Fibromyalgia And Irritable Bowel Syndrome Interaction: A Possible Role For Gut Microbiota And Gut-Brain AxisⅡ

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, andCyanobacteria, with Bacteroidetes and Firmicutes representing more than 90% of the totalbacteria [42]. The ratio between Firmicutes and Bacteroidetes is considered an importantparameter to take into account for the treatment of intestinal disorders [43]. The Bacteroidetesphylum includes Bacteroides and Prevotella genera, Firmicutes phylum includes Clostridium,Eubacterium, and Ruminococcus genera [44]. 

Still, the relative richness of bacterial phyla mayvary significantly among individuals [44]. The relationship between the human host and gutmicrobiota is both commensal and mutualistic: while the host provides an ecological nichefor 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 generatesa stable system that prevents the invasion of pathogenic microorganisms. In addition, gutmicrobes synthesize several classes of nutrients such as branched-chain amino acids, amines,phenols, indoles, phenylacetic acid, and vitamins [41,45–47]. Particularly, Bacteroides areinvolved in the synthesis of biotin, riboflavin, pantothenate, and ascorbate, while Prevotella isinvolved in thiamine and folate synthesis [44]. 

Gut microbiota contributes to the synthesisof 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 thelength of intestinal villi and microvilli.Gut microbiota is considered the principal mediator of the metabolism of indigestiblecarbohydrates, 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 absorbedby epithelial cells either by passive diffusion or active transport through G protein-coupledreceptors such as GPR41, GPR43, and GPR109A [50]. SCFAs, particularly butyric acid, andbutyrate, are known to be fundamental for the maintenance of the intestinal barrier becauseof their capability to promote the expression of mucins, antimicrobial peptides, and tightjunction 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-inflammatorycytokines such as TGF and IL-10 as well as the upregulation of FoxP3, the master transcription factor of regulatory T cells (Tregs) [50]. Butyrate also inhibits histone deacetylaseactivity and downregulates the nuclear factor-κ , one of the main mediators of the inflammatory response [50]. Furthermore, the combination of propionate and butyrateinhibits lipopolysaccharide (LPS)-induced inflammation by activating Tregs and reducingthe production of inflammatory cytokines such as IL-6 and IL-12 [53]. 

Preclinical evidence also suggests that gut microbiota and its metabolites are involvedin modulating behavior and brain processes, including stress responsiveness, emotionalbehavior, and pain modulation [54]. Gut microbiota has been reported to be able tosynthesize a range of neurotransmitters and neurotrophic factors, such as dopamine, noradrenaline, serotonin, gamma amino butyric acid (GABA), acetylcholine, and histamine, thatcan affect the central nervous and peripheral enteric systems [40,55]. Signaling from entericmicrobiota 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 actson enteric microbiota via changes in gastrointestinal motility, permeability, and release 

This connection, known as the gut-brain axis, isextremely important to maintain gastrointestinal homeostasis.The gut-brain axis is also involved in regulating neuronal, endocrine, and immunepathways [38,40,56]. Therefore, a stable microbiota is critical for the maintenance of normalgut physiology and proper transmission along the gut-brain axis. On the contrary,dysbiosis, i.e., the imbalance within gut microbial populations, negatively affects guthomeostasis and might cause an inappropriate activity of the gut-brain axis [43,57], as wellas an impairment of central processing of sensory inputs [57,58]. Numerous risk factorshave been proposed to be associated with the onset of gut dysbiosis: exposure to antibioticsand 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 havebeen recently reported in FM [59,60]. 

Therefore, dysbiosis might represent an unfavorablecondition 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 influencesgut-brain axis communication [61]. In normal conditions, Gram-positive bacteria with103 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]. Thehuman host controls the growth of enteric bacterial populations through several mechanisms. Indeed, gastric acids eradicate microorganisms, peristalsis sweeps the bacteriainto the colon and their access is prevented thanks to the tight junctions between epithelialcells. 

