Innov Clin Neurosci. 2025;23(1–3):23–26.
by Takahiko Nagamine, MD, PhD
Dr. Nagamine is with the Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Hofu, Japan.
FUNDING: No funding was provided for this article.
DISCLOSURES: The author has no relevant conflicts of interest.
ABSTRACT: Chronic pain disorders of unknown etiology, including burning mouth syndrome, chronic pelvic pain, fibromyalgia, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular joint disorders, have been demonstrated to result in a substantial reduction in quality of life. These diseases exhibit a discernible gender bias, manifesting with greater frequency in women. The neurobiological underpinnings of these conditions are characterized by a decline in the volume of white matter in the medial prefrontal cortex and alterations in the connectivity of the default mode network. These conditions are frequently linked to impaired function of the central dopaminergic nervous system. The potential mechanisms connecting the gut microbiota to chronic pain disorders may be the decrease in butyrate-producing bacteria in dopamine signaling and the change in estrobolome in estrogen signaling. Consequently, an approach targeting the gut microbiota using probiotics has emerged as a potential treatment for chronic pain disorders. Keywords: Butyrate-producing bacteria, chronic pain disorders, dopamine, dysbiosis, microbiota-gut-brain axis, neuroinflammation, probiotics
Introduction
Chronic pain disorders, including burning mouth syndrome, chronic pelvic pain, fibromyalgia, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular joint disorders, have been demonstrated to result in a substantial reduction in quality of life. The prevalence of chronic pain disorders is higher in women, and the etiology of these conditions is not fully elucidated.1 These conditions are characterized by intractable pain that persists for months or years and include a range of symptoms, including fatigue, sleep disturbances, and mood disorders. Conventional pharmacological interventions, including analgesics, antidepressants, clonazepam, and gabapentin, are employed; however, the efficacy of these therapeutic agents is inherently constrained.1 Since chronic pain disorders are often accompanied by disruptions to the gut microbiota, an approach based on the brain-gut axis may be considered.2 This article aims to delineate the pathophysiology of chronic pain disorders and propose the possibility of approaching the gut microbiota as a novel treatment method.
Central Mechanisms of Chronic Pain Disorders
The unknown etiology of chronic pain disorders highlights the complexity of these conditions. The pathogenesis of these conditions is multifaceted, involving a complex interplay of genetic, environmental, and psychological factors. Noteworthy pathological mechanisms encompass central sensitization and neuroinflammation.3 Central sensitization is defined as an amplification of neural signaling within the central nervous system (CNS) that lowers the threshold for pain perception and increases the response to painful and nonpainful stimuli.3 The underlying mechanism involves the wind-up phenomenon, which occurs when nociceptive input is repeated or intense, leading to changes in the excitability of neurons in the spinal cord and brain. This phenomenon is characterized by an augmented release of excitatory neurotransmitters such as glutamate, activation of N-methyl-D-aspartate receptors, and alterations in their gene expression. Consequently, typically innocuous stimuli (eg, light touch) may be perceived as painful (allodynia), and painful stimuli are experienced with greater intensity (hyperalgesia).4 Neuroinflammation, defined as the activation of glial cells (ie, microglia and astrocytes) and the subsequent release of pro-inflammatory mediators within the spinal cord and brain, has been identified as a significant contributor to central sensitization. Neuroinflammation plays a critical role in the wind-up phenomenon by enhancing neuronal excitability and synaptic transmission in the CNS.5 This process of central sensitization, driven by neuroinflammation, is a key mechanism in the development and maintenance of chronic pain. Abnormal firing of the nervous system during pain transmission, particularly in the context of chronic pain, leads to significant alterations in neuronal communication and the connectivity of large-scale brain circuits. The association between chronic pain and structural changes, such as alterations in gray matter volume, along with widespread alterations in functional connectivity within the brain, has been well documented.6 These alterations extend beyond the conventional pain-processing regions. The involvement of brain regions in the experience of chronic pain has been welldocumented. These regions, which include the amygdala, prefrontal cortex, nucleus accumbens, hippocampus, and other areas, play a crucial role in emotional processing, reward systems, memory, and stress response. A growing body of research has demonstrated that resting-state functional magnetic resonance imaging studies can reveal altered functional connectivity within large-scale brain networks, such as the default mode network (DMN), salience network, and sensorimotor network, in individuals with chronic pain.7 It has been demonstrated that these alterations have the potential to contribute to the cognitive, emotional, and behavioral comorbidities that are frequently observed in cases of chronic pain.
