Fibromyalgia And Irritable Bowel Syndrome Interaction: A Possible Role For Gut Microbiota And Gut-Brain AxisⅡ
Dec 06, 2023
2. Human Microbiota and Gut-Brain Axis in Health and Disease
The human gut microbiota consists of a complex, dynamic, and heterogeneous ecosystem inhabited by more than a trillion microorganisms including bacteria, archaea, fungi, viruses, protozoa, and helminths interacting with each other and with the host [39–41]. About the bacterial population, the human gut microbiota includes seven phyla: Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria, Proteobacteria, Verrucomicrobia, and Cyanobacteria, with Bacteroidetes and Firmicutes representing more than 90% of the total bacteria [42]. The ratio between Firmicutes and Bacteroidetes is considered an important parameter to take into account for the treatment of intestinal disorders [43]. The Bacteroidetes phylum includes Bacteroides and Prevotella genera, Firmicutes phylum includes Clostridium, Eubacterium, and Ruminococcus genera [44].
Still, the relative richness of bacterial phyla may vary significantly among individuals [44]. The relationship between the human host and gut microbiota is both commensal and mutualistic: while the host provides an ecological niche for all the components of the gut microbiota, some of them contribute to host development, fitness, and metabolism. First of all, by living and replicating on intestinal surfaces, gut microbiota generates a stable system that prevents the invasion of pathogenic microorganisms. In addition, gut microbes synthesize several classes of nutrients such as branched-chain amino acids, amines, phenols, indoles, phenylacetic acid, and vitamins [41,45–47]. Particularly, Bacteroides are involved in the synthesis of biotin, riboflavin, pantothenate, and ascorbate, while Prevotella is involved in thiamine and folate synthesis [44].
Gut microbiota contributes to the synthesis of bile acids, and cholesterol as well as the absorption of calcium, magnesium, and iron [46,48]. In addition, in stress conditions, it enhances the absorption of nutrients by increasing the length of intestinal villi and microvilli. Gut microbiota is considered the principal mediator of the metabolism of indigestible carbohydrates, such as cellulose, pectin, and oligosaccharides, into short-chain fatty acids (SCFAs) (acetate, propionate, and butyrate), that are mainly produced by Firmicutes, Bacteroidetes and some anaerobic gut microorganisms [49].
They are rapidly absorbed by epithelial cells either by passive diffusion or active transport through G protein-coupled receptors such as GPR41, GPR43, and GPR109A [50]. SCFAs, particularly butyric acid, and butyrate, are known to be fundamental for the maintenance of the intestinal barrier because of their capability to promote the expression of mucins, antimicrobial peptides, and tight junction proteins [41,45,51,52]. SCFAs have also been demonstrated to possess anti-inflammatory effects. In particular, through the binding to GPR43, butyrate induces the production of anti-inflammatory cytokines such as TGFβ and IL-10 as well as the upregulation of FoxP3, the master transcription factor of regulatory T cells (Tregs) [50]. Butyrate also inhibits histone deacetylase activity and downregulates the nuclear factor-κβ, one of the main mediators of the inflammatory response [50]. Furthermore, the combination of propionate and butyrate inhibits lipopolysaccharide (LPS)-induced inflammation by activating Tregs and reducing the production of inflammatory cytokines such as IL-6 and IL-12 [53].
Preclinical evidence also suggests that gut microbiota and its metabolites are involved in modulating behavior and brain processes, including stress responsiveness, emotional behavior, and pain modulation [54]. Gut microbiota has been reported to be able to synthesize a range of neurotransmitters and neurotrophic factors, such as dopamine, noradrenaline, serotonin, gamma amino butyric acid (GABA), acetylcholine, and histamine, that can affect the central nervous and peripheral enteric systems [40,55]. Signaling from enteric microbiota to the brain is mediated through epithelial cells, receptor-mediated signaling, and direct stimulation of the lamina propria cells [4]. On the other hand, the brain acts on enteric microbiota via changes in gastrointestinal motility, permeability, and release of signaling molecules in the gut lumen.
This connection, known as the gut-brain axis, is extremely important to maintain gastrointestinal homeostasis. The gut-brain axis is also involved in regulating neuronal, endocrine, and immune pathways [38,40,56]. Therefore, a stable microbiota is critical for the maintenance of normal gut physiology and proper transmission along the gut-brain axis. On the contrary, dysbiosis, i.e., the imbalance within gut microbial populations, negatively affects gut homeostasis and might cause an inappropriate activity of the gut-brain axis [43,57], as well as an impairment of central processing of sensory inputs [57,58]. Numerous risk factors have been proposed to be associated with the onset of gut dysbiosis: exposure to antibiotics and xenobiotics, such as heavy metals and pesticides, obesity, high-fat and high-sugar diets, host genetics, age, and mode of birth [40,51]. Dysbiosis has been associated with the pathogenesis of many inflammatory diseases [17,25,51]. Moreover, alterations in the composition of the gut microbiota have been recently reported in FM [59,60].
