Molecular mechanisms of alcohol's effects on the human body: A review and update

Abstract

Alcohol consumption has been linked to numerous negative health outcomes although it has some beneficial effects on moderate dosages, the most severe of which being alcohol‐induced hepatitis. The number of people dying from this liver illness has been shown to climb steadily over time, and its prevalence has been increasing. Researchers have found that alcohol consumption primarily affects the brain, leading to a wide range of neurological and psychological diseases. High‐alcohol‐consumption addicts not only experienced seizures, but also ataxia, aggression, social anxiety, and variceal hemorrhage that ultimately resulted in death, ascites, and schizophrenia. Drugs treating this liver condition are limited and can cause serious side effects like depression. Serine‐threonine kinases, cAMP protein kinases, protein kinase C, ERK, RACK 1, Homer 2, and more have all been observed to have their signaling pathways disrupted by alcohol, and alcohol has also been linked to epigenetic changes. In addition, alcohol consumption induces dysbiosis by changing the composition of the microbiome found in the gastrointestinal tract. Although more studies are needed, those that have been done suggest that probiotics aid in keeping the various microbiota concentrations stable. It has been argued that reducing one's alcohol intake may seem less harmful because excessive drinking is a lifestyle disorder.

Alcoholic liver diseases and their accompanying repercussions are depicted in this figure. Abnormalities in the microbiota of the gut are observed, which in turn lead to epigenetic abnormalities, alcoholic fatty liver, behavioral alterations, and so on. In addition to an increase in neurotransmission, other symptoms such as delirium tremens, hepatitis, steasis, ascites, and seizure disorders have been spotted. Gamma‐aminobutyric acid treatment, medication treatment, nonpharmacological treatments, pharmacological treatments, and psychological therapies are all part of the treatment and therapy for this condition.

1. INTRODUCTION

1.1. Alcoholic liver disorders

One of the most harmful and deteriorating effects as a result of alcohol intake is alcohol‐induced hepatitis. In chronic conditions, it has been observed that it increases the risk of mortality globally, making it a disease burden on the overall world population.^{[ 1} , ² , ³ , ^{4 ]} Alcoholic LD (liver disease) is one of the primary causes of chronic disease of the liver and has been seen to result in fibrosis and cirrhosis.^{[ 5 ]} Factors contributing to the development of liver insults include dosage, alcohol type, duration of consumption, and patterns of drinking alcohol. It also provides ethnicity and sex. Certain associated factors are the overload of iron, obesity, and genetic factors.^{[ 6 ]}

Alcoholic LD progression involves alcoholic fatty liver and then alcoholic SH (steatohepatitis), where hepatic inflammation is seen. Chronic alcoholic SH has also been found to result in HC (hepatocellular) cancer.^{[ 7 ]} With the passing of each year, the incidence of alcoholic LD (ALD) has been rising. On average, it has been seen that around 4% of deaths are because of alcohol intake each year and approximately 5% of disabilities all over the world. People diagnosed with ALD have been seen to have to take alcohol in large amounts.^{[ 8 ]} Ten to fifteen percent of addicts experience alcoholic liver cirrhosis (ALC). The gut microbial community of ALC patients is known to be dysbiotic, marked by a greater amount of Bacilli and Proteobacteria (especially Gammaproteobacteria). The Bacteroidetes, Ruminococcaceae and commensal taxa Clostridia, as well as Bifidobacterium and Lactobacillus, have decreased in proportion to these alterations. A significant decrease in Roseburia, Lachnospiraceae, Blautia and Faecalibacterium capacities triggers the overgrowth of intestinal bacteria, which, in conjunction with the increased intestinal permeability caused by acetaldehyde, results in a spike in endotoxins and activation of inflammatory cascades in blood, most likely resulting in liver damage.^{[ 9} , ^{10 ]} When looking at the microbiota in the gastrointestinal tract (GI) of people with alcohol dependence syndrome (ADS), liver failure is one of the main things that can make the results of the study confusing.^{[ 11 ]}

1.2. Spectrum of alcohol LD

Fat deposition is a characteristic of the same, ending in the hepatocytes present around the hepatic region portal vein as lipid droplets. Chronic steatosis patients are more prone to fibrosis in the liver tissue. Swollen and dying hepatocytes and infiltration of neutrophils are also seen, which are characteristics of alcoholic hepatitis. Patients have also been found to express fibrosis in the liver, which has been found to end in late‐state cirrhosis in the liver.^{[ 12 ]}