A substantial body of research has demonstrated that individuals with chronic pain disorders exhibit notable alterations in brain circuitry, particularly within the DMN and its connections to regions involved in emotional and sensory processing, including the anterior cingulate cortex, anterior insula cortex, hippocampus, and amygdala.8 The phenomenon of maladaptive neuroplasticity, in which the brain undergoes reorganization to reinforce pain perception, has been observed in individuals afflicted with chronic pain conditions. A notable finding is the observation of reduced gray matter volume in the medial prefrontal cortex (mPFC) in individuals with chronic pain disorders, resulting in altered functional connectivity to the brain‘s pain matrix.9 These results consistently indicate structural and functional changes in the mPFC and its connectivity due to impaired functioning of the basal ganglia dopaminergic system.10 This finding suggests that therapeutic interventions targeting the central dopaminergic nervous system may offer a promising avenue for addressing chronic pain disorders.
Gut Mechanisms of Chronic Pain Disorders
Recent studies have highlighted the pivotal role of the microbiota-gut-brain axis in the context of chronic pain disorders.11 Individuals with chronic pain disorders frequently have dysbiosis, an imbalance in the gut microbiota.12 This condition is typified by a decline in the diversity and stability of beneficial bacteria within the gastrointestinal microbiota. Gut dysbiosis has been demonstrated to result in increased intestinal permeability, otherwise referred to as “leaky gut.” This condition allows bacterial byproducts, such as lipopolysaccharide, to penetrate the bloodstream, thereby inducing systemic inflammation. This inflammation has the potential to affect the nervous system, thereby promoting central sensitization. In addition, the gut microbiota has been demonstrated to generate or regulate the synthesis of neurotransmitters, including serotonin and γ-aminobutyric acid.13 Dysbiosis has been demonstrated to disrupt these pathways, resulting in imbalances in neurotransmitter levels. Consequently, there is a possibility of altered pain perception, mood disorders, and sleep disturbances. Observational studies have identified numerous correlations between sequence-based gut microbiota data and chronic pain disorders. The gut microbiota has the capacity to influence pain in several ways, including the production of inflammatory molecules, modulation of the immune system, synthesis of neurotransmitters, and disruption of the integrity of the gut barrier. However, the findings are often inconsistent across studies, and no specific gut bacteria or neurotransmitters have been identified that influence chronic pain disorders.14 The composition of the gut microbiota is notably diverse, comprising trillions of bacteria from a multitude of species. This composition demonstrates notable interindividual variability, attributable to factors such as dietary intake, genetic predispositions, and environmental influences. While there is a correlation between certain bacterial imbalances (ie, dysbiosis) and chronic pain disorders, identifying specific bacteria as the sole cause of these conditions is challenging.
Regulation of Dopaminergic Neurons by Gut Microbiota
The presence of impaired dopamine function in individuals with chronic pain has been associated with alterations in the composition of the gut microbiota. A recent meta-analysis of the gut microbiota in individuals with chronic pain disorders revealed a decrease in alpha diversity and altered microbiota patterns, indicating a reduction in the relative abundance of the Lachnospiraceae family, the genera Faecalibacterium and Roseburia, and species of Faecalibacterium prausnitzii and Odoribacter splanchnicus, along with an increase in Eggerthella spp. in individuals with chronic pain disorders compared to controls.15 The observed decrease in alpha diversity and the relative decline of certain genera, with the exception of Eggerthella spp., are associated with a decrease in butyrate-producing bacteria.16,17 There is mounting evidence that butyrate-producing bacteria play a critical role in maintaining healthy dopaminergic function in the brain, exerting influence on both dopamine production and dopamine transporter (DAT) expression.18 The presence of butyrate-producing bacteria within the gastrointestinal tract has been demonstrated to exert a significant influence on dopamine production and metabolism. This influence can occur through various pathways, including the reduction of inflammation, the direct impact on neurotransmitter synthesis, and the modulation of DAT expression.18 DAT plays a pivotal role in regulating dopamine signaling by modulating its reuptake from the synaptic cleft. Butyrate has been demonstrated to modulate DAT expression through epigenetic mechanisms, including deoxyribonucleic acid methylation and histone acetylation, thereby influencing the duration and intensity of dopamine signaling.19,20 In addition, a relative increase in Eggerthella spp. has been demonstrated to promote dopamine metabolism and induce a decrease in central dopamine function.21 Eggerthella lenta has been demonstrated to catalyze the hydroxylation of dopamine. This bacterium has been demonstrated to catalyze the degradation of dopamine to m-tyramine through the action of a molybdenum-dependent dehydrogenase.22 Consequently, modifying the gut microbiota has the potential to enhance central dopamine activity.
