Interplay between viral infections and gut microbiota dysbiosis: Mechanisms and therapeutic potential

Abstract

Viral infections, particularly those triggered by emerging pathogens like severe acute respiratory syndrome coronavirus 2, are increasingly recognized for their profound impact on the gut microbiota, causing dysbiosis, a condition characterized by an imbalance in microbial communities. Recent studies suggest that alterations in gut microbiota can influence disease progression, immune responses, and clinical outcomes. The bidirectional relationship between the gut microbiota and the host immune system is crucial in shaping responses to infection. Furthermore, dysbiosis has been linked to exacerbated inflammation, impaired mucosal barrier function, and altered drug metabolism, thereby complicating both disease pathogenesis and treatment efficacy. This review examines the interplay between viral infections and gut microbiota dysbiosis, with a focus on the underlying mechanisms and potential therapeutic strategies to modulate host immunity. We also evaluate the potential of microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, as therapeutic strategies for restoring microbial balance and mitigating the severity of infections. The paper underscores the need for further research to optimize microbiota-targeted therapies and integrate them into clinical practice, offering a comprehensive approach to managing dysbiosis in viral infectious diseases.

Key Words: Viral infection; SARS-CoV-2; COVID-19; Human immunodeficiency virus; Influenza; Hepatitis viruses; Gut microbiota; Dysbiosis; Probiotics; Fecal microbiota transplantation

Core Tip: Viral infections, including those caused by emerging pathogens like severe acute respiratory syndrome coronavirus 2, can profoundly disrupt the gut microbiota, leading to dysbiosis that contributes to immune dysregulation, increased inflammation, and poorer clinical outcomes. These microbiota alterations can influence disease severity, increase susceptibility to secondary infections, and affect the metabolism of medications. Understanding the gut-virus-immune system interplay is essential for developing effective strategies to restore microbial balance. Microbiota-targeted therapies, including probiotics, prebiotics, and fecal microbiota transplantation, offer promising options for managing dysbiosis in the context of viral infectious diseases.

INTRODUCTION

The human intestinal tract harbors a highly diverse consortium of microorganisms - bacteria, archaea, fungi, protozoa, and viruses - collectively known as the gut microbiota[1]. This ecosystem, comprising approximately 10¹³-10¹⁴ cells, contributes to host homeostasis through immunomodulation, nutrient processing, epithelial barrier maintenance, and regulation of neuronal signaling[2,3]. Perturbations in the balance and function of microbial communities that may compromise gut barrier integrity, alter immune responses, and increase susceptibility to secondary infections, termed dysbiosis, have been implicated in a wide range of pathological processes, including immune dysregulation, metabolic dysfunction, neurological disorders, and oncogenesis[4,5].

Human viruses also display organ-specific tropisms, affecting the respiratory tract, gastrointestinal (GI) tract, liver, nervous system, and immune cells. Viral entry is mediated by interactions between surface proteins and host receptors, which initiate downstream pathogenic processes. Importantly, viral-bacterial crosstalk can occur via two principal modes: (1) Direct interactions, where viruses exploit bacterial surfaces or metabolites to enhance infectivity; and (2) Indirect interactions, where virus-induced host damage facilitates bacterial colonization by altering receptor availability, barrier integrity, microbial competition, or immune defenses[6,7]. These interaction patterns are summarized in Table 1[8-20].

Table 1 Human viruses interact with bacteria either directly (via bacterial products that facilitate infection) or indirectly (through host environment changes that favor bacterial colonization).

Viruses	Bacterial partner(s)	Mechanistic basis	Ref.
Direct interactions
Murine norovirus	E. cloacae, enteric microbiota	Bacterial histo-blood group antigen analogs support persistent viral infection in the gut	[8,9]
Influenza virus	Staphylococcus aureus	Bacterial proteases activate viral hemagglutinin through cleavage	[10]
Rotavirus	Gut microbiota (e.g., Escherichia coli, Bacteroides thetaiotaomicron)	Bacterial factors promote viral infectivity while reducing antibody neutralization	[11]
Reovirus T3SA+	Enteric bacteria (Escherichia coli, etc.)	Bacterial lipopolysaccharide mediates enhanced viral binding and replication efficiency	[12]
HIV	Mycobacterium tuberculosis	Mycobacterial components enhance HIV transcriptional activity	[13]
Indirect interactions
Adenovirus	S. pneumoniae	Enhances bacterial attachment to respiratory epithelial cells	[14]
Rhinovirus	Respiratory pathogens	Increases the expression of host cell adhesion molecules for bacterial binding	[15]
Measles virus	Multiple opportunistic pathogens	Systemic immune suppression facilitates secondary bacterial infections	[16,17]
Herpesviruses	Porphyromonas gingivalis, Bacteroides forsythus (now Tannerella forsythia), Campylobacter rectus	Viral immunosuppression enables bacterial colonization of the oral mucosa	[18]
Parainfluenza virus	Streptococcus pneumoniae, Haemophilus influenzae	Viral infection increases bacterial adhesion to the respiratory epithelium	[19,20]

HIV: Human immunodeficiency virus.

Although viruses are not classically linked to the GI tract, growing evidence indicates that respiratory, hepatic, and enteric viruses can also replicate in the gut and disrupt microbial balance[21]. Viral infection can compromise epithelial integrity and alter microbiota composition, shifting from a diverse community with beneficial commensals to one enriched with opportunistic taxa. These changes contribute to increased gut permeability, systemic inflammation, and impaired immune regulation, highlighting the role of gut-viral interactions in infectious disease pathogenesis (Figure 1). This review comprehensively explores the interplay between viral infections and gut microbiota dysbiosis, focusing on underlying mechanisms and potential therapeutic strategies to modulate host immunity.

Figure 1 In homeostasis, the gut microbiota is balanced, dominated by beneficial bacteria such as Bacteroidetes, Firmicutes, and butyrate producers like Faecalibacterium. Viral infection can promote dysbiosis, characterized by expansion of opportunistic bacteria (e.g., Enterococcus, Clostridium, Proteobacteria), disruption of the intestinal epithelium, and release of inflammatory mediators (e.g., interleukin-6, tumor necrosis factor-α). These changes increase gut permeability and susceptibility to systemic inflammation, sepsis, and impaired immune regulation. Created in BioRender (Supplementary material). IL: Interleukin; TNF: Tumor necrosis factor.

INFLUENZA AND GUT MICROBIOTA

Influenza viruses, members of the Orthomyxoviridae family, possess segmented, single-stranded, negative-sense RNA genomes and exhibit pleomorphic virion structures. They are classified into types A (avian/human reservoirs), B (human-specific), C (mild human infections), and D (primarily cattle) based on nucleoprotein antigenicity. Seasonal epidemics driven by influenza A and B viruses occur predominantly in winter and spring due to antigenic shifts[22]. Global influenza burden results in an estimated one billion cases annually, with 3-5 million severe illnesses and 290000-650000 respiratory-related deaths (World Health Organization)[23].

Beyond respiratory pathology, influenza disrupts the gut-lung axis, causing intestinal dysbiosis that impairs metabolic activity and immune regulation[24,25]. Severe influenza A infections (H1N1, H3N2, H5N1, H7N9) reduce gut microbiota-derived short-chain fatty acids (SCFAs), particularly acetate, which are crucial for maintaining gut barrier integrity and modulating host immunity. This reduction increases susceptibility to secondary pneumococcal infections and translocation of enteric pathogens[26]. Dysbiosis also depletes small intestinal intraepithelial lymphocytes, compromising mucosal defense and triggering systemic inflammation via inflammatory crosstalk, while H9N2 infection promotes Proteobacteria overgrowth (e.g., Escherichia coli), suppresses commensals such as Lactobacillus and Enterococcus, and elevates pro-inflammatory cytokines[27-29].

In murine models, influenza induces distinct microbial shifts despite stable total bacterial loads. The abundance of segmented filamentous bacteria (SFB) and Lactobacillus/Lactococcus decrease, whereas Enterobacteriaceae (Proteobacteria) increase. Notably, SFB reduction - normally an inducer of T helper type 17 (Th17) cells - coincides with elevated interleukin (IL)-17A levels and Th17 cell numbers in the intestine, contributing to pathology. Antibiotic pretreatment to deplete the microbiota prevents Enterobacteriaceae expansion and attenuates intestinal inflammation, indicating that dysbiosis is a necessary precursor to local immune dysfunction[30,31].