NAFLD (nonalcoholic fatty liver disease) is defined as hepatic steatosis conditions without a substantial alcohol intake. Though there is a hereditary component to the susceptibility of NAFLD, elevating insulin resistance is closely connected to the disease's start and progression. It encompasses a wide range of liver illnesses, inclusive of steatotic inflammation caused by fibrosis, nonalcoholic steatohepatitis, HC carcinoma, and cirrhosis.^{[ 13 ]} NAFLD affects 25% of the global adult population and is on the rise.^{[ 14 ]} The metabolic syndrome's pathophysiological characteristic is insulin resistance, and NAFLD is considered its hepatic component.^{[ 15 ]} The “two‐hit” paradigm, in which steatosis is regarded as the first strike and oxidative stress and damage is considered the second hits, can explain the NAFLD process.^{[ 16 ]} NAFLD is characterized as a primary syndrome or secondary metabolic syndrome depending on the primary pathophysiology, with insulin resistance being associated with primary NAFLD.^{[ 17 ]} NAFLD may be associated with endocrine abnormalities such as hypothyroidism, growth hormone deficiency, and polycystic ovarian disorders. A contributing hormonal illness influences medication, which may alter the future likelihood of NAFLD.^{[ 18 ]} The growing prevalence rate reflects modern living's excessive power consumption and sedentary lifestyle, which contribute to various detrimental lifestyle‐related illnesses, particularly NAFLD.^{[ 19 ]} NAFLD is distinguished by dyslipidemia, insulin resistance, and a proinflammatory condition. The cornerstone of modern NAFLD management is reducing weight through lifestyle changes, which is difficult for the majority of patients to achieve and sustain.^{[ 20 ]}

Patients with either ALD or NAFLD are seen to develop hepatic steatosis, which generally is asymptomatic. The disease spectrum for both NAFLD and ALD has been found to involve steatosis of benign form to hepatitis and cirrhosis and carcinoma of the HC region as well^{[ 8 ]} (represented in Figure 1). Alcoholic hepatitis has been seen to have been a major and severe form of alcohol‐mediated disease of the liver, with three‐quarters of patients seen to die as early as 90 days after being diagnosed with the same.^{[ 4} , ^{21 ]}

Figure 1.

The above figure represented the combined effect of hepatitis C (HC) and increased alcohol consumption and how it leads to hepatocellular (HC) carcinoma. An increase in alcohol intake leads to an increase in the amount of HC viral RNA, which causes a simultaneous increase in oxidative stress and weakening of the immune system resulting in liver fibrosis. Additionally causes liver cirrhosis, finally leading to HC carcinoma.

1.3. Frequency in the Indian population and globally

It has been estimated by the Centers for Disease Control and Prevention in the year 2013 that there has been a comparatively larger number of people who died due to alcohol intake than the number of people who died due to chronic diseases, with a ratio of 44,000 to 35,000.^{[ 8 ]} In a few studies, it has been reported that alcohol use disorder (AUD) increases the chances of substance use disorder. For example, when it was seen in the case of DSM‐IV, the substance use disorder in such people was seen to be increased by approximately 5.5‐fold. On the other hand, DSM‐V had an approximate increase of 3.3‐fold. Also, it was reported in another study that the use of substances during the ages of early adolescence and late adolescence was seen to increase the risk to the usage of AUD in the early stages of around 18 years 3.5‐fold in the early ages and by 4‐fold in the later ages. Though these studies may indicate a relation between disorder based on substance use and disorder based on alcohol use, the role of the latter in the former is still to be known, for which it has to be explored a lot.^{[ 22 ]} The other example of a substance use disorder is nicotine use disorder. Early introduction to smoking is an indicator of the emergence of drinking disorder along with associated difficulties, especially disorder comorbidity and substance such as nicotine use disorder.^{[ 23 ]} According to family and twin studies, genetic variables may explain up to 50% of the risk for nicotine and AUDs.^{[ 24 ]} Comparable environmental variables also connect nicotine and alcohol use, which may fluctuate throughout stages of development. Koopmans et al. discovered that environmental variables play an important role in the couse of both cigarettes and alcohol in early adulthood, especially in men, but genetic variations constitute the majority of the diversity in adolescence in an investigation of teenage and young adult twins.^{[ 25 ]} Early‐stage of both nicotine and alcohol use is a risk variable of both alcoholism and nicotine use disorders.^{[ 26 ]}

