Inflammation caused by opioid use in the brain and gut exacerbate negative emotions

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Opioid dependence has become a national crisis with serious impact on economic and social welfare, and numerous casualties.

A big goal of ongoing research in combating opioid use disorder is understanding drug withdrawal.

The physical and emotional symptoms of withdrawal can be life-threatening and make up a powerfully negative experience; the fear of these symptoms strongly motivates addiction.

Researchers in the lab of James Schwaber at the Daniel Baugh Institute for Functional Genomics and Computational Biology at Thomas Jefferson University are studying how inflammation contributes to drug withdrawal and dependence.

Their study was published in Frontiers of Neuroscience on July 3.

Opioids can cause inflammation in the brain by inducing immune cells to release inflammatory molecules called cytokines.

The main immune cells in the brain are microglia and astrocytes.

Inflammatory responses induced by opioids have been observed in the central amygdala, a brain region that has been strongly implicated in opioid dependence because of its role in emotion and motivation.

The central amygdala can also be affected by inflammation in other parts of the body, like the gut.

In fact, the communication between the gut and the brain can shape a variety of motivated behaviors and emotional states, including those associated with drug dependence and withdrawal.

The researchers including first author Sean O’Sullivan in Dr. Schwaber’s lab isolated single neurons, microglia, and astrocytes from the central amygdala and studied their genetic profiles in normal, opioid-dependent, and withdrawn rats.

They were surprised to find that the profile of astrocytes changed the most, shifting genetic expression to a more activated state.

This shift correlated strongly with opioid withdrawal.

Furthermore, all three cell types showed a considerable increase in an inflammatory cytokine called TNF alpha in withdrawn animals.

In addition, the researchers also assayed different types of bacteria in the gut of rats and found that certain anti-inflammatory bacteria were suppressed in withdrawn animals, shifting the ratio of gut microbiota and causing a phenomenon called dysbiosis, which can cause inflammation in the digestive system.

It is unclear how these changes influence opioid withdrawal, but the authors propose that the simultaneous inflammation in the gut and central amygdala may be linked to the negative emotional experience of withdrawal.

Immagine correlata

Opioids can cause inflammation in the brain by inducing immune cells to release inflammatory molecules called cytokines. The image is in the public domain.

The findings underscore the highly complex relationship between the gut and the brain, and suggest that inflammation in the gut and brain may exacerbate symptoms associated with withdrawal. Targeting inflammation in these regions may alleviate the negative experience of drug withdrawal, and therefore prevent dependence.

Funding: The study was funded by NIH HLB U01 HL133360, NIDA R21 DA036372 and T32 AA-007463. The authors report no conflict of interest.


One of the main functions of the human gastrointestinal (GI) tract is to sustain the natural interaction between the environment and the body’s interior.

From an evolutionary standpoint, a series of anatomical changes has occurred over time. For example, wider and larger teeth allowed humans to eat a greater amount of plants and fruits[1].

Also, a longer small intestine helped to digest food and absorb nutrients, while removing non-digestible molecules, toxic matter and harmful agents from the body.

During this evolutionary and historical process, humans were able to survive based on this capacity to eat foliage and roots, soil, and all kinds of animals.

For instance, maguey worms, ant eggs, grasshoppers and snails once served as complementary survival foods for the Mesoamericans of Mexico. Later, they became part of the staple foodstuffs in several regions of the country, and paradoxically, they are considered exotic dishes in fancy restaurants today[2].

Globally, the prevalence of GI pathologies varies according to geographical location, which in turn is linked to genetic, environmental, and sociocultural, interactions.

Thus, differences in the incidence and prevalence of GI pathologies may exist between urban and rural populations.

However, regardless of these variables, the most common ailments are those related to bad eating habits and those associated with psychological or emotional factors[3].

As a result of the aforementioned issues, obesity has increased remarkably worldwide, along with its concomitant GI symptoms and associated co-morbidities, including type-2 diabetes and liver diseases such as non-alcoholic steatohepatitis[4].

Obesity ranks as the number one disease in both the United States and Mexico[5,6], while the economic devastation associated with type-2 diabetes and cirrhosis represents a serious problem for health services[7].

Eating less and more exercise has been the simplest proposal for the management of obesity. However, to date, all strategies to combat obesity have failed due to lack of a therapeutic target, or the patient’s lack of knowledge and poor attitude[8]. On the other hand, up to 60% of GI diseases are associated with stress[9].

