates to more than 77 million cases worldwide. The true incidence is likely higher due to underdiagnosis and limited understanding of pathophysiology. Long COVID is linked to cardiovascular, respiratory, metabolic, autoimmune, and psychiatric disorders [4, 5].

Long COVID patients may develop autonomic dysfunction, including POTS and inappropriate sinus tachycardia (IST) [6, 7]. POTS is defined by a ≥ 30 bpm heart rate rise (or >120 bpm) upon standing without orthostatic hypotension [8]. Meanwhile, IST is characterized as a sinus heart rate of greater than 100 bpm at rest without an exact cause of sinus tachycardia [9]. However mechanisms are unclear; symptoms are categorized as POTS or IST with tachycardia [10]. While most IST and POTS cases are in adults, growing evidence also shows these conditions in children. The incidence of such conditions is concerning, but these are treatable if properly diagnosed.

The pandemic caused tremendous harm to individual well-being, economies worldwide, and healthcare institutions [11]. Beyond its acute phase, Long COVID has left many individuals with prolonged symptoms, leading to sustained psychological and physical harm to well-being, even as extensive emergency lockdowns and movement restrictions have been lifted. Vaccines such as mRNA-1273, BNT162b2, ChAdOx1 nCoV-19, and BBIBP-CorV showed high protective efficacies against COVID-19 [12–14].

Some studies suggest vaccination lowers Long COVID risk, but most rely on subjective symptom reporting [15, 16]. Objective diagnoses show vaccination offers little protection against Long COVID. In 41,652 individuals, risk did not differ by vaccination status [17].

Other factors may also reduce Long COVID risk. For example, early antiviral treatment with nirmatrelvir–ritonavir (Paxlovid) has been shown to significantly reduce the risk of developing long COVID [18]. Patients treated within 5 days of infection had a 26% lower risk of post-COVID conditions compared to untreated individuals, suggesting that rapid viral clearance and control of systemic inflammation are important for preventing long COVID. Younger age, lower BMI, absence of comorbidities and lower COVID-19 disease severity lower Long COVID risk [19]. Individuals who had more than five symptoms during the first week of infection were associated with greater risk of long COVID, while those with mild symptoms were at lower risk.

Despite research, no standardized protocols exist and management is largely symptomatic. The heterogeneity of Long COVID makes a universal treatment framework difficult. Moreover, evidence-based guidelines are continually evolving and it is important to evaluate their long-term efficacy and safety require further validation through clinical trials and longitudinal studies. This narrative review aims to synthesize current evidence on the pathophysiological mechanisms of Long COVID and to evaluate non-pharmacological, pharmacological, and probiotic interventions, with particular emphasis on the potential role of probiotics in symptom management. This is done towards the goal of mitigating the burden of Long COVID on affected individuals and healthcare systems worldwide.

Methods

Google Scholar and PubMed were searched for peer-reviewed articles published up to January 2025. Articles were screened for relevance to Long COVID focusing on pathophysiological mechanisms, non-pharmacological and pharmacological management, and probiotic/paraprobiotic interventions. The inclusion criteria for this paper consisted of clinical studies, randomized controlled trials, cohort studies, case series, systematic reviews, and narrative reviews directly addressing Long COVID or post-acute sequelae of SARS-CoV-2 infection. Studies on related topics such as gut dysbiosis, autonomic dysfunction, and immune modulation by probiotics were also considered where relevant. Exclusion criteria included non-peer-reviewed articles, preprints without formal review, studies not directly related to Long COVID, and publications lacking substantial data on treatment outcomes or mechanistic insights. Keywords utilized in the search included “Long COVID”, “post-acute sequelae of SARS-CoV-2”, “pathophysiology”, “POTS”, “IST”, “non-pharmacological”, “pharmacological”, “probiotics”, and “gut microbiota”.

Pathophysiological mechanisms of long COVID

Long COVID exerts its symptoms through multiple pathophysiological mechanisms. Some individuals develop autoimmunity, evidenced by elevated autoantibodies which can increase levels of inflammatory markers such as C-reactive protein (CRP) [20]. Persisting viral SARS-CoV-2 particles in the gut, brain, and lymph nodes result in prolonged activation of immune cells, producing CRP, interleukin-6 (IL-6), and TNF-α [21]. This causes T cell dysregulation and cell-mediated autoimmunity leading to symptoms such as brain fog and dizziness [22]. Gut dysbiosis correlates with digestive symptoms and reduced short-chain fatty acid–producing bacteria [23].