Similar patterns - Proteobacteria expansion, reduced Firmicutes (including SFB and Lactobacillus/Lactococcus), and expanded Bacteroidetes - occur after influenza or respiratory syncytial virus infection, but not after live attenuated influenza vaccines, suggesting that productive viral replication is required to trigger systemic immune responses that disrupt the gut microbiota[32]. Type I interferons mediate Proteobacteria expansion, increasing susceptibility to secondary Salmonella colitis while depleting anaerobes. Lung-derived T cells migrating to the intestine produce type II interferon, indirectly reshaping gut microbial communities and reflecting systemic inflammatory crosstalk (lung → gut) rather than direct viral effects[33] (Figure 2).

Figure 2 Influenza-induced gut microbiome dysbiosis in mice. Acute influenza infection in the respiratory tract alters gut bacterial composition without direct gastrointestinal viral replication, suggesting regulation via systemic immune or physiological signals (e.g., type I/II interferons, caloric restriction). Observed microbial changes include increased Proteobacteria (e.g., Enterobacteriaceae) and Bacteroidetes, and reduced Firmicutes (e.g., segmented filamentous bacteria, Lactobacillus). Studies have primarily focused on specific pathogen-free-housed laboratory mice. Therefore, the relevance to humans or wild mammals with diverse microbiomes remains uncertain. Created in BioRender (Supplementary material). IFNs: Interferons; SFB: Segmented filamentous bacteria.

HUMAN IMMUNODEFICIENCY VIRUS/SIV AND GUT MICROBIOTA

First described in the early 1980s, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) are lentiviruses of the Retroviridae family that replicate as obligate intracellular pathogens. Cross-species transmission of SIV from African non-human primates to humans initiated the HIV pandemic[34]. HIV, the causative agent of acquired immune deficiency syndrome, depletes CD4+ T-lymphocytes, drives chronic immune activation, and disrupts mucosal barriers[35]. Pathogenesis centers on the GI tract, particularly gut-associated lymphoid tissue, where viral replication triggers profound alterations in mucosal immunity[36]. CD4+ T-cell loss is greater in the colon than in the small intestine due to higher viral replication, depletion of Th17/Th22 cells, chronic immune activation, and impaired antigen-presenting cell function[37]. Damage to GI barriers compromises IL-17/IL-22-producing cells, which are critical for mucosal homeostasis. While anti-retroviral therapy (ART) partially restores IL-17+ cells, persistent inflammation may continue to drive their depletion[38].

HIV infection consistently reduces gut microbiota diversity and richness, with more pronounced effects in the large intestine due to its dense bacterial colonization. Cross-sectional human studies reveal an increase in Enterobacteriaceae, Fusobacteria, Erysipelotrichaceae, and Proteobacteria, alongside a decrease in Lachnospiraceae, Ruminococcaceae, Bacteroides, and Rikenellaceae. This dysbiosis correlates with the loss of SCFA-producing bacteria (Faecalibacterium prausnitzii, Ruminococcus spp.) and elevated inflammatory markers[39]. Men who have sex with men with HIV exhibit Prevotella-dominant enterotypes (reduced anti-inflammatory Bacteroides) and elevated fecal calprotectin (a neutrophil-derived inflammation biomarker)[40]. Pro-inflammatory soluble factors, including granulocyte-macrophage colony-stimulating factor, intercellular adhesion molecule 1, IL-1β, IL-12/23, IL-15, IL-16, tumor necrosis factor (TNF)-α, vascular cell adhesion molecule 1, and vascular endothelial growth factor are increased, while the levels of beneficial cytokines (IL-22, IL-13) decrease. Nonhuman primate models recapitulate these findings, linking the expansion of Eubacterium rectale to pro-inflammatory cytokines and Treponema spp. to barrier dysfunction[41].

Clinical and experimental studies further show enteric viral dysbiosis during HIV/SIV progression. SIV-infected macaques exhibit increased pathogenic Adenovirus, which is associated with intestinal epithelial lesions and peripheral CD4+ T-cell depletion. Bacterial and viral dysbiosis amplify key pathogenic features, including CD4+/CD8+ T-cell activation in blood and gut-associated lymphoid tissue, and elevated gut permeability and inflammatory biomarkers. These findings underscore the central role of the gut microbiome in HIV pathogenesis and highlight the potential of microbiome-directed therapies as promising adjuncts to improve clinical outcomes[42,43]. Table 2 summarizes the patterns of HIV-associated gut dysbiosis[44-54].

Table 2 Dysbiosis of gut microbiota in individuals with human immunodeficiency virus infection.