Therefore, dysbiosis might represent an unfavorable condition contributing to FM development. Together with dysbiosis, SIBO (small intestinal bacterial overgrowth) represents another type of qualitative and quantitative alteration of the gut microbiota that influences gut-brain axis communication [61]. In normal conditions, Gram-positive bacteria with 103 organisms/mL mainly colonize the upper tract of the small intestine. On the contrary, during SIBO, the bacterial colonies increase to exceed 105–106 organisms/mL [62]. The human host controls the growth of enteric bacterial populations through several mechanisms. Indeed, gastric acids eradicate microorganisms, peristalsis sweeps the bacteria into the colon and their access is prevented thanks to the tight junctions between epithelial cells.
Moreover, many antimicrobial products contribute to restraining bacterial overgrowth [63,64]. An impairment in one or more of those homeostatic defence mechanisms as well as certain anatomic abnormalities predisposes to SIBO development. Generally, patients with SIBO present nonspecific symptoms, such as bloating, abdominal distension, pain or discomfort, diarrhea, fatigue, anxiety/depression, and weakness [4]. Indeed, a similarity in symptoms between FM and SIBO has been observed, suggesting a possible role of SIBO in FM [65,66].
3. Microbiota Composition in FM Patients: Similarities and Differences with IBS
As previously mentioned, alterations in gut microbiota may affect the gut-brain axis [43,67]. Therefore, it is likely that dysbiosis might play a role in FM pathogenesis by altering the perception and processing of painful stimuli [2,68]. Accordingly, analysis of gut microbiota in FM patients showed an altered composition [59,60].
Specifically, bacteria species belonging to the families of Lachnospiraceae and Ruminococcaceae as well as to Eubacterium and Bifidobacterium genera showed a lower abundance within the gut microbiota of FM patients, while Rikenellaceae family and many species belonging to the Clostridia class were overrepresented [59,60]. Many of the species whose abundance is altered in FM patients are involved in SCFA metabolism. Indeed, Lachnospiraceae are involved in the synthesis of butyric acid, while Eubacterium species and Faecalibacterium prausnitzii, belonging to Ruminoccaceae, produce butyrate [53]. Thus, their depletion would suggest an impaired production of SCFAs, which in turn would negatively affect gut permeability. Since the major part of gut bacteria is Gram-negative-species shedding LPS, a leaky gut barrier may cause its systemic release. In the periphery, LPS can enhance pain perception either by directly interacting with peripheral neurons or by causing the broad activation of the immune system, which in turn secretes inflammatory mediators sensitizing nociceptor neurons [69].
Moreover, SCFAs modulate the permeability of the blood–brain barrier by contributing to the correct organization of the tight junctions [70]. Therefore, in case of SCFA depletion, LPS could also reach the central nervous system (CNS) and act at the central level. Last but not least, SCFAs exert anti-inflammatory activity by reducing leukocytes' chemotaxis, adhesion, and secretion of pro-inflammatory factors, thus counteracting the effects of LPS [71]. However, these beneficial effects are dose-dependent, since high concentrations of butyrate have been shown to promote apoptosis of intestinal cells, thus disrupting the intestinal barrier [72].
In FM patients, several SCFAs-producing bacteria of the Clostridia class are expanded [60]. In line with this observation, the concentration of butyric acid was increased in the serum and urine of these subjects [60,68] supporting the hypothesis of a dysregulated SCFA production in FM patients rather than a deficiency. On the other hand, bacteria from the Bifidobacterium genus participate in neurotransmitter metabolism by synthesizing GABA from glutamate [73]. GABA is the most important inhibitory neurotransmitter within the CNS and acts by inducing neuron hyperpolarization and increasing the excitability threshold, thus counteracting pain perception and transmission by nociceptive neurons. Conversely, glutamate acts oppositely and thus represents the major excitatory neurotransmitter involved in pain sensitization [74].
As a consequence, a reduced presence of bacteria able to produce GABA, such as Bifidobacterium, would alter the GABA/glutamate balance in favor of the latter. Accordingly, peripheral levels of glutamate were found to be increased in FM patients [59]. Overall, this evidence suggests that the enhanced and diffused pain sensitivity observed in FM patients could involve a reduced capability of gut microbiota to produce GABA that, together with an increased permeability of the intestinal barrier, would in turn cause systemic accumulation of glutamate and widespread excitation of nociceptor neurons. Bacterial species belonging to the Clostridia class were also associated with disease severity symptoms, including widespread pain index, pain intensity, fatigue, and sleep alterations [60]. Among Clostridia members, Clostridium cinders have been proposed to enhance pain sensitization because of their role in the production of bile acids. C. scindens is among the few species able to perform 7a-dehydroxylation needed for the conversion from primary to secondary bile acids [75], which has been proposed to participate in nociception [38].
