The Microbiome’s Role in Chronic Pain and Inflammation

Abstract

Context

Pain is a universal experience, one that is meant to protect people from further harm or injury, and chronic pain is prominent worldwide. Inflammation plays a central role in chronic pain.

Objective

The review intended to examine the epidemiology of chronic pain, the ways in which inflammation contributes to it, and the microbiome’s role in it, evaluating the function of the oral microbiome and dietary factors.

Results

The inflammatory response plays a pivotal role in the transition from acute to chronic pain, with various mediators orchestrating a cascade of events that perpetuate pain signaling and sensitization. The microbiome interacts directly with the immune system and plays a fundamental role in addressing inflammation and chronic pain. Dysbiosis within the gut and oral microbiota can fuel systemic inflammation, exacerbating pain symptoms and influencing pain perception through the gut-brain axis. Additionally, microbial metabolites can influence immune function, reducing or perpetuating inflammation, which can further affect the experience of pain. Dietary factors also contribute significantly to inflammation and pain, and poor nutritional choices can exacerbate immune responses and trigger low-grade inflammation, perpetuating chronic-pain conditions.

Conclusions

Moving forward, a holistic approach to chronic pain management is imperative, addressing not only the symptoms but also the underlying inflammatory processes and systemic contributors. Embracing interdisciplinary collaboration and personalized treatment tailored to the individual patient’s needs will be essential in alleviating chronic pain and improving overall quality of life. Through continued research and clinical innovation, healthcare practitioners can work towards more effective and compassionate care for those living with chronic pain.

 

Pain is a universal experience, one that is meant to protect people from further harm or injury. It affects everyone differently, but for some people, pain becomes a debilitating experience that disrupts daily life and leads to long-term health consequences.

Why does pain become chronic for some but not for others? The answer is complex and multifaceted. Typically, chronic pain develops following an injury, multiple injuries, or disease. Pain and inflammation resolve over time for most people, with a return to homeostasis and full function. But sometimes pain shifts from a presenting symptom to a diagnosable condition with a distinct medical definition.¹

Basbaum et al describes pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage.² Pain is a subjective experience involving not only nociception but also emotional, cognitive, and social components.³ Researchers classify pain into three broad categories: (1) nociceptive pain, (2) inflammatory pain, and (3) pathological pain.

 

Nociceptive pain

This pain is sharp, stabbing, burning, or throbbing and is an early-warning, protective pain that occurs in response to tissue-damaging, noxiousintense stimuli.

Inflammatory pain

This pain causes tenderness, aching, and soreness and is adaptive and protective, occurring after tissue damage. It discourages physical contact and movement while the injured body part or tissue is healing.

Pathological pain

This pain causes tingling, aching, and feelings of pins and needles and is maladaptive rather than protective. Damage to, or dysfunction of, the nervous system causes it, whereby sensory signals in the central nervous system (CNS) are amplified and a low threshold exists for pain.

Acute and Chronic Pain

Within each category above, pain can be experienced as either acute (Figure 1) or chronic.

Figure 1.

Anatomy of the Pain Pathway⁵

Acute pain is short-term and intense, functioning as an alarm system to protect people from tissue damage and is largely mediated by nociception.⁴ Nociception is the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers called nociceptors.^1,2 Acute pain demands an immediate response, such as activating a withdrawal reflex and triggering experiences of unpleasantness and emotional anguish.⁵

Chronic pain, on the other hand, arises from a single event, but it often can result from a series of events in which multiple factors contribute to the pain’s duration, intensity, and effects—physical, psychological, social, and emotional, similarly to how multiple factors contribute to many other chronic illnesses.

An important clinical risk factor for developing chronic pain is the presence of acute or chronic pain elsewhere in the body. As pain severity and the number of pain sites increase, the likelihood of chronic pain also increases. Painful stimuli can alter brain chemistry, predisposing individuals to develop chronic pain. This can occur within days of exposure to ongoing painful stimuli and can last for up to a year after the pain has resolved. One of the best ways to reduce the likelihood of developing chronic pain is to prevent acute pain from occurring and manage acute pain well when it does occur.

Epidemiology

Chronic pain is prominent worldwide. Mills et al reports that 1.9 billion people experience recurring tension-type headaches, the most common symptom associated with chronic pain.¹ Those researchers indicate that 10%-14% of those who live with chronic pain are estimated to experience moderate-to-severe, disabling symptoms.

In 2021, an estimated 20.9% of U.S. adults—51.6 million people—experienced chronic pain. Of those, 6.9%—17.1 million people—reported experiencing high-impact chronic pain— chronic pain that substantially restricts daily activities, with a higher prevalence among adults who identified as non-Hispanic American Indian or Alaskan native as well as adults who were divorced or separated or who identified as bisexual (Table 1).^1,6,7

Table 1.