Ref.	Total cases (n)	HIV-related cases (n)	Methodology	Increased taxa	Decreased taxa	Limitations	Conclusion
Rhoades et al[44]	105 (≥ 55 years)	58 LTC-HIV+	16S rRNA sequencing (V4)	Fusobacterium, Lactobacillus, Bifidobacteriales, Prevotella (in low CD4+)	Clostridia (SCFA producers), Oxalobacter, Streptococcus (vs HIV-)	Cross-sectional design; cannot establish causality; majority Caucasian male cohort limits generalizability	LTC-HIV+ individuals show gut dysbiosis - oral taxa enriched, butyrate producers depleted - with Prevotella inversely correlating with CD4+ counts, linking microbial shifts to immune dysfunction and chronic inflammation
Lu et al[45]	91	61 HIV	Metagenomics sequencing	Faecalibacterium prausnitzii, Subdoligranulum sp., Coprococcus comes, Prevotella copri, Prevotella stercorea, Bacteroides coprophilus, Bacteroides coprocola, Bacteroides intestinalis, Bacteroides salyersiae	Bacteroides	Small sample size; cross-sectional; single population (Chinese); ART regimen effects not fully differentiated	HIV infection causes gut dysbiosis; increased butyrate producers (F. prausnitzii, Subdoligranulum sp., C. comes) link to poor CD4+ T-cell recovery and activation; microbiota modulation may aid immune reconstitution
Cook et al[46]	383	HIV- (200) HIV+ undetectable (< 20 c/mL, n = 66) HIV+ suppressed (20-200 c/mL, n = 72) HIV+ viremic (> 200 c/mL, n = 45)	16S rRNA sequencing (V4); IPTW-adjusted models	Viremic group: Peptoniphilus, Porphyromonas, Prevotella, Murdochiella	Viremic group: Bacteroides, Brachyspira, Faecalibacterium, Helicobacter. All HIV+ groups: Bacteroides	Lack of dietary data; residual confounding possible; 16S limits species-level resolution; no data on time since ART initiation	HIV viremia correlates with rectal dysbiosis in a dose-dependent manner; viremic individuals show a pro-inflammatory microbiota (Prevotella, Porphyromonas), while suppressed/undetectable viremia associates with milder dysbiosis
Villar-García et al[47]	44 (HIV+, on HAART)	22 immunologic responders, 22 immunologic non-responders	16S rDNA gene sequencing	Megamonas, Desulfovibrionales (Proteobacteria)	Clostridiales (esp. Clostridiaceae, Catenibacterium), Lachnospiraceae, Proteobacteria	Small sample size; did not analyze fungal mycobiome (including probiotic colonization); cannot establish causality; short intervention period	Saccharomyces boulardii reduced pro-inflammatory Clostridiaceae; immunologic non-responders had higher baseline Lachnospiraceae and Proteobacteria
Dillon et al[48]	32	18 untreated HIV+	16S rRNA sequencing (colonic mucosa and stool)	Prevotella stercorea	Butyrate-producing bacteria: Roseburia intestinalis, Faecalibacterium prausnitzii, Eubacterium rectale (in colonic mucosa)	Small cross-sectional study; sexual preference unmatched; fecal butyrate not measured	HIV reduces colonic butyrate-producing bacteria (e.g., Roseburia intestinalis); low abundance links to microbial translocation and immune activation; butyrate may protect against T cell activation and HIV replication
Dinh et al[49]	21 HIV+ on ART, 16 HIV- controls	21 (chronic HIV, suppressed VL)	16S rRNA pyrosequencing (V3-V5 region)	Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Erysipelotrichi, Erysipelotrichales, Erysipelotrichaceae, Barnesiella	Rikenellaceae, Alistipes	Small sample size; exploratory design; no correction for multiple comparisons; immune activation markers not assessed	ART-treated, virologically suppressed HIV+ individuals show gut dysbiosis with increased Enterobacteriaceae and decreased Alistipes, correlating with elevated sCD14 and inflammatory cytokines (IL-1β, TNF-α)
Lee et al[50]	HIV+ on ART: 26 (16 oIR, 10 sIR) HIV- controls: 20	26 (all on suppressive ART)	16S rRNA sequencing (V4 region, rectal swabs)	Fusobacterium (phylum: Fusobacteria), Gallicola, Bilophila	Lactobacillales, Corynebacterium	Small sample size; all male participants; dietary data not collected; rectal swabs may not fully reflect luminal microbiota	Poor CD4+ recovery on ART associates with increased Fusobacterium, elevated T-cell activation/Tregs, and reduced naïve CD4+ cells
Machiavelli et al[51]	38 (19 mother-child pairs)	12 HEU children; 12 HIV+ mothers	16S rRNA sequencing (V3-V4 region)	HEU children: Faecalibacterium prausnitzii, Prevotella copri, Lachnospiraceae, Klebsiella, Lactococcus, Ruminococcaceae, Enterobacteriaceae	HEU children: Bacteroides uniformis, Paraprevotella	Cross-sectional, small sample; breastfeeding differences between HEU and unexposed children; functional predictions inferred, not measured	HEU children of HIV+ mothers show altered gut taxa and predicted metagenome without changes in diversity, growth, or inflammation markers
Ling et al[52]	83 (Chinese population)	67 HIV+ (35 HAART-naïve, 32 HAART-treated)	16S rRNA pyrosequencing (V1-V3 regions)	Firmicutes, Prevotella, Faecalibacterium, Phascolarctobacterium, Butyricicoccus, Erysipelotrichaceae incertae sedis, Catenibacterium, Dorea, Enterobacter, Enterococcus, Megamonas	Bacteroidetes, Bacteroides, Dialister, Clostridium XIVa, Clostridium XIVb, Barnesiella, Coprococcus	Cross-sectional; all male; sexual behavior not controlled; fecal samples may not reflect mucosa-associated microbiota	HIV-1 infection causes gut dysbiosis (↑ Firmicutes/Bacteroidetes, pro-inflammatory genera); key taxa correlate with inflammation; short-term HAART only partially restores the microbiota
Liu et al[53]	36 (35 male, 1 female)	14 HIV+ (all ART-treated)	16S rRNA sequencing (V3-V4 region)	Fusobacteria, Proteobacteria, Leptotrichiaceae, Desulfovibrionaceae, Enterobacter, Paraprevotella, Allisonella, Anaerovibrio, Howardella	Firmicutes, Lachnospiraceae, Oxalobacteraceae, Eggerthella, Barnesiella, Odoribacter, Oscillospira, Oxalobacter, Roseburia, Alistipes	Small, mostly male cohort; observational; prebiotic/probiotic use uncontrolled; genus-level data limits species resolution	HIV and aging interact to alter the stool microbiome; age-related taxa changes and associations with SCFAs, diet, and inflammation differ by HIV status
Yang et al[54]	16	8 HIV+ (HAART-naïve, low CD4 counts in 6/8)	16S rRNA sequencing (V3-V4)	Proteobacteria, Burkholderia (specifically Burkholderia fungorum), Bradyrhizobium (specifically Bradyrhizobium pachyrhizi), Ralstonia, Fusobacterium	Firmicutes, Lactobacillus	Small sample; case-control design limits causation; no HAART-treated comparison; clinical symptom correlations limited	HIV-induced immunosuppression reduces gut colonization resistance, enabling environmental bacteria (B. fungorum, B. pachyrhizi) invasion and loss of beneficial commensals, causing dysbiosis linked to immune dysfunction

HIV: Human immunodeficiency virus; LTC: Long-term care; SCFA: Short-chain fatty acid; IPTW: Inverse-probability-of-treatment weighting; ART: Antiretroviral therapy; Tregs: Regulatory T cell; HAART: Highly active antiretroviral therapy; IL: Interleukin; TNF: Tumor necrosis factor; oIR: Optimal immune reconstitution; sIR: Suboptimal immune reconstitution; HEU: Human immunodeficiency virus-exposed uninfected children.

Despite heterogeneity in cohort demographics, ART exposure, and sequencing methods, most studies converge on a common pattern of HIV-associated gut dysbiosis. Cross-sectional human and non-human primate data consistently demonstrate depletion of SCFA-producing commensals (Faecalibacterium prausnitzii, Roseburia, Ruminococcus) and enrichment of Proteobacteria, Prevotella, and Fusobacterium. Differences in reported taxa largely reflect variations in study design, such as stool vs mucosal sampling, regional dietary habits, duration of ART, and analytical depth (16S rRNA vs metagenomics). Nonetheless, a shared mechanistic theme emerges: Disruption of mucosal integrity and chronic immune activation mediated by microbial translocation. These consistent microbial and immunologic signatures highlight gut dysbiosis as a central driver of HIV pathogenesis and a potential target for microbiota-based therapeutic modulation.

HEPATITIS VIRUS AND GUT MICROBIOTA

Viral hepatitis cirrhosis is a progressive liver disease caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). It is characterized by widespread hepatic fibrosis, pseudo-lobule formation, and distortion of liver architecture due to persistent viral injury[55]. The liver and intestine communicate bidirectionally via the gut-liver axis, primarily through the portal vein and enterohepatic circulation. This axis facilitates translocation of microbial components and metabolites - including dysregulated bile acids, SCFAs, bacterial products like lipopolysaccharide and peptidoglycan - and immune cell trafficking[56,57].

In HBV infection, bile acid dysregulation and Kupffer cell polarization, mediated by lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, stimulate the secretion of immunosuppressive factors like IL-10 and programmed death ligand 1. In HCV infection, complications arise from gut barrier dysfunction, metabolic dysregulation, and systemic inflammation[58]. Gut dysbiosis is evident at different disease stages. Patients with hepatitis E virus (HEV) infection show elevated Proteobacteria, particularly Gammaproteobacteria and Enterobacteriaceae, which correlate with interferon-gamma levels, serum alanine aminotransferase (ALT), and total bilirubin, suggesting Gammaproteobacteria as a potential biomarker for acute HEV severity[59].

In chronic HBV, early disease stages show selective depletion of Bacteroides spp. without evident liver injury. As the disease progresses, the gut microbiota shifts toward an Alloprevotella-dominant profile, which associates with fewer HBV DNA copies and altered lipid metabolism[60,61]. These gut-liver axis disruptions in HBV and HCV cirrhosis are comprehensively summarized in Table 3[62-74]. Although studies of hepatitis-associated dysbiosis differ in cohort composition, disease stage, sequencing depth, and antiviral therapy, they reveal overlapping microbial signatures across HBV, HCV, and HEV infections. Despite variation in specific taxa, most consistently report enrichment of opportunistic pathogens such as Klebsiella, Streptococcus, and Enterococcus alongside depletion of SCFA-producing commensals including Faecalibacterium, Roseburia, and Agathobacter. Discrepancies among reports largely reflect differences in geography, dietary background, direct acting antiviral or interferon therapy status, and methodological platforms (16S vs metagenomics). Nevertheless, a unified trend emerges in which progressive hepatic injury correlates with loss of microbial diversity, bile acid dysregulation, and pro-inflammatory metabolic shifts, underscoring gut-liver axis imbalance as a hallmark of viral hepatitis pathogenesis.

Table 3 Gut microbiota composition in hepatitis B virus/hepatitis C virus cirrhotic patients.

