Opioid-Induced Gut Microbial Dysbiosis

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1		Patrice Forget	--	3385	2022-08-08 09:35:46	\|
2	layout	Jessie Wu	Meta information modification	3385	2022-08-09 06:13:08	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10081815

Acute (and thus persistent) pain typically begins with nociceptors; the terminal ends of sensory neurons which are found within the peripheral nervous system (PNS) and are often managed with opioids. Opioid-induced dysbiosis (OID) is a specific condition describing the consequences of opioid use on the bacterial composition of the gut. Opioids have been shown to affect the epithelial barrier in the gut and modulate inflammatory pathways, possibly mediating opioid tolerance or opioid-induced hyperalgesia; in combination, these allow the invasion and proliferation of non-native bacterial colonies. Gut microbial dysbiosis is a change in the gut microbiota’s functional or structural configuration that disrupts gut homeostasis and is linked to several diseases. The changes in the balance and composition of gut microbiota are referred to as opioid-induced dysbiosis (OID), and they are linked to a variety of disease states and the development of antinociceptive tolerance.

opioids dysbiosis gut

1. The Pain Pathway and Hyperalgesia

The classic three-neuron chain nociceptive pathway is now understood to be a dual system at each level. The sensation of pain is thought to arrive in the central nervous system (CNS), with the discriminative component of pain (“first pain”) carried separately from the affective-motivational component of pain (“second pain”) ^[1]. In addition to spinal control mechanisms for nociceptive transmission, descending pathways from significant areas of the brain—the cortex, thalamus, and brainstem—can modify spinal functions. The CNS can respond to painful stimuli at multiple levels involved in pain transmission, modulation, and sensation ^[2].

Local circuits in the dorsal horn of the spinal cord play an essential role in processing nociceptive afferent information and influencing the actions of descending pain modulation systems. Opioids have inhibitory effects on target neurons in the short term, while stimulating effects have also been described. Noxious stimulation enhances the neuronal activity and alters gene expression, including immediate-early genes and neuropeptide (i.e., opioid) genes at the spinal and supraspinal levels of the somatosensory system.

1.1. Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia (OIH) is a state of nociceptive sensitization caused by the exposure to opioids. It is characterised by a paradoxical response whereby a patient receiving opioids to treat pain could become more sensitive to certain painful stimuli. Due to central sensitization long-term opioid treatment has the same neuroinflammatory potential responsible for pain chronicity, resulting in paradoxical worsening rather than pain relief ^[3].

Neuroinflammation is a unique type of inflammation occurring in response to noxious stimuli in the peripheral and central nervous systems ^[3]. It begins with altered vascular permeability, followed by leukocyte recruitment and the activation of microglia and astrocytes in the spinal cord and CNS. In many painful states, this mediates and may worsen inflammatory pain. The type of pain experienced might be the same or different from the underlying pain.

According to recent research, cholecystokinin is upregulated in the rostral ventromedial medulla (RVM) during chronic opioid exposure. Cholecystokinin has anti-opioid and pronociceptive properties, activating descending pain facilitation mechanisms from the RVM, enhancing nociceptive transmission at the spinal cord and promoting hyperalgesia. The neuroplastic adaptive changes induced by opioid exposure promote increased pain transmission, resulting in decreased antinociception (i.e., tolerance) ^[4]^[5]^[6].

1.2. Experimental Evidence

To explore OIH in human volunteers, several experiments have been carried out ^[7]^[8]^[9] (such experiments looked at the effect of short-term opioid infusion on an experimental stimulus that had been rendered hyperalgesic prior to the start of drug infusion ^[7]. The second set of studies looked at the effects of opioid antagonist-induced withdrawal on cold pressor pain in volunteers who had become acutely exposed to opioids. Several studies found that a 30 to 90-min infusion of the ultra-short-acting opioid agonist, remifentanil, aggravated pre-existing mechanical hyperalgesia. Aggravation was reflected by a 1.4 to 2.2-fold increase in the hyperalgesic skin area compared to preinfusion measurements. The magnitude of this effect was directly related to the duration of the infusion and the opioid dose. Aggravation of pre-existing hyperalgesia was observed up to four hours after stopping the remifentanil infusion but was no longer present the next day. These changes are consistent with an expanded area of secondary hyperalgesia and the result of enhanced nociceptive signal processing at the spinal cord level ^[7].