Risk Factors for Developing Chronic Pain¹

Risk Factors	Types
Demographic	Advanced age Gender; females report more chronic pain Ethnicity; non-Caucasians report more pain Low socio-economic status Unemployed status Occupational stressors
Lifestyle and Behavior	Smoking Excessive alcohol Sedentary lifestyle Poor nutrition Colder climates/lack of sunshine
Clinical	Pain in multiple locations Comorbid chronic illness/disease, such as cardiovascular disease, cancer, pulmonary disease, and autoimmunity Poor mental health, such as depression, anxiety, posttraumatic stress disorder (PTSD), history of abuse Attitudes and beliefs about pain Obesity Sleep disorders Genetic predisposition; pain tolerance and sensitivity are partially inherited11 Surgical/medical interventions—postoperative pain

Pain and Inflammation

Pain and inflammation go hand-in-hand. Just as chronic inflammation plays a central role in almost all chronic diseases, it’s also evident in chronic pain. Every pain syndrome has an inflammatory profile consisting of the inflammatory mediators that are present in the pain syndrome, and this profile may vary from one person to another or within the same person at different times (Figure 2, Table 2).^2,8

Figure 2.

Peripheral Mediators of Inflammation²

Table 2.

Mediators of Inflammation and Pain²

Mediators	Types
Pro-inflammatory cytokines	Immune cells produce tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) and play a central role in promoting inflammation. Chronic elevation of these cytokines can contribute to persistent inflammation and pain.
Chemokines	They are signaling proteins that regulate the migration and activation of immune cells. They can attract inflammatory cells to tissue injury or inflammation sites, perpetuating the inflammatory response and contributing to pain sensitization.
Prostaglandins	Lipid mediators derive from arachidonic acid metabolism. They play a key role in inflammation and pain by sensitizing pain receptors—nociceptors—and promoting vasodilation and edema. Cyclooxygenase (COX) enzymes catalyze the synthesis of prostaglandins, and nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX activity to reduce inflammation and pain.
Bradykinin	It’s a peptide mediator that increases vascular permeability and sensitizes pain receptors, leading to inflammation and pain. It’s involved in various inflammatory conditions and contributes to the development of chronic pain states.
Substance P	It’s a neuropeptide released by sensory nerve fibers in response to noxious stimuli. It amplifies pain signals by promoting neurogenic inflammation, vasodilation, and the release of other inflammatory mediators.
Nerve Growth Factor (NGF)	It’s a neurotrophic factor that plays a role in the development and maintenance of sensory neurons. Elevated levels of NGF have been associated with chronic pain conditions such as osteoarthritis, neuropathic pain, and inflammatory pain.
Reactive Oxygen Species (ROS)	They are highly reactive molecules that can damage cells and tissues and promote inflammation. Chronic oxidative stress, characterized by an imbalance between ROS production and antioxidant defense mechanisms, can contribute to chronic inflammation and pain.
Neurotransmitters	Glutamate, serotonin, and norepinephrine are involved in pain signaling and modulation. Dysregulation of neurotransmitter systems can contribute to chronic-pain conditions.
Matrix Metalloproteinases (MMP)	They are re enzymes that degrade extracellular-matrix components and regulate tissue remodeling. Dysregulated MMP activity has been implicated in chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
Microglia and Astrocytes	In the central nervous system, microglia and astrocytes are immune cells that play a role in neuroinflammation and pain sensitization. Persistent activation of microglia and astrocytes can contribute to chronic pain conditions, such as neuropathic pain and fibromyalgia.

Inflammation is unavoidable. It’s part of the natural cycle that allows for immune response and healing. However, when inflammation is unchecked or in excess, it can cause detrimental effects leading to localized and systemic injury as well as chronic disease. To help the body withstand the dangers of inflammation, infection, and injury that people face daily, the immune system is primed to recognize danger signals that induce innate and adaptive immune responses. Two such signals include pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern molecules (DAMPs).

DAMPS are endogenous stress proteins or molecules released extracellularly and produced as a result of cell or tissue damage. DAMPs are capable of activating pattern recognition receptors (PRRs) to signal danger upon tissue damage and induce both inflammatory and repair processes. Excessive or persistent signaling mediated by such molecules can fuel a stress-inflammation amplification loop that underlies the pathogenesis of several chronic inflammatory disorders.⁹

Cells within the innate immune system respond to various molecules—known as PAMPS—from different microorganisms. The innate immune system’s PRR-bearing cells and epithelial cells recognize PAMPS and initiate an immune response against those pathogens, which ultimately leads to immunity.¹⁰

Most PAMPs and DAMPs serve as Signal 0s that bind specific receptors to promote autophagy (Figure 3).¹⁰ These receptors include toll-like receptors (TLRs), nucleotidebinding oligomerization domain-like receptors (NOD), and receptors for advanced glycation end-products (RAGE). Autophagy is a cellular recycling and clean-up process by which lysosomes degrade cytoplasmic components, including soluble macromolecules—nucleic acids, proteins, carbohydrates, and lipids—and organelles, such as mitochondria, peroxisomes, and endoplasmic reticulum.¹⁰

Figure 3.