A globalized world comes with high rates of stress and people with GI conditions struggle even more with anxiety, stress, and pain due to extensive lifestyle changes that have an impact on their quality of life.

This unhealthy scenario leads us to ask why do patients overeat?

Alternatively, why after losing weight by a harsh nutritional-medical treatment or even more often after bariatric surgery, patients relapse gaining more weight or recovering the lost weight?

The answer may be related to the imbalance between the food we eat, genes and emotions.

Interestingly, the oldest records that allude to the food-body-emotion interaction is in Ayurvedic Medicine and in the theory of the balance between the natural elements documented by Chinese medicine.

Both are considered precursors of the concepts defined by Hippocrates in which the mind, body and spirit are represented by the Four Humours theory: sanguine, phlegmatic, choleric and melancholic[10].

Based on this background, we may consider that the common denominator of these theories is the balance between the human body and the environment, i.e., what we eat, what we feel and our behavior (emotions) according to the person’s personality (genetics) or character. This balance leads to well-being, health, and happiness, while an imbalance leads to illness.

Modern or scientific medicine, as defined by the concepts derived from Descartes’ scientific method, has achieved significant advances in the understanding of how our body functions, first at the macroscopic and microscopic level, then followed by biochemical-physiological aspects, and most recently at the molecular level[11].

In the last century, modern medicine has focused more on disease than on health, leading to a fragmentation of our scientific knowledge[12].

Gastroenterologists may only address the sick digestive organ, whereas the nutritionist may recommend revisions to the kinds and amounts of the food we eat, but often neither of them consider the food-body-emotion interaction.

In the same sense, the concept of intestinal flora has advanced towards the study of the composition of the intestinal microbiota, which depends precisely on our eating habits. However, genomic medicine raises the question about how the genetic (inside)-environment (outside) interaction occurs.

Currently, nutrigenetics and nutrigenomics are providing knowledge on how food interacts with our genes. With this new knowledge, doctors or health professionals have a new set of molecular tools to study GI disorders and establish genome-based treatment strategies. However, the interaction between eating and emotions has been less understood, causing knowledge again to be atomized throughout other disciplines such as neurology, psychology, psychiatry and even religion, or whatever it may be that leads to a greater degree of spirituality[13].

Returning to the Hippocratic’s concept, in which the balance between body, mind, and spirit is necessary for health, genomic medicine currently may explain at the molecular level how this may occur. Thus, the objective of this mini-review aims to provide an integrated synopsis of the interaction between genes, gut microbiota and emotions to achieve a better understanding of the GI disorders related to bad eating habits and stress-related diseases.

EMOTIONS, INSTINCTS AND BEHAVIOR

Emotions may be defined as mental and physical states that are generated in response to internal or external stimuli. This stimulation can arise from thought (thinking), or through the visual, auditory, somatosensory, gustatory, and olfactory senses.

In the ancient times, one clear example of a stimulus that arises from thought was melancholy, described as an animic state that was present when a person yearned for their homeland and their activities or for loved ones that were no longer with them. Today, this emotion has been denoted as stress, anxiety, and depression, which arises because of various circumstances.

Both thoughts and senses can be activated by an internal or external stimulus, and the basis of this response is instinct, as an essential part of survival[14,15].

Through time, evolution establishes genetically an adaptability, given by the experience, to the surrounding environment.

Eventually, through this adaptability of the human to its environment, a behavior arises, which is based on learning (cognition) and genetic adaptations[16,17]. An easy example to understand how genetic-environmental interactions modulate behavior is through the behavioral traits of different breeds of dogs, whose behavior or character is a mixture of the genetic aspects of the race and training (learning).

From Darwin to contemporary authors, emotions have been given different definitions and classifications to explain the health/disease process. However, it is worth rethinking the concept of instinct.

Instincts are a set of physiological and mental reactions that lead to the preservation of life.

These instincts arise from an internal or external stimulus; subsequently, the body responds by entering in a state of alert followed by a movement. In fact, emotion in Latin means “motion”.

Darwin states that there are different facial expressions related to that movement[18]. These physical changes are fast, specific, and self-limiting; thus, the body may return to the original state after the stimulus disappears or it may chronically persist if the emotion is not resolved, for example, a feeling of resentment.