Fibrin amyloid microclots from vascular inflammation impair oxygen and nutrient delivery, causing fatigue and brain fog [24]. Fatigue also arises from mitochondrial dysfunction, ROS overproduction, and reduced ATP, possibly triggered by viral infiltration during acute infection. Excessive reactive oxygen species (ROS) production in mitochondria leads to mitochondrial and mitochondrial DNA damage, resulting in impaired oxidative phosphorylation, a metabolic shift toward glycolysis, and reduced ATP production [25].

Long COVID also impacts neurological and neuroinflammatory pathways, which explains symptoms such as brain fog, mood disorders, fatigue, and sleep disturbances. Widespread microglial activation associated with prolonged activation of immune cells has been shown to be responsible for the development of neuroinflammatory and neurocognitive symptoms following SARS-CoV-2 infection. Activated glial cells release mediators causing glutamate excess, quinolinic acid pathway activation, cytokine upregulation, and complement dysregulation [26]. There is also evidence of blood-brain barrier (BBB) disruption and sustained systemic inflammation. Increased permeability may allow pro-inflammatory molecules to enter the brain, such as including interferon-γ (IFNγ), IL-6, IL-1β, IL-1RA, and IL-8 among others [27]. A graphical illustration summarizing the pathophysiological mechanisms of Long COVID is shown in Fig. 1.

Fig. 1.

Pathophysiological mechanisms of Long COVID

Multiple mechanisms contribute to the persistence of symptoms in Long COVID. Viral particles can remain in the gut, brain, and lymph nodes, driving chronic inflammation. Autoantibody production and T cell-mediated autoimmunity increase inflammatory markers such as CRP, IL-6, TNF-α. Moreover, gut dysbiosis reduces bacterial diversity and short-chain fatty acid production, leading to gastrointestinal symptoms and systemic inflammation. Persistent vascular inflammation promotes fibrin amyloid microclot formation which impairs oxygen delivery and contributing to fatigue and brain fog. Mitochondrial dysfunction with excessive ROS production lowers ATP generation, further reducing energy levels. Neuroinflammation is fueled by microglial activation, release of pro-inflammatory cytokines, and BBB disruption allowing inflammatory mediators into the CNS.

Non-Pharmacological treatment

Non-pharmacological treatments offer a valuable first-line approach for managing long COVID symptoms before initiating pharmacological interventions. These are particularly important given the absence of standardized pharmacological guidelines. Reports show that lifestyle-based interventions such as graded physical activity and rehabilitation programs are widely studied for Long COVID. An online-guided 3-month exercise intervention in 62 patients with post-COVID syndrome demonstrated benefits in terms of physical performance [28]. While overall exercise capacity and quality of life did not improve significantly, patients with moderate fatigue showed measurable gains in performance, whereas those with severe fatigue derived little benefit. Therefore, exercise may be appropriate only for selected patients and must be carefully tailored to avoid overexertion, especially in individuals with post-exertional symptom exacerbation.

Management of postural orthostatic tachycardia syndrome (POTS), a frequent post-infectious complication of COVID-19, often begins with simple measures such as increased salt and fluid intake. Increasing salt intake can be beneficial for patients experiencing orthostatic intolerance or POTS, as it helps improve blood volume and circulation. Patients are generally advised to consume 2–3 L of water per day and gradually increase sodium intake, starting around 6 g/day and titrating up to 10–12 g/day under medical supervision [29, 30]. Practical strategies include drinking fluids early in the morning before standing, adding salt to meals, or using slow-release salt tablets. Compliance can be challenging, as excessive salt at one time may trigger nausea, and elderly or hypertensive patients may have contraindications. Additional supportive strategies such as avoiding alcohol and caffeine, maintaining hydration, and adopting small frequent meals with fewer refined carbohydrates to promote glycemic stability are recommended [31].

A scoping review on diet and nutrition in Long COVID symptoms reported that whole-diet patterns, diet quality, and nutritional exposures are associated with improvements in inflammation [32]. Ensuring adequate protein intake is also important for recovery. A case report dealing with nutritional modulation of gut microbiota found that a high-fiber diet significantly alleviated severe GI symptoms and also improved non-GI symptoms like anxiety and palpitations [33]. Ensuring adequate protein intake is also important for recovery. Evidence suggests that the standard RDA of 0.8 g/kg/day may be insufficient; instead, 1.0–1.2 g/kg/day is recommended for older adults, and up to 1.5 g/kg/day for individuals with chronic conditions [34]. Many patients fail to meet these higher targets, particularly at breakfast and lunch, which may impair muscle protein synthesis and contribute to fatigue and muscle loss.