Estrobolome
The prevalence of chronic pain disorders is high among menopausal women.23 Estrogen exerts a significant influence on synaptic plasticity, the brain‘s capacity to reorganize itself by establishing new neural connections, a process that is imperative for the optimal functioning of brain networks. Alterations in the composition of the gut microbiota have been demonstrated to exert an influence on estrogen levels, a factor that is imperative in the development and severity of chronic pain conditions. The estrobolome, defined as the collection of gut microbial genes that encodes enzymes capable of metabolizing estrogens, is a critical factor in this regulatory process.24 The estrobolome‘s activity exerts a direct influence on circulating estrogen levels, which can have significant effects on chronic pain conditions, especially in women. The enzyme β-glucuronidase plays a pivotal role in this process. The impact of bacteria that produce this enzyme on estrogen‘s recirculation in the body is significant, including Bacteroides spp., Clostridium spp., and Ruminococcus spp.25 The Eggerthella genus, the sole species to demonstrate a relative increase in gut bacteria in individuals with chronic pain,12 may also play a role in the regulation of female hormones.26 However, given the inherent complexity of the estrobolome, identifying specific species with singular actions is challenging.
The Potential of Probiotics
The presence of chronic pain conditions has been associated with dysbiosis. This imbalance has the potential to induce heightened inflammation and modify the signaling of dopamine and estrogen through the microbiota-gut-brain axis. The influence of the gut microbiome on brain function, including the perception and processing of pain, is a growing area of research. The restoration of a healthy gut microbiome through the introduction of beneficial bacteria, as facilitated by probiotics, holds promise in addressing these imbalances. This restoration has the potential to modulate the microbiota-gut-brain axis, thereby reducing inflammation and altering pain signals. The extant literature suggests potential benefits of probiotics for certain chronic pain conditions, including musculoskeletal pain,27 irritable bowel syndrome,20 fibromyalgia,28 and endometriosis.29 Basic research has demonstrated that probiotics containing butyrate-producing bacteria generate 16 metabolites, including theanine, carnosine, and 3-hydroxybutyrate, and stimulate adult neurogenesis in human-derived neural stem cells, which may contribute to the regeneration of decreased dopamine neurons.30 Consequently, the strategic targeting of the gastrointestinal tract with probiotics emerges as a promising therapeutic approach for addressing chronic pain. However, it is important to acknowledge that individual responses to probiotics can vary considerably. Further studies are needed to investigate specific probiotic strains, dosages, and duration of treatment, including potential markers of dopamine and estrogen metabolism.
Conclusion
In the context of chronic pain disorders, there is a decrease in dopamine signaling due to a decrease in butyrate-producing bacteria and a decrease in estrogen signaling due to changes in the estrobolome. In light of the limited efficacy of pharmaceutical interventions, there is a growing imperative to investigate the potential of probiotic treatments as adjunctive modalities to address dysbiosis.
References
- Garofalo C, Cristiani CM, Ilari S, et al. Fibromyalgia and irritable bowel syndrome interaction: a possible role for gut microbiota and gut-brain axis. Biomedicines. 2023;11(6):1701.
- Ustianowska K, Ustianowski Ł, Machaj F, et al. The role of the human microbiome in the pathogenesis of pain. Int J Mol Sci. 2022;23(21):13267.