The central glutaminergic system has been proposed as a common mechanism for OIH development ^[10]. The excitatory neurotransmitter, N-methyl-D-aspartate (NMDA), may play a role in developing OIH in this system. Silverman¹⁴ outlined the role of NMDA in the development of OIH in a review.

The review highlights how NMDA receptors become activated, and inhibition prevents the development of tolerance and OIH. When the glutamate transporter system is inhibited, there is an increase in glutamate available to NMDA receptors. As a result, there may be a cross-talk of neural mechanisms of pain and tolerance. In the dorsal horn, prolonged morphine administration induces neurotoxicity via NMDA receptor-mediated apoptotic cell death.

These findings point to a mechanism in which inhibiting the NMDA receptor prevents OIH. This NMDA-mediated mechanism sensitizes neurons via the central glutaminergic system and may explain how OIH develops. Spinal dynorphins may also contribute to OIH by increasing the presence of excitatory neuropeptides, which can improve nociceptive input ^[10].

1.3. Antinociceptive Tolerance to Opioids

Given the clinical and social implications of physical dependence and addiction, the mechanisms causing opioid tolerance have been studied for many decades. Despite multiple studies at various levels in different tissues, no single regulatory mechanism can account for all of the variations observed in tolerance development ^[11].

Antinociceptive tolerance is clinically manifested as decreased or lost pain relief from a given opioid dose administered repeatedly or with continuous administration of an opioid over a period of time. The need for increasing opioid doses in chronic pain cases is well documented and is typically presented as a major barrier to providing adequate pain relief over a long period of time ^[4].

The chronic administration of morphine has recently been shown to alter the gastrointestinal tract’s resident microbial composition and induce bacterial translocation across the gut epithelial barrier via mechanisms involving toll-like receptors (TLR) 2 and 4 ^[11].

The primary mechanism for tolerance to the antinociceptive effects of chronic morphine appears to be dysbiosis of the gut microbiome. The precise mechanism by which the gut microbiome influences tolerance development is unknown; however, it is possible that the breakdown of the epithelial barrier, microbial translocation, and inflammation within the colonic wall may alter extrinsic sensory neurons, resulting in tolerance development ^[11].

2. Inflammation and Infection

Drug dependence, including opioids, is associated with inflammation. Opioids can promote the release of pro-inflammatory cytokines from immune cells, which are involved in the upregulation of inflammation ^[12]. The central amygdala is the area of the brain where these inflammatory responses are recognised due to its behavioural and emotional drug-related stimuli role.

The use of opioids for their analgesic actions can have varying effects depending on the length of time they are used. Long-term opioid use can be correlated with decreased effectiveness in pain management ^[13]. In conditions associated with chronic pain, prescription opioids can eventually cause chronic inflammation. Research shows that the cause of this is the body’s response to inflammation: antibody creation ^[14].

2.1. Chronic Opioid Use and Immunosuppression

A study of patients suffering from chronic lower back pain showed that antibodies against opioids were found in chronic opioid users. In contrast, those using over-the-counter medications as an alternative developed no immunity towards these. The study also suggests that the antibody response correlates with the dosage of opioids ^[14].

Opioid use can also be linked to various infections through the immunosuppressive roles induced if used long-term. Research suggests that regular opioid users, who abuse the drug, have a higher prevalence of infections that solely affect immunocompromised patients. Research also reveals that patients that take opioids compliantly have been shown to have latent viruses reactivate or develop during obstetric medical treatment due to reduced immune function ^[15].

2.2. Human Immunodeficiency Virus (HIV)

It is common for opioid abusers to become infected by Human Immunodeficiency Virus (HIV), which damages immune cells, causes immunosuppression, and potentially progresses to acquired immune deficiency syndrome (AIDS), an umbrella term for several life-threatening infections and illnesses due to a damaged immune system by HIV. Opioids have been associated with aiding the development of HIV in the CNS and worsening the neurodegenerative diseases that are caused by chronic HIV ^[16].

2.3. Hepatitis C Virus (HCV)

Opioid abusers may be regularly involved in needle use, sharing and hazardous disposal, and unsafe sex (Table 2). These actions can easily expose them to HIV and the blood-borne hepatitis C virus (HCV). Research shows that opioids can speed up the development of HVC and cause chronic HVC by activating the opioid receptors found on immune cells ^[15]. The immune response to the influenza virus has also been shown to be compromised due to opioid usage. The influenza virus is a common cause of respiratory tract infections, scaling from mild upper respiratory infections to severe pneumonia. Opioids weaken the immune and inflammatory response leading to prolonged clearance of influenza through immunosuppressive actions previously discussed ^[15].