Cognitive pacing, a strategy to manage energy expenditure, is particularly effective for individuals with fatigue and cognitive dysfunction, helping them avoid exacerbation of symptoms from overexertion [35]. Indeed, a retrospective study of 86 individuals with post-COVID-19 syndrome found that patients with high adherence to pacing experienced significantly greater recovery and symptom improvement compared to those with low or moderate adherence [36]. Non-pharmacological approaches are generally safe, patient-centered, and can be tailored to individual needs, making them ideal as initial treatment plans. Nevertheless, the suitability of non-pharmacological treatments is limited in terms of the sample population they can be prescribed to. For example, diets containing high amounts of salt cannot be prescribed to elderly patients with high blood pressure.

Pharmacological treatment

Pharmacological therapies should be explored if patients present with severe or chronic symptoms following the use of non-pharmacological management strategies. Nevertheless, pharmacological therapy of Long COVID for IST or POTS symptoms is moderately successful. Non-selective ß1 selective therapy is usually employed in the early stages of pharmacological treatment of Long COVID-based IST or POTS symptoms. Although dosage adjustments can be made to avoid low blood pressure, such medications are not easily tolerated because of adverse side effects such as discomfort and fatigue. Thus, some physicians advocate instead for the use of non-selective beta-blockers that can block beta-1 and beta-2 receptors, induce vasoconstriction, and prevent excessive blood flow. Oral administration of 10–20 mg propranolol up to 4 times daily may be prescribed for the successful reductions in heart rate, although side effects such as hypotension, bradycardia, and bronchospasm are possible [37]. Pyridostigmine (10 mg dose) may also be administered up to 3 times a day to combat symptoms of severe fatigue and muscle weakness. Following suspected mast cell activation syndrome (immune dysregulation and excessive cytokine production), there have been reports of allergy symptoms, which may be ameliorated through the use of H1 and H2 antihistamines [38, 39].

In a case series, administration of beta blockers, fludrocortisone, midodrine, and ivabradine along with medication to treat headaches, allergies, and neuropathic pain led to a substantial amelioration of POTS symptoms [40]. Persistence of tachycardia despite administration of low-dose beta-blockers may be followed by gradual administration of calcium channel blockers. Dosage must be carefully monitored to bring about a reduction in heart rate [41]. In case pharmacological treatment with beta-blockers and calcium channel blockers is not successful, ivabradine has shown greater promise in terms of symptom amelioration along with better tolerability. Ivabradine causes fewer adverse effects because it is a cardio-selective drug that reduces heart rate without lowering blood pressure by blocking the sinoatrial node’s I-funny channel.

Results from a prospective observational study that assessed ivabradine’s effects in POTS associated with COVID-19 showed that patients who received ivabradine reported subjective symptom improvement within 7 days of starting treatment, along with objectively significant reductions in 24-hour average, minimum, and maximum heart rates and improvements in HRV time domains [42]. In another study, a total of 22 patients with hyperadrenergic POTS, the most common subtype, participated in a randomized, double-blind, placebo-controlled crossover experiment using ivabradine [43]. Individuals were randomly assigned to receive either ivabradine or a placebo for one month before switching to the other therapy for another month. Major improvements in social, physical, and quality of life functioning were reported by the patients. There was a noticeable trend in the decrease of plasma norepinephrine levels. Ivabradine did not cause any notable adverse effects in patients, such as bradycardia or hypotension.

Another medication frequently recommended for POTS patients is pyridostigmine, an acetylcholinesterase inhibitor that promotes parasympathetic nervous system activity and lowers heart rate [44]. Pyridostigmine showed significant benefits in the treatment of POTS, particularly when combined with beta-blockers like Propranolol. Patients receiving pyridostigmine experienced improvements in orthostatic intolerance symptoms, as evidenced by reduced Orthostatic Intolerance Questionnaire (OIQ) scores over 1 and 3 months. Additionally, the combination of pyridostigmine and propranolol (Group 3) led to significant improvements in mental health, as measured by the mental component of the SF-36 survey. Depression scores also improved across all pyridostigmine-treated groups, even in the absence of antidepressant prescriptions. However, pyridostigmine did not show superior efficacy compared to other treatments, such as propranolol or bisoprolol alone, and improvements in physical quality of life were comparable across all groups. Furthermore, its mental health benefits were more pronounced only when combined with propranolol, indicating that combination therapy may be necessary to maximize its effects [45].