Ref.	Total cases (n)	Cirrhosis-related cases (n)	Methodology	Increased taxa	Decreased taxa	Limitations	Conclusion
Elsherbiny et al[62], 2025	80 (60 CHC patients + 20 HCs)	Non-cirrhotic CHC (n = 60)	16S rRNA sequencing (V3-V4)	SVR group: Elusimicrobium, Christensenellaceae R-7 group, Catenibacterium, Oceanobacillus, Candidatus Melainabacteria. Relapsed group: Prevotella, Bifidobacterium, Lactobacillus, Megasphaera, Mitsuokella. Non-treated group: Faecalibacterium, Asteroeplasma, Eubacterium coprostanoligenes, Lachnospiraceae, Akkermansia, Muribaculaceae	SVR group: Actinobacteria. All CHC vs HCs: Reduced diversity; Bacteroides, Agathobacter, Parabacteroides	Single-center design; modest sample size; unmeasured confounders (diet, lifestyle)	DAA therapy markedly modulates gut microbiota; SVR restores microbial diversity and composition toward that of HCs, whereas relapse is characterized by persistent dysbiosis
Huang et al[63], 2023	120 subjects (180 samples)	Control: 60 HCs. CHC (pre-DAA): 60 patients. SVR24 (post-DAA): 60 patients	16S rRNA sequencing (V3-V4)	Ruminococcaceae, Eubacterium, Agathobacter, Alistipes, Bifidobacterium, Klebsiella, Lactobacillus, Actinobacteria, Firmicutes, Lactobacillus	Bacteroidetes, Lachnoclostridium	Relatively small sample size; short follow-up (24 weeks); unmeasured confounders (diet, smoking); baseline differences in liver function between CHC and control groups	Gut microbiota diversity and composition remained unchanged 6 months after DAA therapy; minor differences in CHC vs controls were unaffected by SVR
Honda et al[64], 2025	70 CHB patients + 8 HCs	Functional cure: 18 (HBsAg-, HBV DNA-). Low-titer DNA: 40. High-titer DNA: 12. HC: 8	16S rRNA sequencing (V3-V4)	Clostridium bartlettii, Butyricimonas, Coprococcus catus, Bifidobacterium breve, Campylobacter	Not reported	Small sample size; exploratory design; in vitro SCFA concentrations may not reflect physiological levels in the liver	Butyrate-producing bacteria are enriched in HBsAg-negative patients; sodium butyrate directly suppresses HBsAg production in infected hepatocytes, especially post-infection
Inoue et al[65], 2025	272 (174 active HCV, 75 post-SVR, 23 HCs)	CH-HCV: 95, LC/HCC-HCV: 79, CH-SVR: 29, LC/HCC-SVR: 46, healthy: 23	16S rRNA sequencing; fecal BA profiling; RNA-seq	Blautia, Fusicatenibacter, Roseburia, Faecalibacterium, Subdoligranulum, Collinsella	Streptococcus, Streptococcus salivarius, Eubacterium hallii group, Ruminococcus torques group	Cohort separation for multi-omic analyses; limited SVR48 sample size; partially uses database-derived RNA-seq data	HCV eradication partially restores gut dysbiosis and BA profiles, with post-SVR Blautia enrichment correlating with improved liver fibrosis and function
Li et al[66], 2025	88	AHE-elderly: 58, HCs-elderly: 30, self-healing: 46, non-self-healing: 12	16S rRNA sequencing	AHE-elderly vs HC: Firmicutes, Lactobacillales, Bacilli, Streptococcaceae. Non-self-healing vs self-healing: Bifidobacteriaceae, Bacteroidia, Bacteroides fragilis	AHE-elderly vs HC: Proteobacteria, Bacteroidetes. Self-healing vs non-self-healing: Firmicutes, Bacillus, Lactobacillus, Streptococcus	No significant difference in alpha diversity; lack of longitudinal data; unclear causal relationship between microbiota changes and HEV infection	Bacteroidetes distinguish AHE patients from controls, with Bacteroides fragilis enriched in non-self-healing cases and serving as a predictive biomarker
Li et al[67], 2025	79	HBC: 46, HCs: 33, BA-N: 24, BA-H: 22	16S rRNA sequencing (V4-V5)	Streptococcus, Veillonella, Lactobacillales	Bacteroides, Akkermansia, Clostridiales	Cross-sectional design; small sample size; no BA composition or metabolomic analysis; potential confounders (diet, medication) not fully addressed	HBC dysbiosis features reduced beneficial taxa and increased opportunistic pathogens; Akkermansiaceae decline and Lactobacillales rise with elevated BAs, which correlate with higher Child-Pugh scores, suggesting gut microbiota–BA crosstalk drives HBC progression
Shi et al[68], 2025	123	HBV-LC: 83, HC: 40, MELD < 21: 68, MELD ≥ 21: 15, CTP-C: 22	16S rRNA sequencing (V3-V4)	Klebsiella, Streptococcus, Fusobacterium, Enterococcus	Alistipes, Lachnospira, Agathobacter, Parabacteroides, Roseburia	Single-center design; modest sample size; cross-sectional design limits causal inference; 16S rRNA does not capture full functional potential	HBV-LC patients show gut dysbiosis marked by enrichment of pathobionts (Klebsiella, Streptococcus) and loss of SCFA-producers (Alistipes, Lachnospira), with metabolite alterations (tocopherols, 21-hydroxypregnenolone) linked to specific microbial shifts and disease severity
Honda et al[69], 2021	42	Pre-DAA: 14, EOT: 14, post-24: 14 (samples from the same 14 patients)	16S rRNA sequencing (V3-V4)	Faecalibacterium, Bacillus	Bacteroides, Fusobacterium	Small sample size; lack of a HC group; intra-personal comparison only; cannot determine if pre-treatment microbiota differed from healthy individuals	HCV eradication did not significantly alter overall gut microbiota diversity but increased beneficial taxa such as Faecalibacterium and Bacillus at 24 weeks post-treatment, indicating a positive compositional shift despite stable global diversity
Liu et al[70], 2024	62	OBI: 24, HBV carriers: 18, HCs: 20	16S rRNA sequencing (V3-V4)	Subdoligranulum, Megamonas	Faecalibacterium	Small sample size; all participants were male; potential unmeasured confounders (diet); cannot establish causality	OBI is characterized by enrichment of Subdoligranulum, potentially driving IFN-γ/IL-17A–mediated immune activation that suppresses HBV replication, alongside depletion of beneficial Faecalibacterium
Yan et al[71], 2023	90	30 HCs + 30 HBV-LC + 30 HBV-HCC	16S rRNA sequencing (V3-V4) + flow cytometry	Proteobacteria, Actinobacteriota, Campylobacterota, Streptococcaceae, Enterobacteriaceae, Klebsiella, Streptococcus	Bacteroidota, Firmicutes, Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Rikenellaceae, Barnesiella, Agathobacter, Prevotella	Cross-sectional design; small sample size; dietary/age confounders; 16S limits function	HBV-CLD progression involves enrichment of pro-inflammatory taxa and depletion of butyrate producers, correlating with T-cell immunosuppression
Hsu et al[72], 2022	126	HCV patients: 42 (pre-Tx: 42, post-Tx: 42), HCs: 84	Prospective cohort; 16S rRNA (V3-V4), DADA2, LEfSe; matched controls	Coriobacteriaceae, Staphylococcaceae, Peptostreptococcaceae, Succinivibrionaceae	Morganellaceae, Pasteurellaceae, Moraxellaceae	Short-term follow-up (12 weeks post-DAA); modest sample size; exploratory differential taxa need validation; cirrhosis subgroup is small	Gut microbiota differs between HCV patients and HCs, but DAA-induced viral eradication does not significantly alter diversity or composition, suggesting viremia is not the main driver of dysbiosis
Wang et al[73], 2025	20	Group M (minimal injury): 9, group S (significant injury): 11	Human: Metagenomic sequencing. Mouse: 16S rRNA sequencing (V3-V4), FMT	Parabacteroides distasonis, Bacteroides dorei, Bacteroides finegoldii, Bacteroides ovatus, Bacteroides clarus	Eubacterium sp. CAG_180, Gemmiger formicilis, Oscillibacter sp. ER4, Subdoligranulum variabile, Faecalibacterium sp. CAG_74_58_120	Small sample size (n = 20); FMT from a single cirrhotic donor; mechanistic pathways (BA crosstalk) require further validation	Gut dysbiosis contributes to histological liver damage in early CHB. FMT from an HBV-cirrhosis donor aggravated fibrosis in mice, implicating BA-microbiota crosstalk in disease progression
Yang et al[74], 2023	950	Viral hepatitis: 656 (HBV: 546, HCV: 86, HEV: 24), HC: 294	Meta-analysis of 13 studies; 16S rRNA sequencing (multiple regions)	Butyricimonas, Escherichia-Shigella, Lactobacillus, Veillonella	Clostridia_UCG-014, Dorea, Monoglobus, Ruminococcus	Lack of HAV/HDV data; variability in sequencing regions/platforms; cannot establish causality	Viral hepatitis reduces gut microbial diversity, with specific taxa and functions (tryptophan metabolism, LPS biosynthesis) serving as potential biomarkers and contributing to disease pathogenesis