2.4. Herpes Simplex Virus

Herpes simplex virus (HSV) covers a range of infectious agents which cause oral and genital lesions, encephalitis, infections in neonates and malignant growths. Due to their immunosuppressive effects, opioids delay the HSV clearance, alter the virus itself and reactivate latent HSV ^[15]. Together, this demonstrates that immunosuppression by opioids reduces the body’s ability to fight infections and can exacerbate chronic conditions caused by infections.

3. Gastrointestinal Motility and Pathophysiology of the Gut by Opioids

As discussed above, opioids influence the GI tract by decreasing motility and peristalsis by slowing gastric emptying and increasing resting smooth muscle tone ^[17]. These factors contribute to OIBD.

Increased GI transit time has been shown to cause significant changes in the gut microbiome in constipation-predominant IBS. There are suggestions that similar changes with long-term opioid use could be driving the development of prolonged antinociception tolerance, meaning that they block the detection of painful stimuli ^[18].

The μ (MOR) and δ-opioid receptors (DOR) are the predominant opioid receptors in the GI tract ^[19]. MORs in enteric neurons are involved in the decrease in gut motility. When these receptors are activated, they cause a reduction in the excitability of the neurons and, subsequently, this slows gut motility ^[20].

The MORs are primarily found in myenteric and submucosal plexuses. Their importance in the modulation of gut motility is evident, as this effect is not shown in μ-opioid receptor knockout mice ^[21]. Activation of the MORs on myenteric neurons affects gut motility, as these neurons are responsible for the innervation of smooth muscle. Acetylcholine (ACh) stimulates longitudinal smooth muscles in the gut, and vasoactive intestinal peptide (VIP) and nitric oxide mediate the inhibition of inhibitory neurons in the circular muscles. Opioids prevent neurotransmitter release and therefore bring about the effects of increased tone and reduction of normal peristaltic activity ^[22].

Stimulation of the DORs and MORs on submucosal neurons causes a decrease in secretion and absorption due to the release of ACh and VIP being inhibited. Cl⁻ secretion is promoted while the Na⁺/Cl⁻ absorption is inhibited. This disturbs the water-electrolyte balance, which is vital for digestion and resistance to bacterial infections ^[23].

Opioids decrease enteric neuronal excitation and consequently inhibit neurotransmitter release by altering ion channels. An increase in potassium results in the membrane being hyperpolarized and therefore halts the action potential generation. Sodium and calcium channels are suppressed. Morphine causes sodium channels to be inhibited, thus reducing excitation in the neurons because they cannot reach the threshold for multiple action potential firing ^[24].

3.1. Opioid-Induced Bowel Dysfunction (OIBD)

OIBD refers to the gastrointestinal symptoms associated with the use of opioids. These appear due to slowing intestinal motility, uncoordinated contractions and increased sphincter tone. Symptoms include ‘gastroesophageal reflux, vomiting, bloating, abdominal pain, anorexia, and constipation’ ^[19]. Of these, opioid-induced constipation seems to be of greatest clinical importance and links to upper GI symptoms.

3.2. Opioid-Induced Constipation (OIC)

OIC is described as altered bowel habits and defecation after initiating opioid therapy and is characterised by a reduced bowel movement, exacerbated straining to pass a bowel movement, feeling of incomplete evacuation and/or harder stools ^[25].

Opioids reduce neurotransmitter release by binding to submucosal secretomotor neurons, causing a reduction in chlorine secretion. Consequently, chlorine no longer maintains the osmotic gradient required to allow water into the intestinal lumen and therefore, contributes to OIC. The time in which water can be absorbed is prolonged due to the reduction of gut motility. As water is absorbed, faecal volume is reduced. Peristaltic activity relies on mechanoreceptor activation, and so the decrease in volume further impacts gut motility and OIC ^[26].

Another factor that might promote constipation with opioids is that opioids can increase sphincter tone and cause muscle spasms. Those on opioid therapy become tolerant to the analgesic effects of opioids but not to the GI effects ^[27]. In colonic neurons, β-arrestin-2 prevents tolerance to GI effects, whereas it has the opposite effect in central neurons, where it mediates tolerance.