Pharmacological treatment has also shown promise in ameliorating symptoms of fatigue experienced by Long COVID patients. Evidence indicates that low-dose naltrexone and NAD + therapy is safe and could help certain patients with Long COVID-associated chronic fatigue following COVID-19. In 36 individuals with chronic moderate/severe fatigue following COVID-19, a low-dose of naltrexone (4.5 mg/day) combined with NAD + supplementation by iontophoresis patches may alleviate fatigue symptoms and enhance quality of life [46]. After 12 weeks of treatment, Isman et al. (2024) found a significant improvement in quality of life. Additionally, following 12 weeks of treatment, fatigue scores were considerably reduced. Although mild side effects were previously reported for low-dose naltrexone, the treatment was generally considered to be safe since dose adjustments could effectively ameliorate adverse effects. The iontophoresis patches were associated with only mild, short-lived skin irritation in 25% of patients. Naltrexone has also been shown to possess anti-inflammatory and immunomodulatory properties in a clinical cohort consisting of 59 Long COVID patients [47]. Administration of low-dose naltrexone resulted in reduced negative symptoms, enhanced functional status, and improved clinical outcomes in terms of fatigue, post-exertional malaise, restless sleep, and irregular sleep patterns). Results from a retrospective cohort study consisting of 108 patients further corroborated that low-dose naltrexone was effective in improving fatigue and pain symptoms associated with Long COVID [48]. Intensive, randomized, placebo-controlled clinical trials are required to further test the efficacy of low-dose naltrexone in reducing Long COVID symptoms.

Furthermore, the literature shows that high-dose intravenous immunoglobulin may also be an effective treatment option for improvement of pulmonary, neurologic, and cardiologic Long COVID symptoms. Patients receiving high-dose intravenous immunoglobulin reported significant improvements, including reduced fatigue, increased energy, and resolution of chest pain. Within two weeks, one patient showed normalized thyroid-stimulating hormone levels and resumed normal activities, while others noted improved breathing, cessation of oxygen therapy, and return to full-time work or daily routines [49]. Also, in a cohort of 9 patients with primary humoral deficiency or secondary B-cell depletion, high-dose intravenous immunoglobulin was well tolerated and led to rapid clinical improvement, reduced inflammation, and better radiological outcomes [50].

While pharmacological treatment options have shown promise in Long COVID patients in terms of improvements of POTS, tachycardia, pain, and fatigue, there are no FDA-approved and validated pharmacological treatment guidelines for treatment of these symptoms associated with Long COVID. This has created an urgent need to explore alternative therapies that address these lingering symptoms. One promising avenue is the use of probiotics, which have shown potential in improving gut health and modulating immune responses, offering a complementary approach to managing debilitating symptoms of Long COVID.

Probiotics

Although the pathogenesis and physiological mechanisms of Long COVID are poorly understood, there is substantial evidence that the condition is associated with alterations in the immune system and gut dysbiosis. For example, in recovered patients, there were reductions in Coriobacteriia, Faecalibacterium, and Coriobacteriaceae, with levels of Acidimicrobiia, Eubacteriaceae, and Erysipelatoclostridium elevated relative to controls [51]. Moreover, when compared with healthy controls, symptomatic Long COVID patients showed reductions in short-chain fatty acids (SCFAs)-producing salutary bacteria such as Eubacterium hallii, Subdoligranulum, Ruminococcus, Dorea, Coprococcus, and Eubacterium ventriosum [23]. Therefore, strategies that can directly impact the gut microbiota and immune system, such as probiotics appear to be potential options. Probiotics are defined as living microbes that, when ingested in sufficient quantities, can improve the host’s health [52]. There is overwhelming evidence on the clinical development of probiotics against Long COVID.

A randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of ImmunoSEB (Peptizyme SP, a systemic enzyme complex containing serratiopeptidase, bromelain, amylase, lysozyme, peptidase, catalase, papain, glucoamylase, and lactoferrin) and ProbioSEB CSC3 (a combination of Bacillus coagulans, Bacillus subtilis, and Bacillus clausii) in alleviating Long COVID fatigue [53]. The study included 200 participants, with 100 in the intervention group receiving the supplements for 14 days and 100 in the placebo (maltodextrin) group. By day 14, fatigue resolution was significantly higher in the intervention group compared to the placebo group (91% vs. 15%). Participants in the intervention group also demonstrated greater reductions in total, physical, and mental fatigue scores at all measured time points. The supplements were well tolerated, with no adverse effects reported.