CHC: Chronic hepatitis C; HC: Healthy control; SVR: Sustained virologic response; DAA: Direct acting antiviral; CHB: Chronic hepatitis B; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; SCFA: Short-chain fatty acid; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; CH: Chronic hepatitis; LC: Liver cirrhosis; BA: Bile acid; AHE: Acute hepatitis E; HBC: Hepatitis B-related cirrhosis; MELD: Model for end-stage liver disease; CTP: Child-Turcotte-Pugh; EOT: End of treatment; OBI: Occult hepatitis B virus infection; IFN: Interferon; IL: Interleukin; CLD: Chronic liver disease; FMT: Fecal microbiota transplantation; HEV: Hepatitis E virus; HAV: Hepatitis A virus; HDV: Hepatitis D virus; LPS: Lipopolysaccharide.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 MECHANISMS

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA virus of the Coronaviridae family, first identified as the causative agent of atypical pneumonia in Wuhan, China (December 2019)[75]. Its structural architecture comprises four essential proteins: The spike glycoprotein (S), which mediates host cell entry via angiotensin-converting enzyme 2 (ACE2) receptor binding and contains a unique furin cleavage site that distinguishes it from other betacoronaviruses[76,77]; the envelope protein (E); the membrane protein (M); and the nucleocapsid protein (N). The coronavirus disease 2019 (COVID-19) pandemic, declared by the World Health Organization in March 2020[78], has resulted in approximately 690 million confirmed cases and 6.8 million deaths globally[79].

Beyond its hallmark respiratory manifestations, COVID-19 frequently affects the GI tract. Digestive symptoms such as diarrhea, nausea, and abdominal pain have been associated with worse clinical outcomes[80,81]. This GI tropism arises from high expression of ACE2 receptors, which serve as the primary portal of viral entry, particularly in enterocytes of the small intestine[82]. Numerous GI, hepatobiliary, and pancreatic manifestations have been documented in COVID-19 patients[83].

COVID-19 also disrupts the gut microbiota. It is important to distinguish microbiota, the microbial community itself, from the microbiome, the collective genetic material of these microorganisms[84]. Early in the pandemic, treatment uncertainty led to heterogeneous approaches, often involving antibiotics, corticosteroids, and remdesivir for severe cases[85]. While antibiotics effectively treat bacterial lung infections, their use in COVID-19 has revealed several unintended consequences, including disruption of microbial ecology depending on composition, dose, and duration[84]; paradoxical systemic antiviral activity against enteroviruses such as coxsackievirus B3 and poliovirus in germ-free mice via microbiota-independent pathways[85]; and potential synergy with SARS-CoV-2 orofecal transmission, driving microbiome alterations[86]. Clinical studies demonstrate that COVID-19-induced gut dysbiosis, characterized by depletion of beneficial microbes such as Bifidobacterium and Faecalibacterium and overgrowth of pathogenic taxa such as Enterococcus, directly correlates with disease severity[87].

COVID-19 AND GI TRACT

The molecular pathogenesis of COVID-19 begins when the SARS-CoV-2 spike protein binds ACE2 receptors on host cell surfaces, showing a particular tropism for ACE2-rich pulmonary alveoli and intestinal epithelium[16]. Clinical evidence indicates GI involvement in 2%-79.1% of cases, with manifestations such as diarrhea, nausea or vomiting, and hepatic injury[88]. Preexisting GI disorders, such as inflammatory bowel disease, may increase the risk of severe COVID-19 outcomes. This is partly due to frequent use of glucocorticoids and widespread administration of proton pump inhibitors. The GI tract’s mucosal immune system acts as a critical initial defense, serving both as a physical and immunological barrier, and may also serve as an entry site for SARS-CoV-2. Patients with GI involvement often experience poorer clinical outcomes, potentially due to disruption of the gut-associated immune response[89]. Notably, an immune response activated in one mucosal region can propagate across the entire mucosal system[90]. Viral kinetic studies by Zheng et al[91] show a progressive increase in SARS-CoV-2 fecal shedding, with viral loads peaking between weeks 3 and 4 post-infection. Stool samples retain detectable virus significantly longer than respiratory secretions or blood, with important implications for transmission risk and testing strategies[92].

Clinical meta-analyses reveal distinct patterns of GI involvement. A study evaluated 4805 subjects and found diarrhea in 7.4% of cases, nausea/vomiting in 4.6%, and hepatic dysfunction evidenced by abnormal aspartate aminotransferase (20%) and ALT (14.6%) levels. Emerging evidence also suggests that GI symptoms can precede or occur independently of respiratory manifestations[93]. Patients presenting with GI involvement tend to have higher diagnostic confirmation rates and prolonged symptomatic periods compared to those without digestive complaints[94]. Additionally, GI ischemia has been linked to COVID-19 infection[95].

COVID-19 AND THE MUCOSAL IMMUNE SYSTEM

The GI tract serves as a significant entry point and reservoir for SARS-CoV-2 infection; however, the precise immunological cross-talk between the virus and the mucosal immune system remains to be fully elucidated, particularly at initial infection sites such as the nasopharynx and bronchus-associated lymphoid tissue[96]. Following viral exposure, the gut mucosa mounts a multifaceted response characterized by: (1) Recruitment of diverse immune cells, including neutrophils, dendritic cells, macrophages, and T lymphocyte subsets; (2) Disruption of epithelial barrier integrity, resulting in increased intestinal permeability (“leaky gut”); and (3) Concurrent activation of both inflammatory and protective immune pathways. This leaky gut phenomenon may exacerbate disease severity through systemic bacterial translocation[97,98].

Coordinated activation of CD4+ and CD8+ T cells, plasma cells, and the innate immune system is vital for clearing SARS-CoV-2. Secretory immunoglobulin A provides protection by neutralizing the virus, preventing adhesion, and promoting agglutination without triggering pro-inflammatory complement pathways[99,100]. Although validated data on the degree of mucosal immune responses and COVID-19 severity are limited, protective and tolerance-inducing mechanisms suggest that mucosal immunity is essential for infection resolution[101]. SARS-CoV-2 infection, associated medications, and GI symptoms also influence gut microbiota composition[102]. Xu et al[103] observed declines in beneficial genera such as Lactobacillus and Bifidobacterium in certain COVID-19 patients. Whether dysbiosis is a consequence of infection or contributes to disease remains debated; in this context, therapies that reduce GI permeability may provide clinical benefits[104].

GUT MICROBIOTA AND COVID-19

The gut-lung axis is a critical bidirectional communication network, where gut microbiota composition influences pulmonary immune responses during SARS-CoV-2 infection and vice versa[105]. This microbiota-gut-lung triad operates through three key mechanisms: (1) ACE2-mediated regulation of viral entry and intestinal homeostasis; (2) Microbial metabolite-driven immunomodulation; and (3) Translocation of pathogen-associated molecular patterns. ACE2 serves as both the SARS-CoV-2 receptor and a modulator of GI inflammation, regulating intestinal amino acid transport and antimicrobial peptide production[106,107].