The Roles PAMPs and DAMPs Play in Autophagy and Immunity¹⁰

Chronic inflammation often underpins chronic pain and is a powerful therapeutic target. Identifying and addressing sources of inflammation in the body is an essential part of a comprehensive treatment strategy. Chronic low-grade infections, whether viral, fungal, bacterial, or polymicrobial dysbiosis, are particularly important to assess, because they result in the ongoing production of proinflammatory mediators and the chronic activation of inflammatory pathways throughout the body.

The Microbiome’s Role

The microbiome plays a critical role in chronic inflammation and pain through five main mechanisms: (1) immune regulation, (2) production of microbial metabolites, (3) activation of the gut-brain axis, (4) modulation of neuroinflammation, and (5) regulation of intestinal permeability

Immune regulation

The gut microbiome and the immune system have a tight-knit relationship, shaping one another’s growth, maturation, calibration, and function. An example of this interplay is the creation of secretory immunoglobulin A (sIgA), which acts as a defense to safeguard the intestinal lining against harmful substances—toxins—and invading microbes. SIgA is created in response to bacterial colonization in the gut and involves a specific response tailored to unique microorganisms.¹¹

The constituents of gut microbes can instill a memorylike characteristic in innate immune cells upon their first encounter with PAMPs. This not only initiates proinflammatory responses but also primes and epigenetically alters innate cells to effectively react to future encounters with pathogens.¹²

Dysbiosis, an imbalance in the gut’s microbial composition, can lead to immune dysfunction because an increase occurs in many microbial mediators (Table 3).¹² The failure to control misdirected immune responses ultimately results in chronic inflammation as seen in conditions such as allergies and autoimmune and inflammatory disorders.¹³

Table 3.

Bacterial Components and Inflammation¹²

Microbial Mediators	Where Found	Receptors Activated to Induce Inflammation
Lipopolysaccharides (LPS)	In outer membrane of gram-negative bacteria	Toll-like receptor (TLR-4), which can release tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 (IL-6)
Peptidoglycans	As component of bacterial cell walls, particularly in gram-positive bacteria	Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2)
Lipoteichoic acid (LTA)	As component in cell walls of gram-positive bacteria	Stimulation of production of pro-inflammatory cytokines
Bacterial lipoproteins	As lipid-anchored proteins in cell membranes of gram-negative and gram-positive bacteria	TLR-2
Flagellin	As component of bacterial flagella	TLR-5
Bacterial DNA		TLRs, stimulation of inflammasome complex
Bacterial toxins—exotoxins, endotoxins	As released by bacteria	Direct damage to host cells and tissues

Production of microbial metabolites

Gut microbes produce a wide array of metabolites that can be either beneficial and protective to the host or disruptive and harmful (Table 4).^12,14 Protective metabolites include short-chain fatty acids (SCFAs), bile acids, and neurotransmitters, which can influence immune function, gut-barrier integrity, and pain sensitivity. For example, SCFAs such as butyrate have anti-inflammatory properties and help maintain gut barrier function, while bile acids can activate immune cells and modulate inflammation.¹⁵ Metabolites that are disruptive include lipopolysaccharides (LPS), indole, and quinolinate.

Table 4.

Bacterial Metabolites and Effects^12,15

Metabolites	Beneficial Effects	Detrimental Effects
SCFAs—butyrate, propionate, acetate	Provide anti-inflammatory properties. Protect gut-barrier function. Improve memory and learning. Is neuroprotective.	Propionate can be inflammatory, leading to mitochondrial DNA damage and neurotoxicity.
Bile acids—secondary bile acids	Provide antimicrobial and anti-inflammatory effects. Maintain microbial balance. Support lipid metabolism.	Elevated levels can increase inflammation, cytotoxicity, and gut permeability.
Neurotransmitters—serotonin, dopamine, and gamma (γ)-aminobutyric acid (GABA)	Support mood, sleep, metabolism, and cognition. Protect from neurodegeneration.	Elevated or decreased levels can affect such factors as mood, cognition, and metabolism.
Amino acids and vitamins	Support nutritional needs for producing neurotransmitters and hormones as well as support cellular metabolic pathways.
Trimethylamine N-oxide (TMAO)		TMAO can: Promote atherosclerosis and is associated with many metabolic and cardiovascular diseases Increase cognitive impairment through oxidative stress Disrupt the blood-brain barrier
Indole		Is associated with impaired motor function, depression, and anxiety.
Quinolinate		The metabolite is excitotoxic and neurotoxic and promotes neurodegeneration.
Kynurenine	Is an N-methyl D-aspartate (NMDA) receptor antagonist, which can reduce neurotoxic effects	Elevated levels are linked to cognitive impairments.