In one study consisted of a total of 38 participants, 19 were given VSL#3^®, a probiotic formulation that contains eight strains of B. breve, B. longum, B. infantis, L. acidophilus, L. plantarum, L. casei, L. bulgaricus, and S. thermophiles, and 19 received a placebo [54]. Significant improvement in physical functioning, a decrease in fatigue, and alleviation of gastrointestinal problems were observed in the probiotic group. However, there were no discernible improvements in the symptoms of somatization, anxiety, depression, or performance.

There is also evidence suggesting that paraprobiotics (non-viable bacteria) could be useful in ameliorating Long COVID symptoms. In an experimental study, six long-COVID patients were rigorously observed for more than a year from the onset of COVID-19 in order to assess neurocognitive function, fatigue, depression, alterations in the autonomic nervous system, and quality of life [55]. Following a 4-week course of specified paraprobiotics (17 bacterial species including L. bulgaricus, B. longum spp infantis, and L. salivarius), the patients were reassessed using the same instruments. Before and after therapy, thorough immunophenotyping and gut microbiome studies were also carried out. Data from the app and sensors, as well as patient-reported outcomes, showed improvements in neurological symptoms like depression, fatigue, and dysautonomia. Notably, paraprobiotic therapy decreased the expression of toll-like receptor 2 (TLR2) on T cells and activation markers on B cells and monocytes. A summary of non-pharmacological, pharmacological, and probiotic treatment for Long COVID, with their dosing and symptomatic indications, is provided in Table 1.

Table 1.

Summary of Non-Pharmacological, Pharmacological, and probiotic treatments for long COVID

Category	Treatment	Dosing/duration	Symptomatic indications	Notes/precautions
Non-pharmacological	Salt & fluid intake	2–3 L water/day; sodium 6–12 g/day, divided	Orthostatic intolerance, POTS	Avoid in elderly/hypertensive; nausea if taken in large bolus
	High fiber diet	increased fiber, whole-diet quality	GI symptoms (IBS-like), systemic inflammation	Limited data; case reports show microbiota improvement
	Adequate protein intake	1.0–1.5 g/kg/day; distribute across meals	Fatigue, muscle loss, impaired recovery	Many patients fail to meet thresholds, esp. at breakfast/lunch
	Cognitive pacing	Structured pacing of physical/cognitive activity	Fatigue, brain fog, post-exertional malaise	Adherence strongly predicts recovery
Pharmacological	Propranolol (non-selective β-blocker)	10–20 mg PO, up to 4× daily	POTS, IST; reduces tachycardia, dizziness	Side effects: hypotension, bradycardia, bronchospasm
	Pyridostigmine	10 mg PO, up to 3× daily; sometimes with β-blockers	Fatigue, orthostatic intolerance, cognitive dysfunction	Improves OIQ scores and mental health when combined
	Ivabradine	5–7.5 mg PO, 2× daily	Hyperadrenergic POTS, tachycardia	Better tolerated than β-blockers; avoid if bradycardic
	Low-dose naltrexone + NAD+	Naltrexone 4.5 mg/day + NAD + patch ×12 wks	Fatigue, sleep disturbance, pain, mood, brain fog	Generally safe; mild skin irritation with patches
	Intravenous Immunoglobulin	3-month trial, 0.5 g/kg IVIG every 2 weeks	Severe pulmonary, neurologic, cardiologic symptoms	Expensive, limited evidence; improved function in small cohorts
Probiotics/paraprobiotics	ImmunoSEB + ProbioSEB CSC3 (B. coagulans, B. subtilis, B. clausii)	4 caps/day ×14 days (500 mg enzyme + 5B CFU/cap)	Fatigue, reduced physical/mental exhaustion	Large RCT; 91% fatigue resolution; well tolerated
	VSL#3® (8 strains incl. Bifidobacterium & Lactobacillus spp.)	2 sachets BID ×4 wks (450B CFU/sachet)	Fatigue, GI disturbances	Improved physical functioning; no change in mood symptoms
	Paraprobiotics (heat-killed, 17 strains)	Abiprol 800 mg + Brexibiol 1.12 g/day ×4 wks	Fatigue, depression, dysautonomia, neurocognition	Small pilot (n = 6); reduced immune activation markers
	Fermented foods (yogurt, vegetables)	Variable intake; strains overlap with probiotics	GI support, fatigue	Not standardized; complementary rather than replacement

The incorporation of fermented foods may provide supportive benefits in Long COVID by delivering naturally occurring probiotic strains and metabolites that modulate the gut microbiota and immune system. For example, yogurt and fermented vegetables contain L. bulgaricus, S. thermophilus, L. plantarum, and L. casei, which overlap with strains in VSL#3^® and may help alleviate gastrointestinal disturbances and fatigue through restoration of short-chain fatty acid production and gut barrier integrity. However, dosing and strain diversity are variable compared to standardized sachets. Paraprobiotic treatments act through immune signaling mechanisms involving heat-killed bacteria. This mechanism differs from fermented food, which depends on live microbes and their metabolic activity. Thus, fermented foods can serve as complementary rather than replacements for standardized probiotic or paraprobiotic therapies in the management of Long COVID.