Moreover, many antimicrobial products contribute to restraining bacterial overgrowth [63,64]. An impairment in one or more of those homeostatic defence mechanismsas 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, asimilarity in symptoms between FM and SIBO has been observed, suggesting a possiblerole 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-brainaxis [43,67]. Therefore, it is likely that dysbiosis might play a role in FM pathogenesisby altering the perception and processing of painful stimuli [2,68]. Accordingly, analysis ofgut microbiota in FM patients showed an altered composition [59,60]. 

Specifically, bacteriaspecies belonging to the families of Lachnospiraceae and Ruminococcaceae as well as to Eubacterium and Bifidobacterium genera showed a lower abundance within the gut microbiotaof FM patients, while Rikenellaceae family and many species belonging to the Clostridiaclass were overrepresented [59,60]. Many of the species whose abundance is altered inFM patients are involved in SCFA metabolism. Indeed, Lachnospiraceae are involved inthe synthesis of butyric acid, while Eubacterium species and Faecalibacterium prausnitzii,belonging to Ruminoccaceae, produce butyrate [53]. Thus, their depletion would suggestan 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 gutbarrier may cause its systemic release. In the periphery, LPS can enhance pain perceptioneither by directly interacting with peripheral neurons or by causing the broad activation ofthe immune system, which in turn secretes inflammatory mediators sensitizing nociceptorneurons [69]. 

Moreover, SCFAs modulate the permeability of the blood–brain barrier bycontributing to the correct organization of the tight junctions [70]. Therefore, in case ofSCFA depletion, LPS could also reach the central nervous system (CNS) and act at thecentral level. Last but not least, SCFAs exert anti-inflammatory activity by reducingleukocytes' 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 bacteriaof 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 thana deficiency.On the other hand, bacteria from the Bifidobacterium genus participate in neurotransmitter metabolism by synthesizing GABA from glutamate [73]. GABA is the most importantinhibitory neurotransmitter within the CNS and acts by inducing neuron hyperpolarizationand increasing the excitability threshold, thus counteracting pain perception and transmission by nociceptive neurons. Conversely, glutamate acts oppositely and thusrepresents the major excitatory neurotransmitter involved in pain sensitization [74]. 

As aconsequence, a reduced presence of bacteria able to produce GABA, such as Bifidobacterium,would alter the GABA/glutamate balance in favor of the latter. Accordingly, peripherallevels of glutamate were found to be increased in FM patients [59]. Overall, this evidencesuggests that the enhanced and diffused pain sensitivity observed in FM patients couldinvolve a reduced capability of gut microbiota to produce GABA that, together with anincreased permeability of the intestinal barrier, would in turn cause systemic accumulationof 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 enhancepain sensitization because of their role in the production of bile acids. C. scindens is among thefew species able to perform 7a-dehydroxylation needed for the conversion from primaryto 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 fromFM patients and to be associated with an increased presence of C. cinders and a generalizedmodification in the relative presence of bacterial species deputed to bile acid productionin the gut. Particularly, a reduction in -muricholic acid was reported, which is knownto be degraded by C. scindens. Moreover, -muricholic acid serum concentration negatively correlated with FM symptoms, indirectly supporting the possible pathogenetic role ofC. cinders and bile acid alterations as a downstream mechanism in FM [76,77]. On the otherside, 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 havealso been reported in IBS (Table 1). Ruminococcaceae family, including F. prausnitzii, andBifidobacterium genus are reduced in IBS patients [52,79–81]. F. prausnitziiabundance negatively correlated with symptoms' severity in IBS [82], in line with itsrole in protecting the intestinal barrier through SCFA production. Interestingly, in a noninflammatory IBS-like rat model, disease symptoms and F. prausnitzii depletion wereobserved in animals experiencing stressful events in early life [83], strengthening theconcept 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 bacteriafrom the Bifidobacterium genus have been shown to exert several protective effects toward guthomeostasis, such as upregulation of tight junction proteins as well as downregulationof inflammatory mediators' production from both intestinal and immune cells [84–86].Therefore, the depletion of the Bifidobacterium genus might contribute to the onset of intestinalsymptoms in both IBS and FM. 