Dysbiosis during COVID-19 is well-documented. Beneficial genera such as Lactobacillus and Bifidobacterium are reduced, and microbiota composition correlates with inflammatory cytokine levels, potentially predicting severe outcomes[108-112]. Fecal microbiota analysis reveals enrichment of pathogenic species, decrease in commensals, and reduced microbial diversity, correlating with disease severity[113-116]. Specific reductions in Faecalibacterium prausnitzii, Eubacterium ventriosum, Roseburia, and Ruminococcaceae are associated with higher disease severity, whereas opportunistic pathogens including Actinomyces viscosus, Clostridium hathewayi, Bacteroides nordii, Streptococcus, Rothia, and Veillonella are enriched, distinguishing COVID-19 patients from influenza A cases and healthy controls[115,116].

SARS-CoV-2 infection depletes commensals, reduces bacterial diversity, and allows overgrowth of opportunistic pathogens. Bacteroides species can downregulate ACE2 in the murine gut, inversely correlating with fecal viral load. Dysbiosis may persist after viral clearance, and hospitalized patients can experience blooms of antimicrobial-resistant pathogens, with bacterial translocation contributing to secondary bloodstream infections[116-118]. Gut dysbiosis associated with post-acute COVID-19 syndrome can persist up to one year post-clearance, indicating long-term microbiome alterations[118].

Current evidence on the microbiota-COVID-19 axis is primarily derived from cross-sectional studies, summarized in Table 4[119-126]. Despite differences in patient cohorts, disease severity, sampling time points, and sequencing approaches, studies investigating COVID-19 consistently reveal a shared microbial signature characterized by depletion of butyrate-producing commensals (Faecalibacterium, Roseburia, Eubacterium rectale, Bifidobacterium) and enrichment of opportunistic pathogens (Enterococcus, Klebsiella, Streptococcus). Variations among reports largely stem from treatment heterogeneity, antibiotic exposure, and regional dietary differences, yet the underlying mechanisms converge on mucosal immune dysregulation, epithelial barrier disruption, and altered microbial metabolism - particularly tryptophan and SCFA pathways. These findings collectively support a model in which SARS-CoV-2-induced dysbiosis amplifies systemic inflammation and contributes to prolonged post-acute sequelae through persistent gut-lung-brain axis dysfunction.

Table 4 Studies investigating microbiota and coronavirus disease 2019.

Ref.	COVID-related cases (n)	Methodology	Increased taxa	Decreased taxa	Limitations	Conclusion
de Nies et al[119], 2023	118 subjects COVID-19: 61 (asymptomatic-moderate). Control: 57	Metagenomics, metatranscriptomics, MAG reconstruction, VF/ARG prediction, virome analysis	Prevotella stercorea, Prevotella spp. CAG 520, Roseburia spp. CAG 471, Firmicutes (AM10); Betaherpesvirus; Rotavirus C; VFs & AMR genes (Acidaminococcaceae, Erysipelatoclostridiaceae)	Turicibacter sanguinis, Roseburia faecis, Firmicutes (CAG 145)	Limited to asymptomatic-moderate cases; single-region cohort (Luxembourg); unclear mechanisms linking SARS-CoV-2 to VF/ARG expression	COVID-19 increases the virulence and AMR potential of commensals despite minimal taxonomic shifts, suggesting enhanced pathogenic potential of the gut microbiota
Li et al[120], 2025	121 participants total, NC: 53 (no COVID-19), C3M: 27 (3 months post-recovery), C6M: 41 (6 months post-recovery)	Metagenomic shotgun sequencing; ITS sequencing for fungi	Blautia massiliensis, Kluyveromyces spp., Bacteroides xylanisolvens, Phocaeicola vulgatus, Weissella confusa, Streptococcus thermophilus, Asterotremella spp., Gibberella spp.	Blautia wexlerae, Bifidobacterium pseudocatenulatum, Bifidobacterium longum, Eubacterium rectale, Anaerobutyricum hallii, Pyrenochaeta spp.	Cross-sectional design; excluded long COVID; smaller 3-month group; not generalizable to severe or unvaccinated cases	Mild COVID-19 induces long-term gut bacterial and fungal alterations lasting ≥ 6 months, with partial recovery and persistence of some pathogens
Zhang et al[121], 2023	187 recovered patients (84 symptomatic)	16S rRNA sequencing; clinical surveys (SF-36, SAS, SDS); lab tests; pulmonary function; chest CT	Veillonella	SCFA-producers: Eubacterium hallii group, Subdoligranulum, Ruminococcus, Dorea, Coprococcus, Eubacterium ventriosum group, Agathobacter	Single-center, cross-sectional; no longitudinal monitoring; diet/Lifestyle not fully controlled; mechanisms not clarified	Long COVID (approximately 45% at 1 year) is linked to persistent dysbiosis marked by depletion of SCFA-producing commensals, correlating with impaired quality of life, anxiety/depression, and immune dysregulation, supporting gut-lung and gut-brain axis involvement
Ishizaka et al[122], 2024	56 total, PLWH-CoV: 12 (mild: 7; moderate/severe: 5), PLWH controls: 25, HCs: 19	16S rRNA sequencing	Acute: Enterococcus faecium. Recovery (1-3 months): Roseburia, Lachnospiraceae_unclassified, Faecalibacterium prausnitzii, Eubacterium rectale. Recovered vs long COVID: Prevotella spp.	Acute vs HC: Roseburia, Lachnospiraceae_unclassified. Long COVID vs recovered: Prevotella spp.	Small sample size (n = 12 PLWH-CoV, only 2 PASC); no pre-infection baseline; diet, ART regimens, and variant effects not analyzed	SARS-CoV-2 in PLWH causes persistent dysbiosis, marked by loss of SCFA-producers and enrichment of pathogens, with severity-linked delays in microbiome recovery and risk of PASC
Brīvība et al[123], 2024	146 COVID-19 patients (92 hospitalized, 54 ambulatory) vs 110 HCs	Shotgun metagenomics	Enterococcus faecium, Bacteroides spp., Alistipes, Enterobacteriaceae	Roseburia, Faecalibacterium prausnitzii, Lachnospiraceae, Eubacterium rectale, Prevotella spp.	High antibiotic use; heterogeneous sampling timing; phenotypic heterogeneity across patient groups	Acute COVID-19 shows reduced diversity with loss of butyrate producers; recovery involves their restoration, while Prevotella may protect against long COVID
Sorokina et al[124], 2023	39 post-COVID-19 patients before and after 14-day rehabilitation vs 48 healthy volunteers	Clinical questionnaires, CT; CBC, coagulation, biochemistry; serum IL-6, NSE (ECL); metabolites (GC-MS); microbiota (RT-PCR, colonoflor-16 kit)	Bacteroides spp., Escherichia coli, Enterobacter spp., Staphylococcus aureus, IL-6, succinic acid, fumaric acid, 4-hydroxybenzoic acid	Lactobacillus spp., Bifidobacterium spp., Faecalibacterium prausnitzii, Phenylpropionic acid	Small cohort; no untreated controls; RT-PCR instead of sequencing; limited GI symptom assessment; diet confounded results	Post-COVID-19 is marked by persistent dysbiosis (loss of SCFA-producers, enrichment of pathobionts) and sustained inflammatory/metabolic disturbances not resolved by standard rehabilitation, highlighting the need for personalized microbiome-targeted interventions
Tkacheva et al[125], 2023	178 post-COVID-19 patients: Asymptomatic (A, n = 48), non-infected contacts (N, n = 46), severe (S, n = 86)	16S rRNA sequencing	RF39 (order), Clostridia UCG-014, Oscillospirales UCG-010, Akkermansia, Prevotellaceae (family), Lactobacillus, Romboutsia, Ruminococcus gnavus, Erysipelatoclostridium	Parasutterella, Flavonifractor, Ruminococcus gnavus, Subdoligranulum, Methanobrevibacter, Lachnospiraceae UCG-010, Lachnospiraceae NK4A136, Barnesiella, Eubacterium xylanophilum, Eubacterium siraeum	Cross-sectional (3 months only); no acute phase data; diet/medications not controlled; 16S lacks functional resolution	No major post-COVID microbiome differences by infection/severity at 3 months, but taxa correlated with immune, cardiovascular, and metabolic parameters, highlighting systemic associations beyond direct viral effects
Bredon et al[126], 2025	200 COVID-19 patients vs 102 HCs (Morocco & France cohorts)	Shotgun metagenomic sequencing, machine learning, metabolomics (tryptophan)	Ruminococcus gnavus, Klebsiella pneumoniae, K. variicola, Bacteroides ovatus, Enterococcus; ↑ L-tryptophan biosynthesis	Faecalibacterium prausnitzii, Roseburia spp., Bifidobacterium longum, Dysosmobacter welbionis, Coprococcus comes (SCFA-producers)	Treatment heterogeneity (antibiotics) in the French cohort; ML model not transferable; causality not established	COVID-19 induces gut dysbiosis with depletion of SCFA-producers and enrichment of pathobionts, alongside altered tryptophan metabolism. Dysbiosis correlates with disease severity; the ML model predicted severity in the Moroccan cohort

