Introduction: Chronic fatigue syndrome (CFS) is a long-term disorder characterized by profound fatigue, as well as various cognitive symptoms. Recent evidence suggests that the gut microbiome and its dysbiosis may be involved in the pathophysiology of CFS by affecting the regulation of metabolites related to energy metabolism, neurotransmission, oxidative reactive products, immune system dysfunction, and inflammation. This study explores the molecular mechanisms by which our microbiota contribute to the initiation or progress of the CFS.
Methods: Published literatures in Scopus, PubMed, and NCBI databases were gathered to categorize the factors affecting CFS and their relation with gut microbiota. Pre-prints, research, and review articles were utilized to conduct a comprehensive literature review. The keywords were checked for accuracy using MeSH guidline.
Results: Dysbiosis of the gut microbiome in CFS patients leads to decreased blood serum levels of essential energy-producing metabolites, such as short-chain fatty acids (SCFAs) and amino acids, while increasing fatigue-inducing factors, including lactic acid. Moreover, downregulation in hormones and neurotransmitters secretion, such as serotonin, melatonin, GABA, histamine, glutamate, stress hormones, acetylcholine, and adenosine caused by dysbiosis lead to mental fatigue. Among the main increased gut bacterial species in CFS, some Bacteroides produce glutamate and induce mental fatigue, while decreased species are SCFA-producing Lachnospiracea, Ruminococcus, Faecalibacterium, Dorea, and Anaerostipes, which impact energy metabolism. Reduced neutralization of reactive oxygen species by our microbiota or even generation of oxidative stress by-products of the microbiota leads to chronic fatigue. The overgrowth or the lower abundance of the key species leads to imbalanced metabolites in CFS.
Conclusion: Overall, this study provides a comprehensive analysis of the influencing factors and metabolites and their alternation in CFS, along with highlighting the correlation between gut microbiota dysbiosis and changes in these substances. Gut microbiota imbalances can lead to reduced blood serum metabolite levels, such as SCFAs and amino acids, which contribute to the development of CFS symptoms. Conversely, internal dysfunction may alter metabolite levels, like branched-chain amino acids (BCAAs) and oxygen, potentially affecting the composition of gastrointestinal bacteria. Furthermore, oxidative stress increases and antioxidant levels decrease in CFS patients compared to healthy individuals.
An increase in reactive oxygen species (ROS) producers, such as Enterococcus faecalis within the gut microbiome, generates extracellular superoxide and hydrogen peroxide, which harm colonic epithelial cells. Various studies have shown significant decreases in levels of antioxidant compounds in the liver and gastrocnemius muscle, including vitamin E, superoxide dismutase (SOD), glutathione peroxide (GSH-Px), and catalase (CAT), which are mainly produced by Lactobacillus, Proteobacteria, Pseudomonas, and Firmicutes. In contrast, nucleotide oxidation products like 8-hydroxy-deoxyguanosine (8-OHdG), along with ROS such as superoxide and hydrogen peroxide, and the free radical metabolite malondialdehyde (MDA), have shown a dramatic increase.
Elevated levels of lipopolysaccharides (LPS), which are inflammatory markers linked to Gram-negative bacteria enterobacteria, can increase serum immunoglobulin concentrations and contribute to fatigue. High ceramide levels from LPS breakdown can also harm gut epithelial cells, damaging the barrier and increasing gut permeability. In conditions like ME/CFS, high amounts of pro-inflammatory cytokines, sometimes produced by gut Proteobacteria, are noted. Dysbiosis and metabolic endotoxemia are significant factors in inflammation and oxidative imbalances, leading to a reduction in the tight-junction protein occludin and compromising the integrity of the intestinal barrier.
While the link between inflammation and fatigue remains unclear, markers of inflammation, oxidative/nitrosative stress, and antioxidants have been proposed as potential diagnostic tools, which are linked to key cellular processes. Future research is required to elucidate the portion of the microbiota when both our cells and microbiota can produce the same metabolites. The relationship between gut microbiota dysbiosis and CFS is bidirectional as a sedentary lifestyle can lead to dysbiosis itself.
Keywords: chronic fatigue syndrome, gut microbiota, gut microbiome, Dysbiosis, metabolite