Once the state of alert is initiated, blood flows into specific body areas depending on the situation. For example, blood flows to the legs in case of “fear”, towards the chest and arms in case of “fight”, and to the genitalia when a possible mate is detected or to the stomach when the appetite or hunger arises[16].

Additionally, in regard to the blood flow, Alexander Lowen suggests sorting emotions into positive or negative[19]. Positive emotions are all those that provide well-being and pleasure, while negative emotions generate the opposite. The former favors blood flow whereas the latter generate vasoconstriction, releasing adrenalin and cortisol, which activates stress. Based on Lowen’s concept, one or a set of negative emotions over an extended period could lead to chronic illness.

Therefore, in the medical context, a clear and integrated approach could help us to understand the role of instinct, emotions, and behavior in the health/disease process, and to establish therapeutic targets.

FUNCTIONAL GASTROINTESTINAL DISORDERS AND EMOTIONS

Functional gastrointestinal disorders (FGIDs) are a broad spectrum of chronic abnormalities, some of which arise from dysfunctional brain-gut interactions that can lead to dysmotility and hypersensitivity[2022].

Several factors such as genetic susceptibility, gut physiology, microbiota composition, and psychological factors have been associated with FGIDs[2325]. Episodes of anxiety and depression are experienced more frequently in individuals with FGIDs than in healthy subjects[26,27].

They also have been related to physiological changes in colonic motility, abdominal pain, mucosal blood flow and hyperreactivity among patients with intestinal bowel syndrome (IBS)[22]. Furthermore, negative emotions, stressful life events and personality traits like neuroticism have been associated with IBS, colitis, Crohn’s disease (CD) and dyspepsia[28].

At the same time, impaired attention and emotion regulation elicit symptoms of anxiety, hypervigilance, and hypersensitivity[20,21].

Among patients with FGIDs, quality of life is affected in two ways: first, anxiety and depression seem to predict the presence, severity, and frequency of symptoms[29,30]; and second, GI disorders may exacerbate the presence of negative emotions[31]. In fact, overall GI functions such as hunger, appetite, satiety, digestion, absorption and evacuation are affected by negative emotions[32].

However, the pathophysiological process of how emotions relate to GI disorders is not clearly understood. It has been proposed that homeostatic signals between the GI system and emotions are integrated by the gut-brain axis. This axis comprises the interaction between the endocrine, the immune and the enteric nervous systems[33], which in turn, interact with the autonomic and central nervous systems. For example, chronic stress promotes the release of pro-inflammatory cytokines and C-reactive protein.

This protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis by liberating corticotrophin-releasing hormone from the hypothalamus, which stimulates the activation of the sympathetic nervous system and the secretion of adrenocorticotropic hormone, which finally stimulates the release of cortisol from the adrenal cortex to limit stress[34]. In fact, patients with FGIDs and exacerbated anxiety and depression have high cortisol levels[35]. Due to HPA axis dysregulation the mesolimbic brain reward system (BRS) is altered, resulting in cognitive and emotional disturbance. As a result, FGIDs patients, predominantly IBS patients, are characterized by high rates of hypersensitivity related to GI symptoms such as pain[20].

EMOTIONS AND MICROBIOTA

The gut hosts almost 100 trillion microorganisms that share symbiotic properties with humans. Intestinal microbiota regulates part of the host’s metabolic and energy balance, modulate intestinal motility, and regulate immune system maturation.

Also, it confers protection against pathogens and toxins, regulates cytokines secretion from adipose tissue, insulin signaling and finally, modulates host emotions and cognition[36,37]. The gut microbiota is considered our second genome, because it constitutes 90% of the total number of cells that interact with our bodies[38].

As shown in Figure ​Figure1A,, the gut microbiota can help regulate emotions and cognition because it maintains a two-way communication with the brain[39] using the nervous, endocrine and immune systems[40].

Brain-gut communication is driven by the vagal nerve, which connects to nearly 100 million neurons in the enteric nervous system together with afferent (vagal and spinal) and efferent adrenergic neurons (sympathetic and parasympathetic)[41]. Moreover, certain gut bacteria synthesize neurotransmitters[42] and close to 20 neuropeptides produced in the enteroendocrine cells (central and peripheral neurons) serve as second messengers in the brain, thus regulating mood and cognition[43].

Some of these include substance P, calcitonin, corticotropin releasing factor, pancreatic polypeptide, vasoactive intestinal polypeptide, GLP-1 and somatostatin, neuropeptide Y, and peptide YY, among others[42].

