Microbiome First Approaches in Pain Prevention and Management

Introduction

The Microbiome First initiative is attempting to elevate awareness of the extent to which the human microbiome along with its majority of human genes affects all aspects of human development, health, disease and wellbeing. Including the microbiome in medicine, public health, prevention, nutrition, wellness, and therapeutics is essential if we are to open a path toward sustainable healthcare [1]. In some cases, the human microbiome may play an adjunct role in prevention and therapy while in many cases [e.g., colonization resistance against infections, prevention of noncommunicable diseases and conditions (NCDs)], it should be the first consideration. This opinion article describes the role of the microbiome in pain.

Human microbiota (including commensals and pathobionts) have a central role in pain because they can: cause pain, ablate pain, be damaged by pain medications, inactivate certain pain medications, predispose for opioid addiction, produce opioid tolerance, and affect the success or failure of opioid withdrawal. Given the fact that the human microbiome is not only a target for pain prevention and management but also affects all aspects of pain management, we can no longer afford to manage pain while excluding the human microbiome. This article introduces types of pain and the factors that produce them. It also illustrates examples of the connections between the microbiome and pain and the opportunities to include the microbiome-based applications in pain prevention and relief.

Pain

Chronic pain is one of the most insidious conditions experienced across populations. According to a CDC report on the topic [2], it is one of the most common reasons for seeking medical care. Additionally, it restricts daily activity and can result in opioid dependence and reduced quality of life. A decade ago, pain was touted as a global health priority [3]. In a 2016 estimate by the CDC, 50 million adult Americans carried the burden of chronic pain [2]. Chronic pain rarely exists in isolation. There are frequent comorbidities that arise and increase the burden for those patients who are already dealing with pain. These additional comorbid conditions include but are not limited to depression, anxiety, sleep disturbances, fatigue/lack of energy, and neurocognitive changes [4]. Chronic pain treatment has led to significant problems with the use and misuse of opioids. The problem is significant enough that alternating therapeutics were recently suggested to avoid loss of productivity, addiction, and even opioid-related death [5-7].

The world of pain involves systems biology processes, sensing threshold, and emotions and can be divided into several categories based on location, cause, mechanism and duration (acute vs. chronic). Of the major categories and in keeping with the Rea et al. [8] and Guo et al. [9] reviews, nociceptive pain is usually the result of tissue injury. It is often further subdivided into visceral (a deep internal organ/tissue pain often as a result of damage) and somatic (pain receptors activated in a particular area such as skin, a particular muscle or skeletal region). Bladder or prostate pain would be an example of visceral pain while joint pain from arthritis would be an example of somatic pain. In contrast, inflammatory pain results from immune responses to infections, vaccinations or chronic noncommunicable diseases and conditions (NCDs) driven by inflammation. Infections and vaccinations most commonly result in inflammatory pain.

Finally, neuropathic pain is a category usually caused by nerve irritation or damage. Diabetic peripheral neuropathy would be an example of neuropathic pain [10]. As with the other examples of pain, microbiota can regulate neuropathic pain affecting both the initiation of pain and the thresholds of pain perception [11,12]. Neuropathic pain is considered among the most serious and challenging forms of pain to manage [13]. As Lin et al. point out [11], the power in gut microbiota as regulators of pain including neuropathic pain is that the microbes sit at intersections of immune, neural, endocrine, and metabolic signaling pathways. That complex network has both direct and indirect ways to affect neuropathic pain. The central position of the gut microbiome in the gut-brain axis makes it a preeminent target for pain management strategies.

The microbiome plays a role in virtually all aspects of pain (including initiation and cessation). Pathobionts are one of the primary causes of immune-inflammatory-related pain. One of the most painful infections is caused by the flesh-eating bacteria, Streptococcus pyogenes. Once it penetrates the barrier (e.g., skin), it can result in necrotizing fasciitis. The bacterium takes control of the body’s pain sensing neurons, and this causes the infection to be more painful than it would be otherwise [14]. Numerous other bacteria can produce quite painful infections in different body locations [15]. For example, as described by Chiu et al. [16], Staphylococcus aureus (Staph A), a gram-positive bacterial pathogen, can cause painful skin infections while Salmonella enterica and Escherichia coli are responsible for painful gastrointestinal and urinary tract infections.

