Is There a Link Between Fibromyalgia and Gut Bacteria?

Is There a Link Between Fibromyalgia and Gut Bacteria

Recent studies indicate a link between fibromyalgia (FM) and gut bacteria. Whether this is a causative association or not remains unclear, but certainly these preliminary observations may pave the way for further studies elucidating the pathophysiology of FM.

The first study entitled: ‘Altered microbiome composition in individuals with fibromyalgia’ describes significant differences in several bacterial taxa in FM patients versus healthy controls. As per Amir Minerbi, the first author of this study, from the McGill University Health Centre, Montreal, QC, Canada, “this is the first demonstration of gut microbiome alteration in nonvisceral pain”. Approximately 20 different species of bacteria were found in either greater or lesser quantities in the microbiomes of FM patients.

Dr. Minerbi stated: “We found that fibromyalgia and the symptoms of fibromyalgia contribute more than any of the other factors to the variations we see in the microbiomes of those with the disease. We also saw that the severity of a patient’s symptoms was directly correlated with an increased presence or a more pronounced absence of certain bacteria“.

Species putatively depleted in FM were relatively well characterised and included F. prausnitziiB. uniformisP. copri, and Blautia faecis.

B. uniformis is one of several species that have recently been reported as having altered relative abundance in patients with inflammatory arthritis. B. uniformisis detected in synovial tissues of osteoarthritic joints, whereas P. copri is detected in rheumatoid arthritis synovial fluid.

P. copri is believed to mediate inflammatory response through T helper (Th)17 cell activation. In this study, these species were found in lower abundance in FM patients. Although FM is often considered to be a rheumatologic disease, it seems that at least some species previously found at higher abundance in inflammatory rheumatic diseases are depleted in FM.

Of note, Clostridium scindens and B. desmolans, two bacterial species capable of converting cortisol to androgens by 20α-hydroxysteroid dehydrogenase activity were found in higher abundance in FM patients. Interestingly, abnormal regulation of hypothalamic-pituitary-adrenal axis has been reported in FM patients, although the direction of dysregulation remains controversial.

The second study entitled: Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia reports that the diversity of bacteria is reduced in FM patients. Thus, the abundance of the Bifidobacterium and Eubacterium genera (bacteria participating in the metabolism of neurotransmitters in the host) in FM patients was significantly reduced.

The study also reports a decrease in the abundance of several members of the Lachnospiraceae family, the bacteria involved in butyric acid production. Butyrate, the conjugate base of butyric acid, is produced by a small number of bacteria, including several Eubacterium species.

The authors of this study also detected a significant increase in the serum levels of glutamate in fibromyalgia patients. Also, the abundance of bacteria from Bifidobacterium and Lactobacillus genera (involved in the transformation of glutamate into GABA) was reduced in the FM group. This might contribute to the elevated systemic levels of glutamate.

Interestingly, the authors discuss that “in the presence of excess of glutamate, as observed here, the pain inhibition by GABA might be suppressed in female patients by this E2 (17β-estradiol)-specific regulation. This might partly explain the increased prevalence of FM in the female population”.

The third study entitled: Investigating of Relation Between Fibromyalgia Syndrome and Intestinal Microbiota reports an increase of Bacteroidetes and Bifidobacterium but a decrease of Firmicutes decreased in FM patients. It is known that the balance of Firmicutes and Bacteroidetes phyla in the gut have important effects on intestinal homeostasis, and, thus, it may play a role in fibromyalgia.

Of note, the fourth study investigates in fact the relationship between the reduced diversity in the microbiome and chronic widespread musculoskeletal pain. The chronic widespread musculoskeletal pain (CWP), affecting some 5–15% of the general population, forms part of the fibromyalgia syndrome that includes fatigue and sleep disturbance in addition to CWP.

The study entitled: An association between chronic widespread pain and the gut microbiome indicates that the species Coprococcus comes is significantly depleted in CWP cases.

Coprococcus comes is one of the most important butyrate-producing bacteria. Butyric acid produced by C. comes and other gut commensals exhibits remarkable anti-inflammatory effects in the gut. The authors of this study discuss that a high-fat diet may cause a decrease of Coprococcus species abundance in the gut. Of note, people with CWP are known to have on average a diet higher in fat. Thus, a high-fat diet may promote the decrease of Coprococcus and other anti-inflammatory species that “in turn results in a low-grade inflammation, supporting the development of CWP”.

A bit of History

Fibromyalgia was first described in the early 1800s as a condition called “muscular rheumatism.” The symptoms were stiffness, aches, pains, tiredness, and difficulty sleeping. A MD in Scotland first described the tender points of fibromyalgia in the early 1820s.

Eighty years later, the term “fibrositis” was first used. Because inflammation (swelling) was thought to be a cause of the pain, the ending “itis” was given. In 1976, the name of the condition was changed to “fibromyalgia.” Swelling in the body was no longer believed to be the cause of pain.

A Bit of Pathophysiology & Pathogenesis

Fibromyalgia’s pathogenesis has not been elucidated but may include sympathetic dysautonomia as an explanation to the multiplicity of FM symptoms including its main complaint, widespread pain. Thus, FM may represent a sympathetically maintained neuropathic pain syndrome, and the reports about a small nerve fiber pathology in FM may reinforce this mechanism.

In addition, the role of pro-inflammatory cytokines has been implicated. For example, reports for a positive correlation between widespread pain and serum interleukin (IL)-8 in patients with FM; the presence of high levels of the chemokines CX3CL1 (also known as fractalkine) and IL-8 in FM, and the evidence that microglia in patients with fibromyalgia are hypersensitive and overproducing tumor necrosis factor (TNF)-α.

Moreover, the plas­ma levels of interleukin (IL)-17A are increased in FM patients and IL-17A positively correlates with indices of pain, depression and anxiety, which are symp­toms frequently reported by patients with FM.

The Gut Microbiome and the Brain

The hundred trillion bacteria in the body of an adult human contain about 4 million distinct bacterial genes, with more than 95% of them located in the large intestine. Since most of these genes encode for enzymes and structural proteins that influence the functioning of mammalian cells, the gut microbiome can be viewed as an “anaerobic bioreactor programmed to synthesize molecules which direct the mammalian immune system, modify the mammalian epigenome, and regulate host metabolism”.

Structural components of the microbial cell wall continually stimulate the innate immune system to produce various cytokines, and the bacterial cell wall lipopolysaccharides (LPS) induce the synthesis of the whole spectrum of pro-inflammatory cytokines. Of note, “the adult human gut is believed to contain about one gram of LPS”and “the gut microbiome stimulates a chronic state of low-level activation of the innate immune system in humans, which is influenced by the circadian pattern of adrenal cortical function”.

Moreover, gut bacteria influence the reactivity of the hypothalamic–pituitary–adrenal (HPA) axis; modify the stress response and the induction and maintenance of nREM sleep. They may influence mood, pain sensitivity and normal brain development.

Apparently, further studies are needed to confirm the link, described here, between fibromyalgia and gut bacteria. Whether, and how, some of the above-mentioned pathophysiology pathways and mechanisms are involved remains to be determined.