When opioids bind to MORs G-signalling leads to phosphorylation of the receptor, bringing about β-arrestin-2 recruitment ^[28]. The significance of this molecule has been noted, as β-arrestin-2 knockout mice showed tolerance in the colon ^[11].

With chronic opioid use, there is downregulation of β-arrestin-2 in the ileum, whereas in the colon, β-arrestin-2 continues to be expressed. This explains the difference in tolerance between the ileum and colon, where the ileum becomes tolerant to opioid effects, and in contrast, the colon does not. Receptor recycling occurs in the colon, manifesting as the continued activation of receptors and progressing to OIC ^[20].

4. Therapeutic Options and Treatment Perspectives

Opioid-related GI and neurological disorders are presented in various ways, and clinicians must be aware of the different presentations and treatments available for these side effects.

4.1. Faecal Microbiota Transplantation (FMT)

Faecal Microbiota Transplantation (FMT) is the administration of the entire microbial community from the stool of a healthy donor into the intestinal tract of the recipient in order to normalise or modify the composition and function of the intestinal microbiota ^[29]. In a recent study to combat the effect of OID, the findings suggest a potential role for the gut microbiome in expressing the somatic signs of morphine withdrawal, which might improve opioid dependence and withdrawal therapies as defined by quantification of naloxone-precipitated withdrawal jumps ^[30]. The findings suggest that FMT restores and improves morphine-treated recipient mice microbial communities. In addition, morphine-treated animals receiving FMT from morphine-treated donor mice showed lower levels of naloxone-precipitated opioid withdrawal ^[30].

4.2. Antibiotic Treatment

High antibiotic doses have been shown to result in a more significant levels of microbial clearance. The antibiotics treatment regimen produced a robust suppression of naloxone-precipitated opioid withdrawal in morphine-dependent mice ^[30]. However, in another study, no changes in naloxone-precipitated jumping were observed in morphine-pelleted mice after antibiotic treatment, owing to differences in morphine dosing regimens between studies ^[31].

The antibiotics used in this investigation are neomycin, vancomycin and metronidazole, with a 10-fold increase in dosage compared to the above studies. Antibiotics have been demonstrated to affect the structure and function of the nervous system directly. However, the mechanism is still unclear ^[30].

4.3. Probiotic & Prebiotic Therapy

Probiotics are live, nonpathogenic microorganisms that improve microbial balance, especially in the GI tract ^[32]. During morphine administration, probiotic therapy should be considered. Counteracting opioid-induced increased gut permeability and neuroinflammation may provide a way to prolong morphine’s efficacy while reducing side effects ^[30]. Some examples are listed in Table 1 below.

Table 1. Probiotics and their function.

Probiotics	Function
Bifidobacteria and Lactobacillaeae	Tolerant to morphine, and probiotics containing these bacterial communities can prevent the development of analgesic tolerance in the morphine-treated rats ^[31].
B. longum and L. rhamnosus	Maintain a healthy intestinal barrier ^[33] bacterial translocation, and neuroinflammation by manipulating the gut microbiome ^[34].
Lactobacillus genus	In mice, it was shown to induce opioid and cannabinoid CB2 receptor expression and mediate analgesic activities in intestinal epithelial cells ^[35].

Prebiotics are non-viable food ingredients that are selectively metabolised by intestinal bacteria. Prebiotic dietary modulation of the gut microflora is intended to improve health by increasing the number and/or activity of bifidobacteria and lactobacilli ^[36]. Fructooligosaccharides are considered to be prebiotics and influence ENS function by modulating the gut microbiota. Chronic treatment with fructooligosaccharide prebiotics in diabetic mice fed a high-fat diet (45%) leads to a decrease in body weight associated with a decrease in fasting hyperglycemia ^[37].

4.4. Myosin Light Chain Kinase (MLCK) Inhibitor ML-7

The impact of the inhibitor ML-7, shown in earlier research, is also worth noting as it protects the barrier function of several endothelial and epithelial cell lines ^[38]. Previous studies observed that the gut epithelial barrier was protected against disruption in morphine-pelleted mice and inhibited morphine-induced bacterial translocation ^[39]. ML-7 might be involved in mechanisms other than gut permeability regulation, hence additional research is required.