2. ALCOHOLISM AND NEURAL DISORDERS

The main reason for the disorder based on alcohol use is giving in to the craving of having alcohol in excessive amounts, which results in alteration in that region of the brain responsible for the behavior.^{[ 27 ]} The reinforcing alcohol effects may be mediated primarily by gamma‐aminobutyric acid (GABA), dopamine, endocannabinoids, and opioid peptides. On the other hand, a rise in the glutamatergic systems and corticotropin‐releasing factors act as negative reinforcers to AUD and cause an alteration to the transmission of GABA.^{[ 28} , ^{29 ]}

2.1. Alcoholic seizures and neuro disorders

It has been established that alcoholic seizures are a complex process. People dependent on alcohol have a three times higher chance of getting epilepsy than the normal population.^{[ 30 ]} It has been frequently observed that people who misuse alcohol have partial seizures. Their EEG reports showed abnormalities, a possible after‐effect of injury to the brain. Approximately 9%−25% of epilepticus cases have been suggested as being caused because of alcohol. Therefore, it has been recommended that brain imaging be performed in patients who have symptoms of alcohol‐related seizures. It has become important to acquire the history of a person due to an increase in alcohol misuse in the intake of drugs. Seizures may also result as a result of alcohol withdrawal. Further, the changes in the brain structure have been seen to have been caused because of high alcohol amounts. But, it cannot be established that alcohol alone can lead to epilepsy since the proper diagnosis of the reasons leading to brain injury has not been made.^{[ 31 ]} Brain iron levels tend to be greater in people who consume more than 7 units of alcohol each week. Alcohol‐induced cognitive deterioration may be caused, in part, by iron buildup.^{[ 32 ]}

2.1.1. Delirium tremens (DT)

Alcohol intake causes depression due to an increase in the neurotransmission of GABAaergic, which results in the reduction of the activity of glutamatergic.^{[ 33 ]} In alcohol withdrawal syndrome (AWS), the imbalance in the neurotransmitters causes an influx of calcium into the cells and results in oxidative stress. Therefore, this is why benzodiazepine drugs when given, act by bringing back the balance of the neurotransmitters and are considered the best choice in case of AWS.^{[ 34 ]} The pathway of DT is almost similar as a result of recurrent incidents of alcohol withdrawal, a process known as kindling occurs, which involves the excitability and successive toxicity of the nervous system, which acts as a pre‐step to the development of DT. In a few gene studies, it has been reported that in DT, there is the involvement of the neurotransmitters such as dopamine and glutamate^{[ 35} , ^{36 ]} But, some studies contradict the previous line.^{[ 37 ]}

DT occurs for a shorter period, with the condition persisting for 3−4 days and a maximum to a period of 8 days, and typically ends with a long sleep.^{[ 38} , ^{39 ]} Deaths due to DT are mostly because of complications involved in withdrawal seizures, improper cardiac heartbeat, hyperthermia, or medical‐related disorders. In India, a study conducted showed a mortality rate of 13% among the patients admitted to the surgical wards. This value was much higher when compared to the literature obtained from International Paper.^{[ 39 ]} Another study indicated a mortality rate of 11% with patients admitted due to injury to the head. This might be because of the comorbidities that caused a rise in the mortality rate.

Apart from this, other risk factors such as low levels of magnesium, old age, and the increase in the AWS severity may help predict the incidence factor of DT.^{[ 39 ]} It was also reported in a couple of studies that Gamma Glutamyl Transpeptidase and Alanine Transaminase may also help in significant prediction.^{[ 40 ]} More in‐depth knowledge and research are required in this field the area.^{[ 41 ]}

Dopamine and glutamate involvement in DT

There are different neurotransmitters which are involved in the pathogenesis of DT some of them are dopamine and GABA and glutamate. Dopamine elevation has been scientifically linked to the onset of delirium. Dopamine is linked to many different metabolic processes and channels of calcium, which contribute to significant spikes in dopamine under stress from oxidative damage. Calcium entry into cells boosts the production of dopamine and uncouples oxidative phosphorylation in the mitochondria of the brain. The result is a rise in the generation of toxic dopamine metabolites and a decline in the ATP generation, which suppresses catechol‐O‐methyl transferase (COMT) activity, an essential enzyme for the creation and destruction of dopaminergic in the region of the prefrontal cortex.^{[ 42} , ⁴³ , ^{44 ]} As a result, a rise in dopamine levels may result in hyperactive delirium symptoms such as delusions and hallucinations.^{[ 44 ]} According to several studies, low dopamine levels promote the middle brain and prefrontal regions' atrophy.^{[ 45} , ^{46 ]} We suspect that dopamine is involved in the full chain of biochemical and behavioral actions that may end in delirium. Both glutamate and GABA are believed to be linked to the onset of delirium.^{[ 43 ]} GABA is metabolized by glutamate, a neurotransmitter that inhibits activity. Withdrawal from sedative and hypnotic medication may result in a reduction in GABA levels, which can lead to delirium.^{[ 43 ]}

