Únavový syndrom and fibromyalgia are like two neglected orphans, and the mainstream medical community maintains a very detached attitude toward them. At times they belong in diagnostic classification systems, and at times they do not; the search for their etiopathogenesis follows local national folklore. In Germany, physicians focus specifically on the cardiovascular system, in France on the liver, in the USA on presumed immune dysfunction, and in England on psychosomatics. But a few years ago, the idea emerged from Australia that the cause should be sought in the gut (1).
With the discovery of the importance of the gut brain (gut brain) and the gut microbiome, it is not only possible but perhaps appropriate to return to this central idea. There are several compelling reasons for this. The gut brain is represented by extensive neural plexuses in the intestinal wall and contains at least as many neurons as the entire spinal cord. Linked to it through bidirectional communication channels are the immune system and an equally strong cooperation with the gut microbiome. The gut microbiome is responsible not only for food processing and participation in immunity, but also for the production of many molecules necessary for metabolism, immunity, and activity of the central nervous system (CNS). Most of the total neurotransmitter production occurs here. Connection with the CNS is via the vagus nerve, as well as directly through molecules released into the bloodstream, and indirectly through links to the immune system.
Before coming to the essence of this message, let us recall the often-cited work comparing dietary habits and their consequences for gut microbiome and its products in two populations of children: from Florence and from Burkina Faso. The diet of African children consists mostly of millet, cassava, spicy porridge from local vegetables, beans, occasional chicken, and termites eaten during the rainy season. Florentine children mainly eat pizza, pasta, meat, cheese, cereals, chips, ice cream, and drink sweet soda with it. These dietary differences correspond to differences in microbiome composition as well, with prevalence of Bacteroidetes over Firmicutes in Africa, while in children in Europe it is the opposite. Naturally, molecular production is different as well. With respect to short-chain fatty acids (SCFA), bacteria from African children produce almost three times more than bacteria from Italian children, including acetate, butyrate, and especially propionate. SCFA were present in stool samples of African children at 85 μmol/g of stool, while European children reached 30 μmol/g of stool. This ratio held for all observed groups. For this reason, pathogenic strains in the gut, especially Klebsiella and Escherichia, are represented much less in Africa; Klebsiella is up to eight times more prevalent in European children (2).
Links between primarily autoimmune disease and gut dysbiosis are being explained, refined, and found, whether dealing with allergies (3), gut inflammations (4), and even tumor growth (5).
What is most interesting about the concept of the influence of gut microbes is the fact that changes in overall behavior can sometimes be achieved by mere changes in the gut microbiome and its characteristic production. Results of some procedures in animals—even if they cannot be applied to humans with full certainty—are impressive. Gut bacteria transferred from a depressive mouse to a healthy one induced depressive behavioral changes (typical withdrawal, territorial resignation), changes in the expression of genes for myelin, and prefrontal myelin changes (6). At the same time, first successful therapeutic results are also being specified and confirmed in humans. Sun's meta-analysis study regarding this type of treatment in patients with ulcerative colitis credibly confirms this (7).
Chronic Fatigue Syndrome (CFS) is a condition in which normal activities lead to extreme fatigue in the affected person, which does not disappear after adequate rest. Fecud criteria (8) are usually used for diagnosis. So far, no specific triggers of this state were known, nor, for that matter, etiopathogenetic factors and effective therapeutic procedures. The authors of the cited paper state that they have finally discovered and identified biological markers, both among gut bacteria and among inflammatory markers in plasma.
Gastrointestinal complaints in patients with CFS, occasional reports of partial success of probiotic therapy, and information—although inconsistent—about findings indicating immune changes led an American team from Cornell University in New York to pursue the cause of this condition in gut microbiome dysbiosis and its consequences for immunity.
