Fibromyalgia and gut microbiota: from precision medicine a new hope to unhinge the disease

Fibromyalgia, also called fibromyalgia syndrome (FMS), is a chronic, long-term disorder, characterized by deep pain all over the body (at least in 11 of 18 tender point sites), sleep problems, cognitive impairment, fatigue, anxiety, depression, or feelings of frustration (low mood), “fibro-fog” sensation such as difficulty concentrating or bad memory and muscle stiffness. The symptoms of fibromyalgia are unpredictable and unstable as they can sometimes suddenly improve or get worse, making difficult to handle with a long-term therapy.

Treatment tends to be a combination of lifestyle changes, such as exercise programmes and stress-management techniques, cognitive behavioural therapy (CBT), drugs as antidepressants and pain relievers. Exercise has several important benefits for people with fibromyalgia, including helping to reduce pain and strengthen muscle mass. Although there's currently no consent on a resolutive cure for fibromyalgia, more awareness is being gained on the importance of diet and lifestyle on its genesis.

To date the pathophysiology of fibromyalgia is still poorly understood. Between the causative agents we can include neuroinflammation1, inflammatory processes mediated by an increase in IL-62, irritable bowel syndrome (IBS), a digestive condition that causes stomach pain and bloating3. IBS has been associated with alterations in the composition and diversity of the gastrointestinal microbiota, shedding a light on the importance of a healthy gut microbiota on this disease. Beyond IBS, other investigators studied the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with fibromyalgia, IBS and normal controls. Interestingly, values for hydrogen production detected were significantly higher in patient with fibromyalgia compared to controls and IBS4. Constipation (higher methane production), succinate and lactate increase seem to be other biomarkers of the gut microbiota in the fibromyalgia syndrome, albeit they warrant more systematic and rigorous investigation, as well as the involvement of H. pylori in the pathogenesis of this disease.

The gut microbiome affects many aspects of neurological functioning, including emotional and cognitive effects, and pain management. How? Through the so called “gut-brain-axis”, an intricate bidirectional communication highway between the gut and the brain, through the vague nerve or the bloodstream allowing gut bacterial community to affect the function of brain and central nervous system. Let’s dig into the gut-brain axis and the role of microbial metabolites such as glutamate, GABA (γ-aminobutyric acid) and secondary bile acids, in the fibromyalgia syndrome.

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Gut Microbiota and Fibromyalgia: a new interplay

Several studies, especially on animal models, proved that gut microbiome has a direct impact on pain perception. In which way? The two main mechanisms are the secretion of biologically active metabolites, which include SCFA (short chain fatty acids), bile acids, neurotransmitters, toxins, and pathogen-associated molecular pattern (PAMP), which interact directly with the host immune system. PAMPs include cell wall molecules (such as lipopolysaccharide or LPS), nucleic acids and other antigens, while SCFAs include butyrate, propionate and lactate. The fermentation of dietary fibres by gut bacteria results in the production of short-chain fatty acids (SCFAs). These molecules are essential for the maintenance of the integrity of intestinal barrier, preventing the leaky gut syndrome and other health-related functions such as development and maintenance of the blood-brain barrier. SCFAs have been linked to pain sensation via activity on free-fatty-acid-receptor (FFAR) 2/3, and their regulatory effect on leukocytes5. In particular, butyrate has been linked to visceral hypersensitivity in mice, whereas, in humans, it seems to reduce visceral pain6. People with FM show significantly altered composition of SCFA metabolising bacteria, as well as alterations in the serum and urine levels of SCFA. One of the bacteria normally living in our intestine, Faecalibacterium prausnitzii, normally addressed as one of the main butyrate producers, is often depleted in several intestinal diseases7. Besides, Faecalibacterium prausnitzii?depletion also has been linked to chronic fatigue syndrome, which is highly similar to fibromyalgia, is frequently comorbid with it, and it is considered by some experts to be part of the same spectrum of illnesses. This bacterium is believed to lower pain and inflammation in the digestive tract as well as improving the function of the intestinal barrier. A healthy intestinal barrier, which relies on the presence of Akkermansia muciniphila as well, is pivotal for prevention of several systemic disease, chronic inflammation, pain, emotional stress and fatigue, all conditions that are common in people with fibromyalgia too.

