Oligosaccharides As Potential Regulators Of Gut Microbiota And Intestinal Health in Post-COVID-19 Management Part 2
Sep 08, 2023
6. The Role of Oligosaccharides in Modulating Gut Microbiota and ACE2 Expression for Alleviating Post-COVID-19 Syndrome
SARS-CoV-2 gains entry into host cells by attaching to the ACE2 receptor on the cell surface. ACE2 is present in various cells in the human body, including those of the respiratory and gastrointestinal tracts [121]. Once inside the cell, the virus uses the host cell's machinery to replicate and spread. Polysaccharides and oligosaccharides derived from bacterial, fungal, and marine algal sources are natural compounds that exhibit bioactive properties capable of enhancing the immune system, inhibiting viral replication and infectivity, and providing protection against viral infections [122]. Current research has prioritized the exploration of sulfated polysaccharides and oligosaccharides as promising approaches to combat SARS-CoV-2. For instance, heparin, an anticoagulant medication, has demonstrated remarkable effectiveness at the nanomolar level in preventing the transmission of SARS-CoV-2[123]. This is accomplished by inhibiting viral attachment and reducing the formation of blood clots. Furthermore, sulfated polysaccharides derived from plants and marine organisms have displayed encouraging inhibitory effects against the virus in laboratory experiments, effectively diminishing viral replication and reducing infectivity [124]. These molecules can bind to both ACE2 and the spike protein of SARS-CoV-2, which facilitates the virus's attachment to ACE2 [125,126]. By doing so, sulfated oligosaccharides can competitively prevent the virus from entering host cells, potentially reducing the severity of post-COVID-19 symptoms (Figure 3)
Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.
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Post-COVID-19 patients may harbor a small viral load in their bodies even after recovering from the acute phase, which can activate intestinal ACE2 receptors and cause gastrointestinal symptoms such as diarrhea [127]. Previous studies using gnotobiotic rats lacking natural gut microbiota found that the presence of gut microbiota is associated with increased expression of ACE2 mRNA in the colon. This increased expression of ACE2 could increase susceptibility to SARS-CoV-2 infection and affect disease severity [128]. The gut microbiota regulates ACE2 expression, with a healthy microbiome promoting higher ACE2 expression and less severe disease. Certain bacteria, such as Bacteroides dorei, Bacteroides ovatus, Bacteroides thetaiotaomicron, and Bacteroides massiliensis, downregulate ACE2 expression in murine models, highlighting the interrelationship between the gut microbiome, ACE2 expression, and viral infection [53]. The effect of Firmicutes species on ACE-2 receptor expression is not consistent. However, recent studies have indicated that modulating the gut microbiota composition by increasing the abundance of Bacteroidetes and decreasing the levels of Firmicutes may have a beneficial impact in inhibiting the entry of SARS-CoV-2 through the downregulation of ACE2 expression in the intestinal epithelial cells [129].
The gut–lung axis is a two-way communication pathway that facilitates the exchange of information between the gut microbiota and the respiratory system [130]. Growing evidence shows that the gut microbiota influences respiratory health, while the respiratory system affects gut microbiota composition. The immune system, critical in both the gut and lungs, is believed to mediate the gut–lung axis, along with ACE2 expression in both organs [131]. Studies reveal that the gut microbiota modulates ACE2 expression in the respiratory system and that treatment with Lactobacillus rhamnosus can increase ACE2 expression in the lungs, mitigate influenza virus-induced lung injury, and improve lung function [132].
Various oligosaccharides, including fructo-oligosaccharides, xylooligosaccharides, galactooligosaccharides, and pectin-oligosaccharides, have been shown to selectively promote the growth of beneficial gut bacteria such as Bifidobacteria and Lactobacilli. These probiotic-derived bacteria produce molecules such as lipopeptides, including subtilisin from Bacillus amyloliquefaciens, curvation A from Lactobacillus curvatus, sakacin P from Lactobacillus sake, and lactococci Gb from Lactococcus lactis, which possess a higher binding affinity to human ACE2 [133]. By competitively inhibiting the action of these probiotic-derived molecules, SARS-CoV-2's mandatory connection with host epithelial cells expressing ACE2 for entry and reproduction is prevented. Moreover, research has demonstrated that the gut microbiota produces SCFAs that can influence the expression of intestinal ACE2. Brown et al. demonstrated that colonization with Clostridia-enriched bacteria resulted in a significant increase in fecal propionate and butyrate, as well as a decrease in ACE2 expression in the intestines and lungs of specific pathogen-free mice [134]. Similarly, other research has shown that butyrate treatment can decrease the expression of ACE2, along with various other genes related to host defense and immune response [135]. These findings suggest that SCFAs may play a role in inhibiting SARS-CoV-2 entry into host cells by lowering ACE2 expression. Therefore, targeting and modulating the gut microbiome using oligosaccharides could be a potential strategy to reduce post-COVID-19 symptoms.
7. Conclusions
The global outbreak of COVID-19 has had a profound influence on the lifestyles of individuals across the globe and can cause long-term health effects, including post-COVID-19 syndrome. This syndrome may persist for weeks or months and can include symptoms such as gut dysbiosis, diarrhea, fatigue, and abnormal pain. Disruptions in the gut microbiota can contribute to various gastrointestinal symptoms and an increased risk of infections. Furthermore, dysbiosis in the gut microbiota can lead to increased inflammation and oxidative stress, which can contribute to chronic symptoms and the development of post-COVID-19 syndrome. Therefore, balancing the intestinal microbiota through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation has emerged as a promising therapeutic approach for alleviating post-COVID-19 symptoms.
Personalized nutrition is an emerging field that could provide new opportunities for promoting gut health in post-COVID-19 management. Combining oligosaccharides with other probiotics and prebiotics could lead to more significant improvements in gut health and immune function. Oligosaccharides are derived from natural resources and are non-toxic, making them a convenient and low-cost method for promoting gut health and reducing the risk of gastrointestinal symptoms and infections. They can stimulate the growth of beneficial gut bacteria while inhibiting the growth of harmful bacteria, promoting the production of functional metabolites such as short-chain fatty acids (SCFAs). SCFAs have numerous health benefits, including immune modulation and anti-inflammation. Bile salts, another important gut-derived metabolite, may also have antioxidant and anti-inflammatory capabilities that can help reduce inflammation and oxidative stress. Moreover, the gut microbiota and ACE2 receptors play crucial roles in the pathogenesis of COVID-19 and may also be implicated in the development of post-COVID-19 syndrome. Oligosaccharides may modulate the gut flora and the expression of ACE2 in the gut, highlighting the potential importance of gut microbiota modulation in post-COVID-19 symptom management.
However, further research is necessary to determine the optimal dosage and timing of oligosaccharide supplementation in post-COVID-19 management. Additionally, it is essential to consider the source and type of oligosaccharide, as different types can have varying effects on the gut microbiota. Future research should focus on identifying the specific oligosaccharides that are most effective in promoting gut health. In conclusion, oligosaccharides are potential regulators of gut microbiota and intestinal health in post-COVID-19 management.
Author Contributions: Conceptualization, S.Z., and K.T.; writing—original draft preparation, K.-L.C.; funding acquisition, S.Z., and K.-L.C.; writing—review and editing, K.-L.C., S.C., B.T., S.V., S.Z., and K.T. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported in part by Key-Area Research and Development Program of Guangdong Province (2020B1111030004), The Innovative Team Program of High Education of Guangdong Province (2021KCXTD021), and The Program for Scientific Research Start-up Funds of Guangdong Ocean University (2023).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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