The ‘microgenderome’ provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro-immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression. Results revealed significant sex-specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota.

BackgroundThe pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of d-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of d-lactic acidosis (d-la).Methods d-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high d-lactate levels. Fifty-nine d-la episodes were included in the qualitative synthesis comparing d-la symptoms with ME/CFS diagnostic criteria. A narrative review of d-la mechanisms and relevance for ME/CFS was provided.ResultsThe majority of neurological disturbances reported in d-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported d-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS.LimitationsInterpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for d-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined.ConclusionsShared symptomatology and underlying microbiota–gut–brain interactions raise the possibility of a continuum of acute (d-la) versus chronic (ME/CFS) presentations related to d-lactate absorption. Measurement of d-lactate in ME/CFS is needed to effectively evaluate whether subclinical d-lactate levels affect neurological symptoms in this clinical population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1229-1) contains supplementary material, which is available to authorized users.

BackgroundPreliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of d-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS.MethodsAn open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 × 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4-week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (d-lactate free multistrain probiotic, 5 × 1010 cfu twice daily). 2 × 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post-intervention for microbial, lactate and clinical outcomes. Ancillary non-parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes.ResultsLarge treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine d:l lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females.ConclusionsResults support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of d-lactate. Further investigation of lactate concentrations are needed to elucidate any role of d-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment.Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview=trueElectronic supplementary materialThe online version of this article (10.1186/s12967-018-1392-z) contains supplementary material, which is available to authorized users.

The microgenderome defines the interaction between microbiota, sex hormones and the immune system. Our recent research inferred support for the microgenderome by showing sex differences in microbiota-symptom associations in a clinical sample of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). This addendum expands upon the sex-specific pattern of associations that were observed. Interpretations are hypothesized in relation to genera versus species-level analyses and D-lactate theory. Evidence of sex-differences invites future research to consider sex comparisons in microbial function even when microbial abundance is statistically similar. Pairing assessment of clinical symptoms with microbial culture, DNA sequencing and metabolomics methods will help advance our current understandings of the role of the microbiome in health and disease.

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