COVID: Coronavirus disease; COVID-19: Coronavirus disease 2019; MAG: Metagenome-assembled genome; VF: Virulence factor; ARG: Antibiotic resistance gene; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; NC: No coronavirus disease 2019; ITS: Internal transcribed spacer; CT: Computed tomography; SCFA: Short-chain fatty acid; PLWH-CoV: Severe acute respiratory syndrome coronavirus 2-infected people living with human immunodeficiency virus; PLWH: People living with human immunodeficiency virus; HC: Healthy control; PASC: Post-acute sequelae of coronavirus disease 2019; ART: Antiretroviral therapy; CBC: Complete blood count; IL: Interleukin; NSE: Neuron-specific enolase; ECL: Electrochemiluminescence; GC-MS: Gas chromatography-mass spectrometry; RT-PCR: Reverse-transcription polymerase chain reaction; GI: Gastrointestinal; ML: Machine learning.

DYSBIOSIS RELATED TO COVID-19 TREATMENT

During the early phases of the pandemic, patients frequently received antibiotics due to uncertainty regarding COVID-19 treatment, with broad-spectrum antibiotics commonly administered in cases of pneumonia[127]. Antibiotics are well-known modifiers of gut microbiota, and even short-term use can reduce microbial diversity, promoting intestinal dysbiosis that may persist even after viral clearance[128,129].

The effects of antibiotics vary with type, dosage, and duration, and may include impaired absorption of macronutrients and micronutrients, as well as increased levels of opportunistic intestinal bacteria such as Streptococcus, detectable up to 2 months post-treatment[130,131]. Studies prior to the pandemic showed that azithromycin reduced microbiota composition by 23% and Shannon diversity by 13%, mainly affecting Bacteroidetes and Firmicutes, though these changes were generally short-term[132]. Recent investigations have explored long-term effects of SARS-CoV-2 on GI dysbiosis via the microbiota-gut-lung axis, which may increase the risk of new colorectal cancer diagnoses or worsen existing conditions. Probiotics may stabilize microbial ecology and protect the integrity of the respiratory and GI tracts, although immune-modulatory responses can influence their effectiveness[133].

The connection between SARS-CoV-2 and the gut microbiome, including states of eubiosis and dysbiosis and related factors, is illustrated in Figure 3. Antibiotics, diet, lifestyle, medications, probiotics, and SARS-CoV-2 infection can all affect gut microbiota, potentially leading to dysbiosis. This imbalance may compromise immune responses, resulting in hyperinflammation, cytokine storms, multiorgan failure, and even death[127-133].

Figure 3 Severe acute respiratory syndrome coronavirus 2 interacts with the gut microbiota, influencing host outcomes. A preserved balanced microbiota supports effective immune responses, infection resolution, and mild or asymptomatic disease (eubiosis). In contrast, disruption of the microbiota (dysbiosis) contributes to failed immune responses, hyperinflammation, cytokine storm, multiorgan failure, and severe disease or death. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; FMT: Fecal microbiota transplantation.

MICROBIOTA-TARGETED INTERVENTIONS

Accumulating evidence indicates that gut dysbiosis compromises host immunity, exacerbating viral pathogenicity. Microbiota-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation (FMT), aim to restore microbial balance and demonstrate efficacy in reducing the severity of viral infections[134]. In HIV, probiotic administration elevates CD4+ T-cell counts and alleviates gut-related clinical symptoms (e.g., diarrhea, nausea)[135]. For respiratory viruses, clinical trials in adults have revealed that specific probiotics reduce the incidence of influenza (H1N1/H3N2) and symptom severity, while elevating key immune markers, including serum interferon-gamma and secretory immunoglobulin A in the gut and salivary compartments. Preclinical evidence further supports the antiviral effects; supplementation with Lactobacillus plantarum, Enterococcus faecium, and Lactobacillus salivarius inhibits transmissible gastroenteritis coronavirus in swine models[136,137]. Strategies for modulating the gut microbiota to combat viral infections are comprehensively summarized in Table 5[138-150].

Table 5 Therapeutic effects of probiotic supplementation on infectious disease outcomes.

Probiotic/strain	Virus	Model	Individuality	Mechanism against viral infection	Ref.
Lactobacillus casei 393	HIV-1 (pseudovirus)	In vitro (TZM-bl cells)	HIV-infected adults	Expresses CD4; binds HIV-1 pseudovirus; ↓ infection approximately 60%-70%	[138]
Lactobacillus rhamnosus GR-1 and L. reuteri RC-14	HIV	Clinical (24 adult women)	HIV-infected women	Resolved diarrhea; ↑/stable CD4 in 11/12 vs 3/12 control	[139]
Lactobacillus acidophilus ATCC 4356 engineered with human CD4 (in yogurt)	HIV-1	In vitro & humanized BLT mice	HIV-infected women (Nigeria)	Surface CD4 binds HIV gp120; blocks viral entry	[140]
Lactobacillus casei Shirota (in fermented milk)	HIV	Clinical (children, n = 60)	HIV-infected Vietnamese children	↑ CD4+, Th2, Th17; ↓ Tregs, CD8+ activation; ↓ viral load	[141]
Lactobacillus casei Shirota	EBV, CMV (herpesviruses)	Clinical (athletes)	Healthy athletes	↓ Plasma EBV and CMV IgG titres in seropositive individuals suggest improved immune control of viral reactivation	[142]
Lactobacillus rhamnosus GG	Rotavirus, Cryptosporidium	Clinical (children)	Children with gastroenteritis	Improved intestinal barrier function (↓ L:M ratio); ↑ serum IgG (rotavirus); ↓ reinfection rates in rotavirus-positive children	[143]
Lactobacillus casei Shirota	Norovirus	Clinical (elderly)	Older adults in a care facility	Shortened fever duration; modulated gut microbiota (↑ Lactobacillus, Bifidobacterium; ↓ Enterobacteriaceae); ↑ acetic acid	[144]
Lactobacillus rhamnosus GG	Rhinovirus	Clinical (infants)	Preterm infants (32-36 weeks)	↓ RTI incidence, ↓ rhinovirus infections; no effect on severity or shedding	[145]
Enterococcus faecium NCIMB 10415	Swine influenza A (H1N1, H3N2)	In vitro (cell culture)	Porcine macrophage and epithelial cells	↓ Virus titers (up to 4-log); ↑ cell viability; ↑ NO release; ↓ TNF-α, IL-6, TLR3; ↑ IL-10, IFN-α; direct virus trapping by bacteria	[146]
Bifidobacterium longum BB536	Influenza	Clinical (elderly)	Elderly (mean age 86.7 years)	↓ Influenza and fever incidence, ↑ NK cell activity and neutrophil bactericidal activity; maintained innate immunity	[147]
Bifidobacterium adolescentis SPM0212	HBV	In vitro (HepG2.2.15 cells)	Human hepatocyte-derived cell line	↓ HBsAg and extracellular HBV DNA; ↑ MxA, STAT1 expression via IFN pathway; active antiviral components < 30 kDa	[148]
Bifidobacterium lactis DSM 32246, Bifidobacterium lactis DSM 32247, Lactobacillus acidophilus DSM 32241, Lactobacillus brevis DSM 27961, Lactobacillus helveticus DSM 322426	SARS-CoV-2	Clinical (hospitalized)	Hospitalized COVID-19 patients (Italy, n = 70)	↓ Progression to respiratory failure; ↑ symptom resolution (fever, diarrhea, dyspnea); ↓ ICU admission and mortality; modulation of gut-lung axis; potential ↑ Nrf2/HO-1 antiviral pathways	[149]
Lactobacillus gasseri SBT2055	RSV	In vivo and in vitro	BALB/c mice and HEp-2 cells	↓ RSV titer; ↓ IL-6, TNF-α, IL-1β, CCL2; ↑ IFN-β, IFN-γ, OAS1a, ISG15; ↓ SRCAP expression linked to RSV replication	[150]