- Ji RR, Nackley A, Huh Y, et al. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129(2):343–366.
- Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.
- Vergne-Salle P, Bertin P. Chronic pain and neuroinflammation. Joint Bone Spine. 2021;88(6):105222.
- Liu Q, Liao Z, Zhang Y, et al. Pain- and fatigue-related functional and structural changes in ankylosing spondylitis: an fRMI Study. Front Med (Lausanne). 2020;7:193.
- Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci. 2008;28(6):1398–1403.
- Alshelh Z, Marciszewski KK, Akhter R, et al. Disruption of default mode network dynamics in acute and chronic pain states. Neuroimage Clin. 2017;17:222–231.
- Serafini RA, Pryce KD, Zachariou V. The mesolimbic dopamine system in chronic pain and associated affective comorbidities. Biol Psychiatry. 2020;87(1):64–73.
- Kummer KK, Mitrić M, Kalpachidou T, Kress M. The medial prefrontal cortex as a central hub for mental comorbidities associated with chronic pain. Int J Mol Sci. 2020;21(10):3440.
- Garvey M. The association between dysbiosis and neurological conditions often manifesting with chronic pain. Biomedicines. 2023;11(3):748.
- Goudman L, Demuyser T, Pilitsis JG, et al. Gut dysbiosis in patients with chronic pain: a systematic review and meta-analysis. Front Immunol. 2024;15:1342833.
- Ojeda J, Ávila A, Vidal PM. Gut microbiota interaction with the central nervous system throughout life. J Clin Med. 2021;10(6):1299.
- Roche KE, Bjork JR, Dasari MR, et al. Universal gut microbial relationships in the gut microbiome of wild baboons. Elife. 2023;12:e83152.
- Goudman L, Demuyser T, Pilitsis JG, et al. Gut dysbiosis in patients with chronic pain: a systematic review and meta-analysis. Front Immunol. 2024;15:1342833.
- Shi Z, Li M, Zhang C, et al. Butyrate-producing Faecalibacterium prausnitzii suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway. Gut. 2025;74(4):
557–570.
- Ho T, Elma Ö, Kocanda L, et al. The brain-gut axis and chronic pain: mechanisms and therapeutic opportunities. Front Neurosci. 2025;19:1545997.
- Hamamah S, Aghazarian A, Nazaryan A, et al. Role of microbiota-gut-brain axis in regulating dopaminergic signaling. Biomedicines. 2022;10(2):436.
- Green AL, Hossain MM, Tee SC, et al. Epigenetic regulation of dopamine transporter mRNA expression in human neuroblastoma cells. Neurochem Res. 2015;40(7):1372–1378.
- Nagamine T. The role of the gut microbiota in individuals with irritable bowel syndrome: a scoping review. Medicina (Kaunas). 2024;60(11):1895.
- Nagamine T. Commentary: gut dysbiosis in patients with chronic pain: a systematic review and meta-analysis. Front Immunol. 2024;15:1445334.
- Maini Rekdal V, Bess EN, Bisanz JE, et al. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science. 2019;364(6445):eaau6323.
- Pavlović JM, Derby CA. Pain in midlife women: a growing problem in need of further research. Womens Midlife Health. 2022;8(1):4.
- Salliss ME, Farland LV, Mahnert ND, Herbst-Kralovetz MM. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Hum Reprod Update. 2021;28(1):
92–131.
- Ervin SM, Li H, Lim L, et al. Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens. J Biol Chem. 2019;294(49):18586–18599.
- Yokoyama S, Oshima K, Nomura I, et al. Complete genomic sequence of the equol-producing bacterium Eggerthella sp. strain YY7918, isolated from adult human intestine. J Bacteriol. 2011;193(19):5570–5571.
- Li R, Boer CG, Oei L, Medina-Gomez C. The gut microbiome: a new frontier in musculoskeletal research. Curr Osteoporos Rep. 2021;19(3):347–357.
- Roman P, Estévez AF, Miras A, et al. A pilot randomized controlled trial to explore cognitive and emotional effects of probiotics in fibromyalgia. Sci Rep. 2018;8(1):10965.