These last two neuropeptides play a major role in body energy homeostasis[44]. The endocrine system regulates the release of gut bacteria neurotransmitters[43] and ghrelin, influencing the levels of neurotransmitters such as dopamine[45] whereas the brain controls the neuroendocrine factors. Finally, adhesion molecules maintain the integrity of the intestinal mucosa, which serves as a physical and chemical barrier against pathogenic bacteria[46]. Also, antigen recognition of pathogen-associated molecular patterns are recognized by the Toll-like receptors, modulating the activation of the immune response against nocive bacteria[47].

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Figure 1
Gut-brain axis and dysbiosis. A: The gut microbiota maintains a two-way communication with the CNS using hormones, neuropeptides, NT, cytokines and the afferent (vagus nerve) and efferent signals (adrenergic nerve); B: Alterations in the energy balance circuit and BRS that lead to negative emotions chronically activate the HPA axis elevating cortisol levels. Cortisol results in dysbiosis, allowing pathogens to permeate the gut barrier and activate inflammation. Unhealthy dietary patterns also lead to dysbiosis, inflammation and negative emotions. CNS: Central nervous system; BRS: Brain reward system; CRH: Corticotrophin-releasing hormone; ACTH: Adrenocorticotropic hormone; HPA: Hypothalamus-pituitary-adrenal.

As shown in Figure ​Figure1B,1B, alterations of the BRS and negative emotions, together with other unhealthy lifestyle factors produce a dysbiosis, which is an imbalance between beneficial and non-beneficial bacteria[46]. As mentioned before, activation of the HPA axis[40] releases free systemic stress hormones such as adrenaline, noradrenaline, and cortisol that promote bacterial growth of pathogens such as E. coli (E. coli0157), Yersinia enterocolitic, and Pseudomonas aerugins that further promote the synthesis of pro-inflammatory cytokines[43]. This scenario facilitates the loss of intestinal mucosa integrity. Lipopolysaccharides, pathogenic bacteria and toxins can permeate into the systemic circulation producing a metabolic endotoxemia[48,49]. This state generates pro-inflammatory conditions, insulin resistance and metabolic abnormalities related to chronic diseases[50].

Furthermore, a Western diet containing a high-sugar and high-fat composition contributes to dysbiosis and to a lower production of short-chain fatty acids from fiber fermentation, which have an anti-inflammatory role[51]. A high-fat diet promotes inflammation by increasing the expression of TNF-α and IL-6 inflammation-related cytokines, and macrophage infiltration[52]. Moreover, epidemiological studies have shown that central obesity and BMI are predictors of depression, anxiety and low quality of life[53,54]. Dysfunctions in adipose tissue are implicated in the development of stress and depression[55]. Adipocytes mediate a neuro-inflammatory profile affecting emotion and cognitive brain regulatory centers[56]. Also, inflammation is related to neurobiochemical alterations such as impaired serotonin synthesis, depletion of melatonin and tryptophan and neuronal damage in the hippocampus due to altered glutamatergic pathways[57]. Moreover, the prevalence of psychopathologies increases proportionally with the number of obesity-related metabolic diseases and metabolic syndrome components such as abdominal obesity, hypertriglyceridemia, and reduced high-density lipoprotein levels[58,59].

In this vein, changes in gut microbiota composition and diversity are related to immune-mediated diseases such as colitis, inflammatory bowel disease (IBD) and CD. For example, when compared to healthy subjects, patients with colitis have a reduced abundance of Akkermansia (phylum Veruccomicrobia), which promotes mucin degradation and protection against toxins[60]. Bacteria composition and diversity is also affected in IBD patients, who show a reduced number of Firmicutes and a higher number of Proteobacteria and Tenericutes; increases in E. coli populations is also associated with IBD[61]. Patients with CD tend to have a decreased number of the beneficial bacteria Firmicutes and increased number of Bacteroidetes when compared with healthy controls, together with reductions in bacteria gene protein expression related to nutrient and energy metabolism, intracellular traffic and defense[62].


Source:
Thomas Jefferson University
Media Contacts: 
Karuna S Meda – Thomas Jefferson University
Image Source:
The image is in the public domain.

Original Research: Open access
“Single-Cell Glia and Neuron Gene Expression in the Central Amygdala in Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis”. Sean O’Sullivan et al.
Frontiers in Neuroscience. doi:10.3389/fnins.2019.00665

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