HIV: Human immunodeficiency virus; BLT: Bone marrow-liver-thymus; Th: T helper; Tregs: Regulatory T cells; EBV: Epstein-Barr virus; CMV: Cytomegalovirus; IgG: Immunoglobulin G; L:M: Lactulose:mannitol; RTI: Respiratory tract infection; TNF: Tumor necrosis factor; IL: Interleukin; TLR: Toll-like receptor; IFN: Interferon; NK: Natural killer; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; MxA: Myxovirus protein A; STAT1: Signal transducer and activator of transcription 1; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019; ICU: Intensive care unit; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1; RSV: Respiratory syncytial virus; CCL2: C-C motif ligand 2; OAS1a: Oligoadenylate synthetase 1a; ISG15: Interferon-stimulated gene product 15.

Prebiotics are non-digestible dietary fibers that selectively stimulate the growth and activity of beneficial bacteria in the colon, conferring health benefits to the host. These compounds function through three primary mechanisms: (1) Modulation of gut microbial composition; (2) Enhancement of intestinal barrier function; and (3) Production of microbial metabolites with systemic effects[151]. The most clinically studied prebiotics include: Inulin-type fructans, fructo-oligosaccharides, galacto-oligosaccharides, trans-galactooligosaccharides, and xylo-oligosaccharides[152]. Natural dietary sources rich in these compounds include Jerusalem artichokes, asparagus, garlic, and unripe bananas. Following intestinal fermentation, prebiotics yield two key classes of bioactive metabolites: SCFAs, including acetate, propionate, and butyrate, and gaseous byproducts, such as hydrogen, carbon dioxide, and methane. These metabolites exert pleiotropic effects by upregulating tight junction proteins (occludin, zonula occludens-1) and regulatory T-cell populations, while suppressing pathobiont colonization and enhancing gut hormone secretion (glucagon-like peptide-1, peptide YY)[153].

FMT is the therapeutic transfer of processed donor stool containing intact microbial communities (e.g., Bacteroides, Faecalibacterium, Prevotella, Ruminococcus), bioactive metabolites [bile acids, SCFAs, anti-inflammatory mediators, gamma-aminobutyric acid, serotonin precursors (5-hydroxytryptophan)], and functional components (e.g., antimicrobial peptides), which can modulate host antiviral immunity to the recipient via the gut-immune axis[154] (Figure 4).

Figure 4 Fecal microbiota transplantation for Clostridioides difficile infection. The process and effect of fecal microbiota transplantation in patients with Clostridioides difficile infection are presented. In step 1, stool containing a healthy microbial community is harvested from a healthy donor. The donor microbiota includes Bacteroidia, Clostridia (Lachnospiraceae, Ruminococcaceae), butyrate producers (Faecalibacterium, Roseburia), and Microviridae, along with low levels of potential pathogens such as Escherichia coli, Klebsiella, and Enterococcus. In step 2, the donor fecal sample is transplanted into the intestine of a patient with disrupted gut microbiota resulting from a Clostridioides difficile infection. The infected microbiome is characterized by elevated levels of Gammaproteobacteria (Escherichia coli, Klebsiella), Clostridium XI/XVIII, Enterococcus, Veillonella, and Caudovirales. In step 3, following transplantation, the patient’s gut microbiome is restored to a composition resembling that of a healthy donor, with the re-establishment of beneficial bacteria and a reduction in pathogenic species, thereby promoting recovery and preventing the recurrence of Clostridioides difficile infection. Created in BioRender (Supplementary material). E. coli: Escherichia coli; C. difficile: Clostridioides difficile.

Clinical evidence demonstrates the multifaceted benefits of FMT: In individuals with HIV, it reduces gut permeability biomarkers and enhances microbial diversity; murine studies show that it attenuates influenza-induced lung pathology via TLR7-dependent pathways following antibiotic-induced dysbiosis; and poultry models confirm its role in conferring protection against avian influenza by shaping mucosal immunity[155]. FMT drives microbiome restoration by replenishing diversity (e.g., increased Bacteroidetes/Firmicutes ratio), enhances the intestinal barrier by upregulating tight junction proteins (occludin, zonula occludens-1), reduces intestinal permeability, modulates immunity by attenuating pro-inflammatory cytokines (TNF-α, IL-6) while promoting regulatory T-cell responses, and restores functional pathways including SCFA production and bile acid metabolism[156].

Emerging applications highlight its broader potential: FMT has been proven safe in COVID-19 patients with concurrent Clostridioides difficile infection, supporting cautious use in viral comorbidities[157]. Preclinically, FMT ameliorates virus-induced fatty liver disease by reprogramming microbiomes (reducing Proteobacteria, restoring Ruminococcaceae), improving metabolic markers (normalizing ALT/aspartate aminotransferase and hepatic triglycerides), and suppressing inflammation via downregulation of TLR4/nuclear factor kappa B signaling[158].

FUTURE DIRECTIONS

Unravelling the bidirectional interactions between viral infections and gut microbiota dysbiosis remains a frontier with profound implications for precision medicine. Longitudinal and mechanistic studies are needed to establish causality and temporal dynamics of microbiota changes during infections such as SARS-CoV-2, influenza, and HIV. Most current data are cross-sectional, limiting insight into whether dysbiosis drives or results from disease progression. A deeper understanding of interindividual variability in microbiome composition, shaped by genetics, diet, environment, and comorbidities, will be essential for developing personalized microbiota-targeted therapies. High-resolution multi-omics combined with machine learning could reveal microbial signatures and functional pathways relevant for precision medicine[159-162]. Beyond bacteria, the virome and mycobiome require systematic investigation, as these underexplored microbial communities likely influence host-pathogen interactions and immune responses. Microbiota-based interventions such as probiotics, prebiotics, and FMT demand rigorous evaluation for safety, strain selection, dosing, and timing, particularly in immunocompromised patients with HIV or severe COVID-19. Integration of microbiome research with knowledge of the gut-lung and gut-brain axes will be crucial to understanding systemic consequences of dysbiosis and designing holistic approaches to acute infections and post-viral syndromes such as long COVID. Well-designed randomized controlled trials incorporating microbiome endpoints are needed to translate research into effective therapeutics and clinical guidelines. Bridging mechanistic insights with translational studies will be pivotal to unlock the therapeutic potential of the gut microbiota in viral disease management[163-165].

CONCLUSION

Viral infections profoundly alter the gut microbiota, leading to dysbiosis that can intensify disease severity, impair innate and adaptive immune defenses, and promote secondary infections. Evidence from influenza, HIV/SIV, hepatitis viruses, and SARS-CoV-2 consistently shows that microbial imbalance is closely linked to systemic inflammation, disrupted mucosal immunity, altered cytokine signaling, and unfavorable clinical outcomes. Restoring microbial homeostasis through probiotics, prebiotics, dietary modulation, or FMT shows promising potential to enhance antiviral immunity, modulate SCFA production, alleviate GI symptoms, and reduce disease severity. However, translating these microbiota-targeted strategies into clinical practice requires careful consideration. Intervention efficacy is influenced by patient heterogeneity, timing relative to infection, concurrent antibiotic exposure, and biosafety concerns surrounding microbial transfer. Standardization of microbial formulations, dosing regimens, and delivery routes, alongside rigorous long-term safety monitoring, remains essential. Future studies integrating multi-omics analyses, mechanistic immunology, and controlled clinical trials are crucial to optimize microbiota-based therapies for viral infections and their systemic sequelae.