Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery

Abstract

BackgroundThere is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions.MethodsA pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-β-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis.ResultsFM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-β-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1β negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001).ConclusionBiomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.

Restrictive Diets in Patients with Fibromyalgia: State of the Art

“…In FM, the low effectiveness of treatments [ 3 ], relationship with IBS [ 8 ], increased intestinal permeability [ 9 , 10 ], and previous literature on the effectiveness of restrictive diets [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] could contribute to changing the dietary habits of patients [ 4 , 5 ] with the avoidance of food groups such as cereals or dairy products [ 5 ], which could negatively affect their physical and mental health.…”

“…In the context of the relationship between irritable bowel syndrome, or IBS, and FM [ 8 ], an increased intestinal permeability compared to healthy controls [ 9 , 10 ], and previous literature on the effectiveness of different types of restrictive diets in FM patients [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] could also influence their modification of dietary habits and their avoidance of food groups.…”

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

“…SCFAs have anti-inflammatory effects and contribute to intestinal barrier maintenance [135]. Increased bacterial translocation and GI permeability are reported in ME/CFS patients [125,[136][137][138][139][140] caused by GI inflammation as part of the "leaky gut" hypothesis [140,141]. Treatments for GI disturbances trialled in ME/CFS patients aim to restore a healthy microbiome, by either removing pathogenic microbes or by the supplementation of or replacement with beneficial (probiotic) microbes (Table S4).…”

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives

“…However, it is postulated that intestinal dysbiosis leads to immunometabolic alterations ( e.g. reduced production of antimicrobial peptides, short-chain fatty acids (SCFAs), altered tryptophan/kynurenine pathway), which causes a disturbed intestinal barrier, increased bacterial translocation, consecutive systemic inflammation as well as neuroinflammation and neuroimmune dysfunction ( Figure 1 ) ( 14 , 46 , 47 ). Further large cohort studies are lacking in order to better understand causal or functional relationships between the microbiome, neuroinflammation and neurocognitive diseases.…”

“… The gut-brain and microbiota-immune-axis as major molecular pathomechanisms resulting in ME/CFS development with potential treatment options based on the intestinal microbiome (modified after 26) ( 14 , 33 , 46 , 47 ) Created with . Arrow up means "increase", arrow down means "decrease".…”