4.5. Opioid-Induced Constipation (OIC)

The most common and widely reported adverse effect of opioid use is OIC, which affects 40–80% of opioid users. After a diagnosis of OIC is made, physicians can use the bowel function index (BFI) to evaluate patients’ symptoms and ask patients to rank the following symptoms from 0 (not at all) to 100 (extremely severe) in the previous seven days: a feeling of incomplete bowel evacuation, ease of defecation, and patient’s judgement of constipation ^[39].

Although laxatives are recommended as first-line agents for OIC treatment, they do not relieve OIC symptoms in all patients ^[40]. They can cause side effects such as flatulence, bloating, and a sudden urge to defecate, interfering with daily activities. As a result, several new and more specific pharmacological approaches are emerging ^[41].

Several treatment guidelines recommend that Peripherally Acting μ Opioid Receptor Antagonists (PAMORAs) should be considered when starting opioid therapy or in patients with OIC who do not respond to laxatives. One of the most suitable PAMORAs for daily administration is oral Naloxegol. In two randomised, placebo-controlled phase 3 trials, naloxegol was considerably more effective than placebo in the overall patient population. In both studies, patients classified as laxative-inadequate responders were given 25 mg, and in one study, 8.5 mg ^[42].

Relying on one treatment for opioid-induced dysbiosis in acute and chronic pain is insufficient. Opioids have immunosuppressive effects in peripheral immune cells but pro-inflammatory effects in the CNS. As a result, vaccines have emerged as one of the most promising preventative/therapeutic alternatives to combat Opioid Use Disorder (OUD). The vaccine will produce opioid-specific antibodies that bind to the target opioid, limiting drug-induced behavioural and pharmacological effects and lowering drug distribution to the brain ^[42]. Anti-opioid vaccines can be used in conjunction with FDA-approved medications due to their selectivity. However, the current research has several limitations, such as being limited to male mice and rats and the Specific Pathogen-Free (SPF) condition did not accurately capture the microbiome changes seen in chronic opioid users ^[43]. Hence, more research is needed to examine the relationship between the microbiome and vaccination against OUD.

Another approach to combat OUD is Quantitative Systems Pharmacology (QSP). A QSP technique studies the dynamic interactions between drugs and a biological system quantitatively, allowing for a better understanding of the system’s behaviour rather than the individual components. Understanding how different components of the biological system interact can help researchers find biomarkers to predict disease severity and treatment outcomes ^[44].

Chronic opioid treatment causes a substantial loss in gut barrier integrity and bacterial migration. The loss of gut barrier integrity can exacerbate viral infection and sepsis, which has serious clinical implications given the propensity to use opioids in emergency settings. Following chronic opioid therapy, it has been demonstrated that both Gram-positive and Gram-negative bacteria invade the liver, spleen and lymph nodes. Restoring the gut flora is a clear target for improving opioid efficacy and reducing withdrawal symptoms ^[45].

Table 2. Summary of microbials related to the gut.

Microbial	Effect on the Gut
Mycobacterium	Major pathogen of IBD ^[46]
Escherichia coli	Major pathogen of IBD ^[46]
Clostridium difficile	Major pathogens of IBD ^[46]
Lactobacillaceae	Association with Parkinson disease ^[17]
Enterococcaceae	Association with Parkinson disease ^[17]
Alistipes	Increases prevalence in depression ^[45]
Faecalibacterium prausnitzii	Has anti-inflammatory properties that promote gut health. Decrease in this bacteria can have consequences on the epithelial integrity of the gut ^[47].
Human Immunodeficiency Virus (HIV)	HIV is a virus that attacks its own immune system. Opioids have been associated with aiding the development of HIV in the CNS and worsening the neurodegenerative diseases that are caused by chronic HIV ^[16].
Hepatitis C virus (HCV)	Opioid abusers may be regularly involved in needle use, sharing and hazardous disposal, and unsafe sex. These actions can easily expose them to HIV and blood-borne HCV ^[15].
Herpes Simplex Virus	Herpes simplex virus (HSV) covers a range of infectious agents which cause oral and genital lesions, encephalitis, infections in neonates and malignant growths. Opioids delay the HSV clearance, alter the virus itself and reactivate latent HSV ^[15].
Bifidobacterium genus	Probiotics that normally live in the gut ^[12].

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Subjects: Gastroenterology & Hepatology

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Karen R. Thomas

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Patrice Forget

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Update Date: 09 Aug 2022

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