Although none of the formulations above included a prebiotic component, prebiotics may play supportive roles by enhancing the growth of beneficial commensals, including Bifidobacterium and Faecalibacterium species, which are depleted in Long COVID and are key producers of short-chain fatty acids [56, 57]. Restoration of these bacteria and their metabolites could complement the actions of probiotics or paraprobiotics. Future trials may explore synbiotic formulations which contain both probiotic and prebiotic combinations, which could provide broader and more sustained clinical benefit by both replenishing specific strains for their persistence and activity.

Evidence from the literature indicates that Long COVID symptoms may have to do with the persistence of viral loads in the body. For example, residual viral proteins and RNA were detected in gastrointestinal and hepatic tissues as well as in plasma, stool, and urine samples of recovered COVID-19 patients [58]. The mechanism of action of probiotics in Long COVID may be understood by considering probiotics being implicated as a possible link between the elimination of viral infection, the adaptive and innate immune systems, and helping to explain the mechanism through which immune homeostasis is restored and inflammation is reduced in Long COVID. Figure 2 illustrates how probiotics modulate the intestinal immune system by enhancing mucosal barrier integrity, activating dendritic cells and macrophages to stimulate cytokine production, promoting Tregs for anti-inflammatory effects, facilitating B cell-mediated IgA antibody production, and driving CD4⁺ and CD8⁺ T cell responses to eliminate persisting viral pathogens and reduce inflammation.

Fig. 2.

The mechanism of action of probiotics in Long COVID. Probiotics are recognized by dendritic cells, key antigen-presenting cells, in the lamina propria. Activated DCs release cytokines like IL-12, IL-6, and TNF-α, which influence both innate and adaptive immunity. DCs present antigens to CD4⁺ T cells, activating helper T cells, and contribute to the activation of CD8⁺ T cells, which kill infected cells. Goblet cells in the intestinal epithelium are stimulated to enhance mucin secretion, which strengthens the mucosal barrier, preventing pathogen invasion and maintaining gut integrity. Macrophages initiate phagocytosis and the secretion of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which help eliminate pathogens. Moreover, probiotics stimulate Tregs, which release anti-inflammatory cytokines such as IL-10 and TGF-β to reduce chronic inflammation. Probiotics also lead to the activation and maturation of B cells, leading to the production of IgA antibodies by plasma cells which enhances mucosal immunity by neutralizing pathogens and toxins. Lastly, probiotics promote the differentiation of CD4⁺ helper T cells and CD8⁺ cytotoxic T cells through the involvement of cytokines such as IFN-γ, IL-17, and TNF-α

Conclusion

Long COVID is a persistent multisystem condition with major global health implications. Current evidence suggests roles for immune dysregulation, viral persistence, chronic inflammation, autonomic dysfunction, and gut dysbiosis in its pathogenesis, but mechanisms remain poorly characterized. While symptomatic management and repurposed pharmacological agents such as beta-blockers, ivabradine, low-dose naltrexone show promise, no standardized or approved treatments exist. Probiotics represent a novel strategy supported by early data linking gut health to systemic inflammation, but validation in large randomized controlled trials is required. Future research should prioritize: (i) clarifying key molecular mechanisms, (ii) identifying biomarkers for diagnosis and prognosis, and (iii) developing targeted, evidence-based therapies. Addressing these gaps will be critical to reducing the long-term burden of Long COVID on patients and healthcare systems.

Author contributions

Study Design: K.K., H.X.L., and A.D.I.A.; Data Collection: K.K.; Data Interpretation: K.K., H.X.L., and A.D.I.A.; Manuscript Preparation: K.K.; Literature Search: K.K.; Manuscript Editing and Review: A.D.I.A. and R.A.R.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Sunway University Research Accelerator Grant (GRTIN-RAG-DBS-14-2024).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable

Competing interests

The authors declare no competing interests

Not applicable.