First, they sequenced microbial genes from stool of a total of 48 patients and 39 controls. Here they found fundamental differences between the microbiome of healthy and affected individuals. In those compared with healthy subjects, they observed reduced relative abundance and lower diversity among strains belonging to Firmicutes. They also found a higher amount of bacteria classified as pro-inflammatory, specifically an excess of Enterococcus and Streptococcus species, and among anaerobes Prevotella predominated very strongly. Conversely, there was a marked reduction in the presence of important protective butyrate producers: Faecalibacterium. Using these data as a diagnostic criterion, they were able to correctly diagnose almost 83% of patients with CFS.
At the same time they also determined inflammatory markers in plasma: CRP, i.e. C-reactive protein, intestinal fatty acid-binding protein (I-FABP), lipopolysaccharides (LPS), their binding protein (LBP), and soluble CD14 (sCD14).
C-reactive protein (CRP) is a substance secreted by the liver as a response to bacterial inflammation, and today its measurement is entirely routine and has replaced the former (those who remember still recall) erythrocyte sedimentation rate. Lipopolysaccharides (LPS), also known as lipoglycans or endotoxins, are large molecules carrying antigens found on the surface of gram-negative bacteria that trigger a strong immune response. Their binding protein (LBP) is a soluble acute-phase protein that binds LPS and carries it to the target cell containing surface recognition receptors CD14 and TLR4. These, upon encountering LBP, trigger an immune response. Intestinal fatty acid-binding protein (I-FABP) is a protein originating from necrotic enterocytes and is a marker of intestinal wall damage. CD14 acts as a co-receptor alongside receptor TLR4 for detection of bacterial lipopolysaccharides, but also other pathogens, and in this study its soluble form (sCD14) was measured.
In patients with CFS, the authors found increased blood markers typical of microbial translocation, namely higher values of LPS, LBP, and sCD14. LBP values correlated with LPS and sCD14 values, and LPS values also correlated with sCD14 values. In discussing their findings, they write verbatim: Our microbiome analyses show that the gastrointestinal tract of patients with CFS represents a pro-inflammatory milieu. This condition may damage the intestinal epithelium, increase microbial translocation and thereby trigger an immune response. It has previously been found that in CFS, there is disruption of the mucosal barrier, which is confirmed by increased plasma concentrations of IgA and IgM to LPS originating from gram-negative bacteria. Increased permeability and higher LPS values were also described in patients with liver disorders, alcoholic and nonalcoholic steatohepatitis, and also in inflammatory bowel diseases, indicating activation of endotoxin-signaling pro-inflammatory cascades. High plasma LPS levels may be a result of increased endotoxin production with changes in the gut microbiome.
Unfortunately, it is still not clear whether the above changes are a cause or consequence of the disease process. That does not prevent the development of therapeutic approaches aimed at reducing local inflammation, modifying and normalizing the microbiome, and restoring immune integrity of the gastrointestinal system.
Source: Giloteaux L, et al.: Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis / chronic fatigue syndrome. Microbiome. 2016 Jun 23;4(1):30-42 Author: MUDr. Radkin Honzák, CSc. *References:
(1) Borody TJ, Nowak A, Finlayson S. The GI microbiome and its role in chronic fatigue syndrome: a summary of bacteriotherapy. ACNEM J. 2012;31(3):3–8 (2) De Filippo C, et al.: Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A. 2010,17;107(33):14691–14696 (3) Hua X, et al.: Allergy associations with the adult fecal microbiota: Analysis of the American Gut Project. EBioMedicine 3 (2016) 172–179 (4) Campieri M, Gionchetti P: Bacteria as the cause of ulcerative colitis. Gut 2001;48:132–135 (5) Goldszmidz RS, et al.: Host immune response to infection and cancer: unexpected commonalities. Cell Host Microbe. 2014 March 12; 15(3): 295–305 (6) Gacias M, et al: Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife, 2016; 5 DOI: 10.7554/eLife.13442 (7) Sun D, et al.: Fecal Microbiota Transplantation as a Novel Therapy for Ulcerative Colitis: A Systematic Review and Meta-Analysis. Medicine (Baltimore). 2016 Jun;95(23):e3765. doi: 10.1097/MD.0000000000003765 (8) Fukuda K, et al.: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–9