- Chadchan SB, Popli P, Ambati CR, et al. Gut microbiota-derived short-chain fatty acids protect against the progression of endometriosis. Life Sci Alliance. 2021;4(12):e202101224.
- Namihira M, Inoue N, Watanabe Y, et al. Combination of 3 probiotics restores attenuated adult neurogenesis in germ-free mice. Stem Cells. 2025;43(2):sxae077.
Gut Microbiota as a Therapeutic Target for Chronic Pain Disorders
Innov Clin Neurosci. 2025;23(1–3):23–26.
by Takahiko Nagamine, MD, PhD
Dr. Nagamine is with the Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Hofu, Japan.
FUNDING: No funding was provided for this article.
DISCLOSURES: The author has no relevant conflicts of interest.
ABSTRACT: Chronic pain disorders of unknown etiology, including burning mouth syndrome, chronic pelvic pain, fibromyalgia, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular joint disorders, have been demonstrated to result in a substantial reduction in quality of life. These diseases exhibit a discernible gender bias, manifesting with greater frequency in women. The neurobiological underpinnings of these conditions are characterized by a decline in the volume of white matter in the medial prefrontal cortex and alterations in the connectivity of the default mode network. These conditions are frequently linked to impaired function of the central dopaminergic nervous system. The potential mechanisms connecting the gut microbiota to chronic pain disorders may be the decrease in butyrate-producing bacteria in dopamine signaling and the change in estrobolome in estrogen signaling. Consequently, an approach targeting the gut microbiota using probiotics has emerged as a potential treatment for chronic pain disorders. Keywords: Butyrate-producing bacteria, chronic pain disorders, dopamine, dysbiosis, microbiota-gut-brain axis, neuroinflammation, probiotics
Introduction
Chronic pain disorders, including burning mouth syndrome, chronic pelvic pain, fibromyalgia, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular joint disorders, have been demonstrated to result in a substantial reduction in quality of life. The prevalence of chronic pain disorders is higher in women, and the etiology of these conditions is not fully elucidated.1 These conditions are characterized by intractable pain that persists for months or years and include a range of symptoms, including fatigue, sleep disturbances, and mood disorders. Conventional pharmacological interventions, including analgesics, antidepressants, clonazepam, and gabapentin, are employed; however, the efficacy of these therapeutic agents is inherently constrained.1 Since chronic pain disorders are often accompanied by disruptions to the gut microbiota, an approach based on the brain-gut axis may be considered.2 This article aims to delineate the pathophysiology of chronic pain disorders and propose the possibility of approaching the gut microbiota as a novel treatment method.
Central Mechanisms of Chronic Pain Disorders
The unknown etiology of chronic pain disorders highlights the complexity of these conditions. The pathogenesis of these conditions is multifaceted, involving a complex interplay of genetic, environmental, and psychological factors. Noteworthy pathological mechanisms encompass central sensitization and neuroinflammation.3 Central sensitization is defined as an amplification of neural signaling within the central nervous system (CNS) that lowers the threshold for pain perception and increases the response to painful and nonpainful stimuli.3 The underlying mechanism involves the wind-up phenomenon, which occurs when nociceptive input is repeated or intense, leading to changes in the excitability of neurons in the spinal cord and brain. This phenomenon is characterized by an augmented release of excitatory neurotransmitters such as glutamate, activation of N-methyl-D-aspartate receptors, and alterations in their gene expression. Consequently, typically innocuous stimuli (eg, light touch) may be perceived as painful (allodynia), and painful stimuli are experienced with greater intensity (hyperalgesia).4 Neuroinflammation, defined as the activation of glial cells (ie, microglia and astrocytes) and the subsequent release of pro-inflammatory mediators within the spinal cord and brain, has been identified as a significant contributor to central sensitization. Neuroinflammation plays a critical role in the wind-up phenomenon by enhancing neuronal excitability and synaptic transmission in the CNS.5 This process of central sensitization, driven by neuroinflammation, is a key mechanism in the development and maintenance of chronic pain. Abnormal firing of the nervous system during pain transmission, particularly in the context of chronic pain, leads to significant alterations in neuronal communication and the connectivity of large-scale brain circuits. The association between chronic pain and structural changes, such as alterations in gray matter volume, along with widespread alterations in functional connectivity within the brain, has been well documented.6 These alterations extend beyond the conventional pain-processing regions. The involvement of brain regions in the experience of chronic pain has been welldocumented. These regions, which include the amygdala, prefrontal cortex, nucleus accumbens, hippocampus, and other areas, play a crucial role in emotional processing, reward systems, memory, and stress response. A growing body of research has demonstrated that resting-state functional magnetic resonance imaging studies can reveal altered functional connectivity within large-scale brain networks, such as the default mode network (DMN), salience network, and sensorimotor network, in individuals with chronic pain.7 It has been demonstrated that these alterations have the potential to contribute to the cognitive, emotional, and behavioral comorbidities that are frequently observed in cases of chronic pain.