Gut bacteria have been shown to produce and release a wide range of neurotransmitters, as part of the interplay of the gut-brain axis. Bacteria can either produce and/or consume a wide range of mammalian neurotransmitters: dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid (GABA). Accumulating evidence in animals and preliminary human studies are showing that microbiota-based interventions can manipulate the neurotransmitter levels. Between others butyrate-producing bacteria, Parabacteroides merdae and A. muciniphila were shown to increase the GABA/glutamate ratio in the brains of mice, thus decreasing all CNS excitability and performing a protective anti-seizure effect8. Interestingly, P. merdae was one of the species for which the highest fold increase in FM patients was observed, possibly explaining symptoms such as fatigue, mood change, sleeping problems and cognitive dysfunction. P. merdae has been linked to the antiepileptic effect of the ketogenic diet, in several mouse model, through the regulation of amino acid γ-glutamylation. However, this data is in contrast with some other studies on FMS, confirming an inverted trend toward reduction in butyrate-producing bacteria, increase in the leaky-gut syndrome, depletion of GABA and increase in glutamate in FMS9,10. In relation to pain, a mismatch of excitatory and inhibitory neurotransmitter concentrations (either increased levels of the excitatory neurotransmitter glutamate/glutamine or decreased levels of the inhibitory neurotransmitter GABA) has been observed, specifically the insular cortex. Clos-Garcia9 used quantitative polymerase chain reaction (qPCR) to detect bacterial gene expression related to glutamate metabolism and, with surprise, they found five out of six glutamate degrading genes at significantly higher levels in fibromyalgics than controls. However, even if contradictory, they detected higher serum levels of glutamate in the fibromyalgia group. It is consistent with other data reporting a role for glutamate in the central nervous system (CNS) and in pain signalling. The bacteria involved in glutamate and GABA metabolism in these two studies were different: Bifidobacterium and Lactobacillus in Clos-Garcia’s study9, and Akkermansia muciniphila and Parabacteroides spp., in Minerbi’s8.

It is interesting to keep in mind the relationship between GABAergic pain inhibition and gender as fibromyalgia is 3 times more prevalent in women than in men. It is possibly related to the ability of steroid 17β-estradiol (E2) to suppresses the GABAergic inhibition in female rats via a sex-specific oestrogen receptor and endocannabinoid-dependent mechanism11 (Tabatadze et al., 2015).

Worth mentioning is also the role of the secondary bile acid metabolizing bacteria in fibromyalgia.?Secreted by the liver, human bile acids help the body digest fatty foods but also carry out many biological activities in the body, such as toxin removal. Once metabolized in the gut by our microbiota, they are recirculated to the liver and blood and become secondary bile acids. New research, who need to be supported by further evidence in the future, hypothesized that people affected by fibromyalgia could lead a proper signature of the disease in their bile acids, for their unique composition. How does it come to the gut microbiota?

Dr Minerbi, form the Alan Edwards Pain Management Unit at the McGill University Health Centre (MUHC), leader of the study, explained that “The change in bile acids that we observed in patients with fibromyalgia in our study is distinct enough to be used as an effective biological signature to detect individuals with fibromyalgia. That’s an important step forward, considering that diagnosing fibromyalgia is often a long process that requires eliminating other conditions that can cause similar symptoms”. In this study, 16S rRNA sequencing together with metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in 84 women (2 cohorts of 42, with fibromyalgia and healthy controls). Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, and significant alterations in the serum concentration of secondary bile acids were also detected, including a marked depletion of α-muricholic acid12. It is indeed a promising data, a new circulatory, non-invasive biomarker, a biological signature of the FMS that opens a new scenario on an early detection and tempestive intervention on the patient.

To wrap up, a reduction in the bacterial diversity is evident in the FMS. This is also related to the reduced microbiota diversity in other pain disorders, such as chronic fatigue syndrome, or disorders related to a shortage of butyrate-producing bacteria (mostly Firmicutes). Interestingly, the studies mentioned in this article all converge to a reduction in the abundance of several bacterial strains associated with healthy microbiome, such as those linked to SCFA production (Bifidobacterium, Eubacterium and Lachnospiraceae) and/or other beneficial bacteria in the Firmicutes phylum (such as Lactobacillus). Dorea is increasing, while Eubacterium species (butyrate-producer) drops in FMS. Finally, according to Minerbi8 and Clos-Garcia’s9 studies, the species putatively depleted in FM were relatively well characterised and included F. prausnitzii, B. uniformis, P. copri, and Blautia faecis. By the other side, Roseburia, Papillibacter and Subdoligranulum were detected in higher abundance.

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Eating habits and Fibromyalgia: green lights vs red lights

Fibromyalgia has both social and economic effects, due to the multiple symptomatology and chronic, long-term fatigue, pain, mental and gastro-intestinal discomfort. Quality of life is quite often poor and in severe conditions people are also unable to work. To date, effective treatment is not available and optimal management of FMS includes early diagnosis, pain control, nonpharmacological therapy as a first-line, such as dietary intervention and proper lifestyle, with the pharmacological option to be chosen only in case of lack of effect. As nutritionist and sport lover I personally recommend the synergy of good eating-habits and daily exercise as first intervention in FMS, albeit precise exercise-based protocols need to be customised according to the situation.