Accordingly, secondary bile acids were found to be significantly altered in the serum from FM patients and to be associated with an increased presence of C. cinders and a generalized modification in the relative presence of bacterial species deputed to bile acid production in the gut. Particularly, a reduction in α-muricholic acid was reported, which is known to be degraded by C. scindens. Moreover, α-muricholic acid serum concentration negatively correlated with FM symptoms, indirectly supporting the possible pathogenetic role of C. cinders and bile acid alterations as a downstream mechanism in FM [76,77]. On the other side, bile acids are toxic for Gram-positive bacteria and induce the expansion of Clostridia, depleting beneficial species at the same time [78].
Thus, through a positive feedback loop, bile acids might further enhance the gut dysbiosis observed in FM. Interestingly, the alterations in gut microbiota composition observed in FM have also been reported in IBS (Table 1). Ruminococcaceae family, including F. prausnitzii, and Bifidobacterium genus are reduced in IBS patients [52,79–81]. F. prausnitzii abundance negatively correlated with symptoms' severity in IBS [82], in line with its role in protecting the intestinal barrier through SCFA production. Interestingly, in a noninflammatory IBS-like rat model, disease symptoms and F. prausnitzii depletion were observed in animals experiencing stressful events in early life [83], strengthening the concept that neurotransmission can modulate gut microbiota composition through the gut-brain axis, which in turn affects the onset of painful stimuli. On the other hand, the bacteria from the Bifidobacterium genus have been shown to exert several protective effects toward gut homeostasis, such as upregulation of tight junction proteins as well as downregulation of inflammatory mediators' production from both intestinal and immune cells [84–86]. Therefore, the depletion of the Bifidobacterium genus might contribute to the onset of intestinal symptoms in both IBS and FM.
However, due to its capacity to lower inflammation at the systemic level [86] and to produce GABA [73], the Bifidobacterium genus might also likely affect CNS. Bifidobacterium genus abundance has been demonstrated to be negatively associated with depression in IBS patients [87,88]. More conflicting evidence has been reported regarding Lachnospiraceae. An enrichment in this bacterial family was specifically observed in IBS patients with diarrhea [89–91].
However, when gut microbiota in IBS patients was characterized regardless of intestinal symptomatology, a general depletion of Lachnospiraceae was reported [92–94].
Possibly, this discrepancy might be due to the enrichment/depletion of specific species within this family, which have not been characterized in detail in these studies. Of notice, low levels of Lachnospiraceae were reported in IBS patients showing anxiety and depression [93,95,96], which are common symptoms in FM [25], suggesting that Lachnospiraceae may be specifically involved in the onset of psychological distress observed in the two diseases.
Although very little data are available about the increased abundance of C. cinders in IBS [97], the role of bile acids in the disease is otherwise well recognized. Increased levels of fecal bile acids have been reported in IBS patients, particularly those with diarrheic symptoms. Indeed, bile acids are involved in several phenomena associated with diarrhea, such as increased intestinal permeability, gut motility, and abdominal pain [98]. Accordingly, C. scindens expansion has been specifically reported in diarrheic IBS patients [99].
In contrast to FM (Table 1), the abundance of the Eubacterium genus in IBS patients has been recently found to be increased in IBS and to correlate with severity symptoms, similar to Lachnospiraceae [89,99]. On the other hand, Rikenellaceae, which are expanded in FM, are usually depleted in IBS [90,91], although some authors correlated their abundance with psychological symptoms [95]. Quantitative alterations within gut microbiota have also been reported in FM. Indeed, the majority of FM patients have been found to test positive for SIBO, as assessed by a lactulose hydrogen breath test [65,66]. SIBO incidence was higher in FM compared to IBS patients and correlated with pain severity [66], while the usage of antibiotics relieved intestinal symptoms in both FM and IBS [65,100].
It has been proposed that the expanded overall bacterial population could cause the massive translocation of bacterial endotoxins through a damaged intestinal barrier, resulting in increased inflammation and hyperalgesia shared by FM and IBS [39]. However, FM patients tended to produce more hydrogen than IBS ones [66], suggesting that, together with general bacterial increase, the expansion of certain species involved in pain sensitization might specifically occur in FM. Overall, this evidence indicates that gut dysbiosis might be a common leading cause for the onset of both FM and IBS. Dysbiosis together with SIBO is involved in the pathogenesis of FM and IBS and similarities in gut microbiota alterations could explain the two diseases' overlapping symptoms.
Natural Herbal Medicine For Relieving Constipation-Cistanche
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