A substantial body of research has demonstrated that individuals with chronic pain disorders exhibit notable alterations in brain circuitry, particularly within the DMN and its connections to regions involved in emotional and sensory processing, including the anterior cingulate cortex, anterior insula cortex, hippocampus, and amygdala.8 The phenomenon of maladaptive neuroplasticity, in which the brain undergoes reorganization to reinforce pain perception, has been observed in individuals afflicted with chronic pain conditions. A notable finding is the observation of reduced gray matter volume in the medial prefrontal cortex (mPFC) in individuals with chronic pain disorders, resulting in altered functional connectivity to the brain‘s pain matrix.9 These results consistently indicate structural and functional changes in the mPFC and its connectivity due to impaired functioning of the basal ganglia dopaminergic system.10 This finding suggests that therapeutic interventions targeting the central dopaminergic nervous system may offer a promising avenue for addressing chronic pain disorders.
Gut Mechanisms of Chronic Pain Disorders
Recent studies have highlighted the pivotal role of the microbiota-gut-brain axis in the context of chronic pain disorders.11 Individuals with chronic pain disorders frequently have dysbiosis, an imbalance in the gut microbiota.12 This condition is typified by a decline in the diversity and stability of beneficial bacteria within the gastrointestinal microbiota. Gut dysbiosis has been demonstrated to result in increased intestinal permeability, otherwise referred to as “leaky gut.” This condition allows bacterial byproducts, such as lipopolysaccharide, to penetrate the bloodstream, thereby inducing systemic inflammation. This inflammation has the potential to affect the nervous system, thereby promoting central sensitization. In addition, the gut microbiota has been demonstrated to generate or regulate the synthesis of neurotransmitters, including serotonin and γ-aminobutyric acid.13 Dysbiosis has been demonstrated to disrupt these pathways, resulting in imbalances in neurotransmitter levels. Consequently, there is a possibility of altered pain perception, mood disorders, and sleep disturbances. Observational studies have identified numerous correlations between sequence-based gut microbiota data and chronic pain disorders. The gut microbiota has the capacity to influence pain in several ways, including the production of inflammatory molecules, modulation of the immune system, synthesis of neurotransmitters, and disruption of the integrity of the gut barrier. However, the findings are often inconsistent across studies, and no specific gut bacteria or neurotransmitters have been identified that influence chronic pain disorders.14 The composition of the gut microbiota is notably diverse, comprising trillions of bacteria from a multitude of species. This composition demonstrates notable interindividual variability, attributable to factors such as dietary intake, genetic predispositions, and environmental influences. While there is a correlation between certain bacterial imbalances (ie, dysbiosis) and chronic pain disorders, identifying specific bacteria as the sole cause of these conditions is challenging.
