This study aimed to assess the relationship between the gut microbiota and metabolites in PLWH following SARS-CoV-2 infection. The major findings of this study are as follows: (i) SARS-CoV-2 infection significantly altered the composition of the gut microbiota; (ii) seven differentially enriched human metabolic pathways are worthy of attention; and (iii) Spearman correlation analysis showed close relationships between two differentially abundant microbiota members and five differentially abundant fecal metabolites, which might affect specific human metabolic pathways.
During SARS-CoV-2 infection, PLWH were confronted with various physical and psychological stressors. Consistent with a previous report [19], the current study revealed that the gut microbial composition of PLWH was significantly altered after SARS-CoV-2 infection. The LC-MS untargeted metabolomics analysis identified seven differentially enriched metabolic pathways (protein digestion and absorption, central carbon metabolism in cancer, aminoacyl-tRNA biosynthesis, mineral absorption, ABC transporters, arginine and proline metabolism, and phenylalanine metabolism) in the PLWH. To obtain more detailed information on the microbiota-host interaction, Spearman correlation analysis of the differentially abundant microbiota members and differentially abundant metabolites was performed. The results revealed that two differentially abundant microbiota members correlated closely with five differentially abundant fecal metabolites, which might have specific effects on the metabolic pathways of PLWH. Specifically, decreases in various fecal metabolites (including creatine, phenylethylamine, and L-Phenylalanine) correlated with various differentially abundant bacteria (including g_Lactobacillus and g_Lactiplantibacillus), which might impact the human metabolic pathways related to arginine and proline metabolism, phenylalanine metabolism, protein digestion and absorption, and aminoacyl-tRNA biosynthesis.
Two differentially abundant bacteria, g_Lactobacillus and g_Lactiplantibacillus, identified in our study might have insidious effects on PLWH during SARS-CoV-2 infection. Notably, g_Lactobacillus is involved in the production and utilization of SCFAs [20]. SCFAs influence the immune response through two primary mechanisms. Firstly, unmetabolized SCFAs can travel directly to the lungs via the bloodstream, where they activate G protein-coupled receptors (GPCRs) or inhibit histone deacetylases, thus modulating immune functions [21]. Secondly, SCFAs can migrate to the bone marrow through the circulation, where they promote the differentiation of macrophage and dendritic progenitor cells (MDPs) into Ly6C– monocytes. These monocytes then travel to the lungs and differentiate into anti-inflammatory alternatively activated macrophages (AAMs). These AAMs reduce the recruitment of neutrophils and stimulate regulatory T cells (Tregs) to produce anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-β), thereby decreasing lung injury and inflammation [22, 23]. Considering these factors, the notable effectiveness of g_Lactobacillus in mitigating and treating human diseases offers considerable therapeutic promise.
Additionally, g_Lactiplantibacillus might be another potential probiotic for PLWH. Research involving animal models and human clinical trials have shown that some Lactiplantibacillus plantarum strains, when administered orally, effectively modulate respiratory immunity and boost resistance to bacterial and viral infections. This enhancement in the immune response was observed across various age groups, including children, adults, and the elderly, helping to protect them against respiratory infections, such as pneumococcal pneumonia, the common cold, and influenza-like illnesses [24]. Notably, L. plantarum, and its exopolysaccharides (EPSs), induces an antagonistic effect against human rotavirus. MA104 cells (a rotavirus-susceptible cell line) treated with the strain or its EPSs showed significantly lower numbers of cytopathic alterations and reduced viral replication when compared with untreated controls [25]. Our study showed that the significant decrease in g_Lactiplantibacillus correlated with the abundance of metabolites (e.g., creatine and phenylethylamine) in feces, which might impact human metabolic pathways, including arginine and proline metabolism and phenylalanine metabolism.
The current study is the first to reveal the intestinal microbiota-host interactions after SARS-COV-2 infection by combining gut microbiome and metabolomic analyses. Preventative measures, such as adjusting the gut microbiota by increasing potential probiotics (e.g., g_Lactobacillus and g_Lactiplantibacillus) as well as offsetting the metabolites (e.g., creatine, phenylethylamine, and L-phenylalanine) via dietary adjustment or nutritional supplements, might be beneficial to the health of PLWH during SARS-COV-2 infection. However, it is important to recognize the limitations of this study. First, other critical microorganisms, such as viruses, bacteriophages, yeasts, and fungi, also play significant roles in microorganism-host interactions and could be involved in the development of various disorders and diseases. Second, while several potentially affected human metabolic pathways were hypothesized, the study could not establish direct causality between the differentially abundant microbes, differentially abundant metabolites, and altered human metabolic pathways. Further research is necessary to explore whether and how the microbiota influences the PLWH during SARS-CoV-2 infection. Third, the environment faced by PLWH during SARS-CoV-2 infection is complex, making it difficult to control for factors such as individual habits (e.g., diet, sleep, and activity), socio-economic conditions, and access to healthcare. The primary focus of this study was on the overall impact of SARS-CoV-2 infection on the gut microbiome and metabolome in PLWH. This research provides valuable insights into the physiological disorders that might arise during SARS-CoV-2 infection, as evidenced by changes in the gut microbiome and metabolome. Future prospective studies on SARS-CoV-2 infection should incorporate comprehensive analyses using multiple psychological and physiological scales. Additionally, cellular and animal studies are needed to verify the underlying causal relationships between SARS-CoV-2 infection, physical disorders, and alterations in the gut microbiome and metabolome.