Staph A can also cause pain via pore forming toxins [17]. Gram negative bacteria, which carry lipopolysaccharide (LPS), can cause direct activation of the TRPA1 ion channel on nociceptors resulting in pain and can also cause signaling via Toll-like receptor 4 (TLR-4). Nociceptors also detect bacterial N-formyl peptides [16]. Fungal pathogens (e.g., Candida albicans) can induce calcium flux in nociceptors and viral pathogens also have some TLR routes to affect neurons [16]. Infectious (or septic) arthritis is a joint pain condition. A variety of pathobionts can be involved including the agent of Lyme disease (Borrelia burgdorferi) [18] and Mycoplasma hominis [19].

The airways are also a target for especially painful infectionrelated diseases. Bronchiectasis is a highly painful airway infection that often results in a chronic condition with lung scarring. It is also comorbid with asthma and can exacerbate an already challenging and painful experience for the patient [20]. While a number of pathobionts have been associated with bronchiectasis including some viruses, two bacteria are of particular interest for their association with disease severity: Pseudomonas aeruginosa [21] and Staph A [22], both having the capacity to form biofilms. It is important to recognize that when pathobionts are involved in pain-inflicting conditions that can become chronic, colonization resistance affords a natural and effective protection against pathobionts within the microbiome. For example, there are several combinations of commensal bacteria that work against carriage of Staph A including Staphylococcus epidermidis [23]. Using Microbiome First applications, we should never miss an opportunity to optimize front-line protection against dangerous pathogens [21].

Vaccinations most commonly resulting in pain appear to be those with high ISAR scores. ISARs are inflammation-related solicited adverse reactions including local pain, redness, swelling or induration and systematic fever [24]. High ISAR scores are often indicative of a high immune reaction response to the vaccine [24]. Vaccination induced pain has been associated with autoimmune/ inflammatory syndrome induced by adjuvants (ASIA syndrome). A recent example has been the cases of subacute thyroiditis resulting from the Sinovac Biotech SARS-CoV-2 vaccine [25] as well as from the Oxford-AstraZeneca, United Kingdom vaccine [26]. Examples of pain-associated acute disseminated encephalomyelitis (ADEM) have also resulted from a single dose of the SARS-CoV-2 mRNA vaccine (Moderna COVID-19 Vaccine, Moderna TX, Inc. USA) [27]. Bozkurt et al. [28] reviewed examples of cases of myocarditis with chest pain resulting from both of the mRNA vaccines from Pfizer- BioNTech and Moderna. Salmon et al. [29] detail five examples of vaccines that passed though safety testing; yet when they were administered, they produced inflammatory-autoimmune-pain syndromes. Two of the vaccine examples are the SARS1 Pandemrix vaccine and narcolepsy, and the human papillomavirus vaccine and complex regional pain syndrome.

With noncommunicable diseases it is clear that microbiome dysbiosis is a significant instigator of these diseases and conditions. This is all the more reason to use microbiome management as a pain reducing strategy. Virtually any NCD can have significant immune-inflicted pain associated with it because they are all driven by underlying inflammation. Additionally, most patients with NCD eventually develop additional comorbid NCDs [1]. Hence, a life-course pain reduction plan should include effective microbiome balance. As an example of the pervasiveness of painful NCDs, musculoskeletal NCDs (e.g., hip and knee osteoarthritis, rheumatoid arthritis, back and neck pain, and gout) number more than 150 different conditions [30] and more than 100 autoimmune conditions [31].

The topic of the capacity of the gut microbiome to regulate pain has been the subject of many recent reviews. Table 1 [8,9,11,32- 51] illustrates and summarizes 23 of these review articles that detail a variety of aspects surrounding pain initiation, detection, biochemistry, and management. As captured among these reviews, there has been an explosion of research on this topic over the past five years. The good news is that the complexity of pain and its perception is largely being deconstructed by knowledge of the gut. As a result, factors controlling the microbiome’s bi-directional signaling to the immune system, brain, neurological and endocrine systems are being laid bare and executive pathways determining the initiation and perception of pain are being revealed. Importantly, these review articles also detail the probiotic, prebiotic, and rebiosis strategies that have been used thus far in pain prevention and remediation. Examples are included that focus on pain associated with gastrointestinal issues (ulcerative colitis and irritable bowel), osteoarthritis, probiotics and headaches, post-surgical pain, neurologic and visceral pain, menopausal status, the risk-benefit role of opioids, the connections between microbiota and microglia activation, and gut microbiota as pertains to pain hypersensitivity vs. tolerance.

While a variety of microbiome studies are described within the review articles in Table 1, the most recent preclinical and clinical trials from the past 2-3 years are highlighted in Table 2 [52-71]. Several areas of activity are notable. First, pain in children (e.g., abdominal) seems to be an area where there is significant interest in the use of pre- and probiotics. Possibly this is because of the hesitancy to immediately prescribe opioids for children. The examples of recent preclinical and clinical trials show that a wide array of pain associated conditions can benefit from microbiome rebiosis. However, it is also clear that additional trials with larger numbers of patients and more standardized probiotic treatments will be helpful in guiding clinical applications.