Regulation of Dopaminergic Neurons by Gut Microbiota
The presence of impaired dopamine function in individuals with chronic pain has been associated with alterations in the composition of the gut microbiota. A recent meta-analysis of the gut microbiota in individuals with chronic pain disorders revealed a decrease in alpha diversity and altered microbiota patterns, indicating a reduction in the relative abundance of the Lachnospiraceae family, the genera Faecalibacterium and Roseburia, and species of Faecalibacterium prausnitzii and Odoribacter splanchnicus, along with an increase in Eggerthella spp. in individuals with chronic pain disorders compared to controls.15 The observed decrease in alpha diversity and the relative decline of certain genera, with the exception of Eggerthella spp., are associated with a decrease in butyrate-producing bacteria.16,17 There is mounting evidence that butyrate-producing bacteria play a critical role in maintaining healthy dopaminergic function in the brain, exerting influence on both dopamine production and dopamine transporter (DAT) expression.18 The presence of butyrate-producing bacteria within the gastrointestinal tract has been demonstrated to exert a significant influence on dopamine production and metabolism. This influence can occur through various pathways, including the reduction of inflammation, the direct impact on neurotransmitter synthesis, and the modulation of DAT expression.18 DAT plays a pivotal role in regulating dopamine signaling by modulating its reuptake from the synaptic cleft. Butyrate has been demonstrated to modulate DAT expression through epigenetic mechanisms, including deoxyribonucleic acid methylation and histone acetylation, thereby influencing the duration and intensity of dopamine signaling.19,20 In addition, a relative increase in Eggerthella spp. has been demonstrated to promote dopamine metabolism and induce a decrease in central dopamine function.21 Eggerthella lenta has been demonstrated to catalyze the hydroxylation of dopamine. This bacterium has been demonstrated to catalyze the degradation of dopamine to m-tyramine through the action of a molybdenum-dependent dehydrogenase.22 Consequently, modifying the gut microbiota has the potential to enhance central dopamine activity.
Estrobolome
The prevalence of chronic pain disorders is high among menopausal women.23 Estrogen exerts a significant influence on synaptic plasticity, the brain‘s capacity to reorganize itself by establishing new neural connections, a process that is imperative for the optimal functioning of brain networks. Alterations in the composition of the gut microbiota have been demonstrated to exert an influence on estrogen levels, a factor that is imperative in the development and severity of chronic pain conditions. The estrobolome, defined as the collection of gut microbial genes that encodes enzymes capable of metabolizing estrogens, is a critical factor in this regulatory process.24 The estrobolome‘s activity exerts a direct influence on circulating estrogen levels, which can have significant effects on chronic pain conditions, especially in women. The enzyme β-glucuronidase plays a pivotal role in this process. The impact of bacteria that produce this enzyme on estrogen‘s recirculation in the body is significant, including Bacteroides spp., Clostridium spp., and Ruminococcus spp.25 The Eggerthella genus, the sole species to demonstrate a relative increase in gut bacteria in individuals with chronic pain,12 may also play a role in the regulation of female hormones.26 However, given the inherent complexity of the estrobolome, identifying specific species with singular actions is challenging.
The Potential of Probiotics
The presence of chronic pain conditions has been associated with dysbiosis. This imbalance has the potential to induce heightened inflammation and modify the signaling of dopamine and estrogen through the microbiota-gut-brain axis. The influence of the gut microbiome on brain function, including the perception and processing of pain, is a growing area of research. The restoration of a healthy gut microbiome through the introduction of beneficial bacteria, as facilitated by probiotics, holds promise in addressing these imbalances. This restoration has the potential to modulate the microbiota-gut-brain axis, thereby reducing inflammation and altering pain signals. The extant literature suggests potential benefits of probiotics for certain chronic pain conditions, including musculoskeletal pain,27 irritable bowel syndrome,20 fibromyalgia,28 and endometriosis.29 Basic research has demonstrated that probiotics containing butyrate-producing bacteria generate 16 metabolites, including theanine, carnosine, and 3-hydroxybutyrate, and stimulate adult neurogenesis in human-derived neural stem cells, which may contribute to the regeneration of decreased dopamine neurons.30 Consequently, the strategic targeting of the gastrointestinal tract with probiotics emerges as a promising therapeutic approach for addressing chronic pain. However, it is important to acknowledge that individual responses to probiotics can vary considerably. Further studies are needed to investigate specific probiotic strains, dosages, and duration of treatment, including potential markers of dopamine and estrogen metabolism.
Conclusion
In the context of chronic pain disorders, there is a decrease in dopamine signaling due to a decrease in butyrate-producing bacteria and a decrease in estrogen signaling due to changes in the estrobolome. In light of the limited efficacy of pharmaceutical interventions, there is a growing imperative to investigate the potential of probiotic treatments as adjunctive modalities to address dysbiosis.
References
557–570.
92–131.
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