Activation of the gut-brain axis

The gut microbiome communicates bidirectionally with the CNS through the gut-brain axis, impacting brain function and behavior. Imbalances and changes in gut-microbiota composition have been linked to mood disorders such as depression and anxiety, which frequently occur together with chronic pain. Stress-induced shifts in the gut microbiome can intensify inflammation and sensitivity to pain by affecting neuroendocrine and immune pathways.¹⁶

Modulation of neuroinflammation

Gut microbes can influence neuroinflammation and pain processing by producing neuroactive molecules such as serotonin, dopamine, and gamma (γ)-aminobutyric acid (GABA), which can modulate neuronal activity and pain-signaling pathways. Alterations in the gut microbiota’s composition have been linked to changes in pain perception and sensitivity in preclinical and clinical studies.¹⁶

Regulation of intestinal permeability

The gut microbiome plays a crucial role in maintaining intestinal-barrier function and preventing the translocation of microbial products and toxins into systemic circulation. Dysbiosis and disruption of the gut barrier can lead to increased intestinal permeability—leaky gut, allowing bacterial products, such as LPS, to move into systemic circulation and activate immune cells, prompting systemic inflammation. Rooks and Garrett have implicated chronic low-grade inflammation, driven by dysbiosis and microbial-derived factors, in a variety of chronic-pain conditions, including fibromyalgia, migraine, and neuropathic pain.¹⁵

The Oral Microbiome

Poor oral health and oral dysbiosis are associated with an increased risk of systemic inflammation.¹⁷ The bacterial level of the oral cavity makes it the second-most heavily colonized part of the human body, next to the gastrointestinal tract.¹⁸ Dental plaque, also known as oral biofilm, is associated with the development of periodontal problems as well as dental caries due to the bacteria contained within the biofilm.¹⁹

Sedghi et al suggest three underlying mechanisms connecting oral dysbiosis to systemic pathology: movement of oral pathogens from the oral cavity into systemic circulation, circulation of microbial toxins, and systemic inflammation caused by immune responses to oral microbes.²⁰ Systemic inflammation can increase the risk for chronic pain; therefore, clinicians should consider an assessment of oral health and oral dysbiosis for every patient presenting with chronic pain.

Diet and Inflammation

Dietary factors can be direct or indirect causes of inflammation and are primarily important in chronic pain conditions. Current research suggests that dietary intake has a direct impact on the immune system, leading to increases in cytokine levels and directly affecting pain. A poor diet can trigger a series of immune responses and activation of glial cells, which results in low-grade inflammation and elicits CNS sensitivity that contributes to chronic pain.²¹

Functional abdominal-pain disorders have been associated with food intolerance and malabsorption.²² Similarly, food sensitivities can activate inflammatory immune responses, which may contribute to chronic pain throughout the body.

Discussion

Chronic pain is a multifaceted, complex phenomenon that significantly impacts the lives of millions worldwide. While pain serves as a vital warning signal to protect people from harm, its transformation into a chronic condition presents a substantial challenge for patients and healthcare providers. The journey from acute injury to chronic pain involves complex interactions between biological, psychological, social, and environmental factors.

The inflammatory response plays a pivotal role in the transition from acute to chronic pain, with various mediators orchestrating a cascade of events that perpetuate pain signaling and sensitization. Identifying and addressing sources of inflammation in the body is a critical component of comprehensive pain-management strategies.

The microbiome interacts directly with the immune system and plays a fundamental role in addressing inflammation and chronic pain. Comprising trillions of microorganisms, the gut microbiota influence numerous bodily functions, including digestion, nutrient absorption, and immune response.

Dysbiosis within the gut and oral microbiota can result in heightened intestinal and gingival permeability, enabling harmful substances to escape into the bloodstream. This can fuel systemic inflammation, exacerbating pain symptoms and influencing pain perception through the gut-brain axis. Additionally, microbial metabolites can influence immune function, reducing or perpetuating inflammation, which can further affect the experience of pain.

Dietary factors also contribute significantly to inflammation and pain. Poor nutritional choices can exacerbate immune responses and trigger low-grade inflammation, perpetuating chronic pain conditions.

Conclusions

Moving forward, a holistic approach to chronic pain management is imperative, addressing not only the symptoms but also the underlying inflammatory processes and systemic contributors. Embracing interdisciplinary collaboration and personalized treatment modalities tailored to an individual patient’s needs will be essential in alleviating chronic pain and improving overall quality of life. Through continued research and clinical innovation, healthcare practitioners can work towards more effective and compassionate care for those living with chronic pain.