However, due to its capacity to lower inflammation at the systemiclevel [86] and to produce GABA [73], the Bifidobacterium genus might also likely affect CNS.Bifidobacterium genus abundance has been demonstrated to be negatively associated withdepression in IBS patients [87,88].More conflicting evidence has been reported regarding Lachnospiraceae. An enrichmentin this bacterial family was specifically observed in IBS patients with diarrhea [89–91].

However, when gut microbiota in IBS patients was characterized regardless of intestinalsymptomatology, a general depletion of Lachnospiraceae was reported [92–94]. 

Possibly,this discrepancy might be due to the enrichment/depletion of specific species within thisfamily, which have not been characterized in detail in these studies. Of notice, low levels ofLachnospiraceae were reported in IBS patients showing anxiety and depression [93,95,96],which are common symptoms in FM [25], suggesting that Lachnospiraceae may be specificallyinvolved in the onset of psychological distress observed in the two diseases. 

Although very little data are available about the increased abundance of C. cinders inIBS [97], the role of bile acids in the disease is otherwise well recognized. Increased levelsof fecal bile acids have been reported in IBS patients, particularly those with diarrheicsymptoms. Indeed, bile acids are involved in several phenomena associated with diarrhea, such as increased intestinal permeability, gut motility, and abdominalpain [98]. Accordingly, C. scindens expansion has been specifically reported in diarrheic IBSpatients [99].

In contrast to FM (Table 1), the abundance of the Eubacterium genus in IBS patients has beenrecently found to be increased in IBS and to correlate with severity symptoms, similarto Lachnospiraceae [89,99]. On the other hand, Rikenellaceae, which are expanded in FM, areusually depleted in IBS [90,91], although some authors correlated their abundance withpsychological 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 assessedby a lactulose hydrogen breath test [65,66]. SIBO incidence was higher in FM compared toIBS patients and correlated with pain severity [66], while the usage of antibiotics relievedintestinal symptoms in both FM and IBS [65,100]. 

It has been proposed that the expandedoverall bacterial population could cause the massive translocation of bacterial endotoxinsthrough a damaged intestinal barrier, resulting in increased inflammation and hyperalgesia shared by FM and IBS [39]. However, FM patients tended to produce more hydrogenthan IBS ones [66], suggesting that, together with general bacterial increase, the expansionof certain species involved in pain sensitization might specifically occur in FM.Overall, this evidence indicates that gut dysbiosis might be a common leading cause forthe onset of both FM and IBS. Dysbiosis together with SIBO is involved in the pathogenesisof FM and IBS and similarities in gut microbiota alterations could explain the two diseases'overlapping symptoms.

Natural Herbal Medicine For Relieving Constipation-Cistanche 

Cistanche is a genus of parasitic plants that belongs to the family Orobanchaceae. These plants are known for their medicinal properties and have been used in Traditional Chinese Medicine (TCM) for centuries. Cistanche species are predominantly found in arid and desert regions of China, Mongolia, and other parts of Central Asia. Cistanche plants are characterized by their fleshy, yellowish stems and are highly valued for their potential health benefits. In TCM, Cistanche is believed to have tonic properties and is commonly used to nourish the kidney, enhance vitality, and support sexual function. It is also used to address issues related to aging, fatigue, and overall well-being. While Cistanche has a long history of use in traditional medicine, scientific research on its efficacy and safety is ongoing and limited. However, it is known to contain various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which may contribute to its medicinal effects.

has long been used in Traditional Chinese Medicine as a remedy for constipation. It is believed to have a mild laxative effect, which can help promote bowel movements and induce constipation. This effect may be attributed to various compounds found in Cistanche, such as phenylethanoid glycosides and polysaccharides. Moistening the Intestines: Based on traditional use, Cistanche is considered to have moisturizing properties, specifically targeting the Intestines. Promoting hydration and lubrication of the Intestines may help soften tools and facilitate easier passage, thereby relieving constipation. Anti-inflammatory Effect: Constipation can sometimes be associated with inflammation in the digestive tract. Cistanche contains certain compounds, including phenylethanoid glycosides and lignans, that are believed to have anti-inflammatory properties. Reducing inflammation in the intestines may help improve bowel movement regularity and relieve constipation.