Several studies indicate the benefits of adequate nutritive advice to FM patients. For example, antioxidant rich diets reported to be beneficial, with clinical improvement in FM symptoms13. Multiple antioxidant dietary plans, designed to target muscle cells, local inflammation, and pain-related metabolic pathways, currently, are the most promising intervention. A combination of various antioxidant including selenium, GSH (glutathione) precursor amino acids, taurine, carnosine and anserine as histidine-containing dipeptides, melatonin, as well as plant-derived substances, flavonoids and isothiocyanates, represent a successful approach. Antioxidant vitamins such as vitamin C and vitamin E can play a beneficial role in the management of certain typical symptoms of FMS, since they are good in protecting cerebellar functions, memory, emotive responses as well as muscle function. Vitamin D supplementation should also be considered in the management of FMS, after assessment of baseline blood levels. ?Low serum vitamin D levels are quite often linked to chronic pain, depression and anxiety in fibromyalgic patients14 but are also responsible of severe muscle weakness and bone frailty. Vitamin D deficiency or insufficiency is associated with osteo-metabolic disorders, nonspecific musculoskeletal conditions and FMS, also because the daily recommended intake of 400 IU is quite often considered insufficient for the real needs15. Another important nutrient is selenium in FMS. The selenium status in the FM patients was found to be significantly reduced compared to healthy people (median 77 μg/l; range: 50–118 μg/l), and it is interesting, considering that skeletal muscle disorders characterized by fatigue, muscle pain, and proximal weakness have been documented in patients with selenium deficiency, in a similar way to the FM patients13. ?Presumably, selenium exerts its protective effects as a component of the GPX family of enzymes, key endogenous antioxidants. Magnesium is another essential nutrient in FM patients. Its deficiency quite often leads to a low-grade chronic systemic inflammation with a minor increase in pro-inflammatory cytokines and C-reactive protein (CRP), contributing to accentuating health problems associated with the FMS.

Between foods, ancient grain products as well as extra-virgin olive oil (EVOO) seems to play a pivotal role in patient with FMS, because of the attenuation in oxidative processes, general body pain, fatigue and tiredness, together with sleepiness quality and mental status improvement. While EVOO can protect women with FM against cardiovascular disease, acting as a valid therapeutic nutrient in patients with FM, and participate in the control of the inflammation and body pain through the action of the oleocanthal, the positive effect on health status of the ancient grains seems to be due to the higher content of macro- and microelements (such as magnesium, phosphorus, potassium, selenium and zinc) other than carotenoids and polyphenols, compared to refined wheat14. Ancient grains include varieties of wheat, wild rice, millet,?barley,?teff,?oats, and?sorghum, and the pseudocereals?quinoa,?amaranth,?buckwheat, and?chia. The Mediterranean Diet is between the different diet models the one that most embrace all these kinds of food, as therefore is recommended on the FMS. It is a good source of mineral and vitamin through high fresh food daily intake (400-500 g of fruit and vegetables), it ensures high amounts of antioxidants and fibres as well as plant-derived proteins. Fish, as natural source of anti-inflammatory, polyunsaturated fatty acids Omega3, oily dried fruits, and white, low-fat meat, good source of carnosine and anserine, are also part of the MedDiet.

Nevertheless, low-gluten diet, low FODMAPs (Fermentable Oligo-Di-Mono-saccharides And Polyols) diet, low-calory diet could also be beneficial for patients with FM, albeit evidences are more related to IBS in the low FODMAPs diet, and to non celiac gluten sensitivity in the low-gluten diet. Both conditions elicit similar symptoms (of gastrointestinal discomfort and higher gut permeability) to the ones presented in the FMS. However, these kinds of diets are not long-term sustainable since they provide a long list of food restriction, and they are not promoting gut microbiota balance and proliferation.

A cross-sectional study on the dietary habits (through a food frequency questionnaire) on 486 women with FMs (aged 35 to 65) was recently performed in Andalucia, Spain. The objective was to explore the association of dietary habits with mental health, depression, and optimism. The study showed that the consumption of fresh food, such as fruit, vegetables and fish on a daily, or almost-daily basis, would be associated with more positive psychological and social outcomes in these women, whereas an excessive intake of cured meats and sweetened beverages was related to worse scores in optimism and depression outcomes16.

This is one example between a plethora of scientific evidence of how eating-habits and preferences can shape our health, physically and mentally without exclusion, acting on inflammatory pathway, gut microbiota modulation and gut-brain axis, neurotransmitter and hormone release, cellular crosstalk, and metabolism.

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My suggestion? Give health your maximum priority in life, over fatigue, shortage of time and bad preferences in food choices. Be active, optimist, and exigent with the diet, every day. Feed yourself of real food, natural and sustainable more than processed and ready-to eats. Take care of your gut microbiota through a daily dose of fermented food and high fibre intake. Enjoy life, that is too short to be wasted and remember to take care of your body that is the only place you will always have to live!

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