Table 1: Examples of Recent Reviews on Microbiota, Pain, and Pain Management.

Table 2: Examples of preclinical and clinical studies on the role of the microbiome in pain thresholds and pain management.

Microbiota And Analgesics: Opioid Response, Tolerance, Addiction and Withdrawal

A heavy reliance on pharmaceutical control of pain has several issues. Commonly used painkillers (opioids and non-steroidal anti-inflammatory drugs [NSAIDs]) are among the drugs known to damage the microbiome as discussed by Dietert [1]. While opioids are a category of drugs that have been used in pain management [72], they are also a drug category that has a significant opportunity to cause abuse [73]. This has most recently been seen with regards to fentanyl [74]. Recently, there is a search for multimodal pain management to reduce the reliance on opioids [75,76]. The gut microbiome plays essential roles both in the incentive salience end of drug reward behavior and in the pain of withdrawal response as was recently reviewed by Ren and Loftipour [77] and García- Cabrerizo et al. [78]. Additionally, opioid tolerance is one of the features of a dysbiotic microbiome [79]. This contributes to ever increasing doses of opioids that are required to produce the painkilling effect. It is part of the addiction cycle. There is evidence that rebiosis should be helpful in reversing opioid tolerance connected to microbiome dysbiosis. Zhang et al. [80] found that morphine tolerance established in germ free mice was able to be reversed using probiotics.

A second issue with pharmaceutical control of pain is that NSAIDs have been shown to damage the gut microbiome [81,82]. The specific damage impairs colonization resistance and creates increased susceptibility to Clostridioides difficile infection-induced colitis and dysregulates inflammation [83]. Even if microbiota are not used in a multimodal pain control strategy, the microbiome needs to be rebiosed following pharmaceutical therapy. Otherwise, there is a likelihood that the drugs will become less effective, more likely to become addictive and the microbial dysbiosis they create will put the patient at a greater risk of both infections and NCDs.

Conclusion

This opinion article provides both recent reviews and preclinical and clinical trials to illustrate the benefits of considering the microbiome at every step in the pain preventative and management process. The microbiome and, in particular, the gut microbiome exerts such a pervasive control over systems biology units (e.g., the microimmunosome, the gut-brain axis, the gut-bile axis, the gut-hepatic axis) and metabolism that efforts to manage chronic pain in the absence of managing the microbiome are far more likely to end in a reduced quality of life (either through ongoing pain, depression, and/or drug dependency). A concluding summary of four major benefits to be gained by putting the microbiome first in pain management is shown as follows:
1. Microbiome first action can be useful as a pain preventative. Because microbiota can regulate immune and neurogenic inflammation, there is an opportunity to stop neuronal activation and immune-inflicted tissue damage before lower back pain requires a surgical solution. This is what was found with lumbar injury and avoidance of the need for herniated disc surgery.
2. Inattention to the microbiome presents a long-term problem when it comes to pain. NSAID and opioid treatment for pain causes damage to the gut microbiome. If uncorrected, this creates a vicious cycle of trouble. There is an increase in drug tolerance (less effective drug action per dose) and for opioids there is a greater risk of addiction. Withdrawal is more difficult if the microbiome is in dybiosis. Additionally, the dysbiotic gut microbiome loses colonization resistance increasing the risk of serious pathobiont infections. There is also an increased risk for loss of gut barrier integrity and for the emergence of new NCDs. These new diseases will lead to increased pain and disease burden. None of these complications are necessary when appropriate attention is given to the microbiome.
3. Regular attention to the microbiome has benefits that include and extend beyond pain as an outcome. Better regulation of the body’s immune system and inflammatory responses means that a lower prevalence of pain is likely over time. Having a better balance of receptor-driven perception of pain also means that there is a better chance to keep pain as an acute event rather than a lifelong chronic burden. It is a useful step toward sustainable healthcare.
4. Maintaining a healthy microbiome can reduce the comorbidities of pain. Because some NCDs like depression are very common comorbidities of chronic pain, managing the microbiome can help to eliminate these comorbidities. The gut as well as the gut microbiota are potent producers of neuroactive peptides. Balance among the gut microbiota produce improved neurological health. As a result, a healthy, managed gut microbiome enhances resiliency against pain-associated depression.

Conflict of Interest

The authors declare that there is no conflict of interest.

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