2.1.2. AWS

When a person who consumes alcohol in excessive amounts and persistently over a long‐time duration stops abruptly, symptoms showcased by such individuals after 6−24 h have been characterized under AWS. The symptoms include seizures, psychotic behavior, among others. For the prevention of seizures, drugs such as benzodiaphenes (long‐acting—diazepam or intermediate‐acting—lorazepam), antiepileptics (such as carbamazepine as a benzothiophene substitute), and psychotic behavior antipsychotics (such as haloperidol) have been suggested.^{[ 34 ]} One of the many side effects in alcoholics has been observed to be malnourishment, more precisely thiamine (vitamin B1), causing a higher risk of developing Wernicke encephalopathy.^{[ 8} , ^{47 ]}

2.1.3. Alcohol abstinence

One of the major steps toward treatment is the acceptance by the patients that they are alcohol addicted. Alcohol abstinence can help resolve various hepatic disorders and help improve the survival rate of cirrhotic liver patients. And hence here lies the major challenge, to preventing relapse in such patients. One of the emerging treatments and management methods is the psychological group support meetings for remaining sober for quite a long time. Simultaneous recognition and treatment of any psychiatric conditions displayed by the patients may deem helpful.^{[ 8 ]} In individuals who have been habituated to heavy drinking, pharmacotherapy (e.g., drugs like acamprosate) may help resist alcohol intake.^{[ 48} , ^{49 ]}

In contrast, drugs like topiramate help reduce the craving for alcohol intake.^{[ 50 ]} Another similar example is disulfiram which induces pain in the abdominal region and causes vomiting and nausea; such uneasiness discourages patients from alcohol consumption.^{[ 8 ]} One thing to note here is that these drugs have yet to pass the approval from FDA for treating ALD, only used for treating the issue of dependency on alcohol.^{[ 51 ]} In an experimental trial, baclofen and placebo were compared on their effectiveness in controlling the urge of patients to consume alcohol. It was observed that baclofen had caused the patients to reduce the number of drinks daily.^{[ 52 ]} Few drugs have been seen to have induced hepatotoxicity in patients with problems in the liver, and thus, it has been suggested that such drugs should not be given to them.^{[ 53 ]}

Other factors such as obesity and smoking pose a risk that may act as independent risk factors and may progress to alcohol LD. Therefore, instead of leading a sedentary life, physical exercise and a decline in smoking may be helpful. Viruses such as hepatitis C (HCV) virus have also been seen as another independent factor that increases the risk for ALD^{[ 54 ]}; by increasing oxidative damage and a change in the immunity of the cells. Therefore, screening for this virus may be helpful before the treatment process begins.^{[ 8 ]}

2.1.4. Alcohol psychosis

It is necessary to recognize the comorbidity pattern of disorders based on alcohol use and various psychiatric disorders to know which one is seen first in the patients and properly understand the connection between them, which might help treat the already existing disorders. Aggression and breaking the rules become the externalizing disorders, while fear and sadness become the internalizing disorder. Under such a situation, disorder based on alcohol use has been assorted under the factors of externalizing type. Further, it may be noted that this conforms to substance use disorders and is a subfactor of AUD.^{[ 55 ]}

Along with this, sometimes personality disorder also commonly occurs parallel with ASD. Such individuals usually resort to aggression, seem to lack empathy toward others, may manipulate and lie, and may also have suicidal tendencies.^{[ 56 ]} In the United States, AUD and anxiety‐related disorders have been put under the highly prevalent diagnoses of psychiatric disorders.^{[ 57 ]} It has been estimated in various epidemiological surveys that the prevalence of the use of alcohol in individuals who have anxiety‐related conditions has an approximate range of 30%.^{[ 58 ]} A study in young adults of the age group of 19−21 indicated that social anxiety disorder was found to increase the AUD risk at a young age, especially in women.^{[ 59 ]} Psychotic disorders induced by alcohol may occur secondarily due to schizophrenia or triggered by overconsumption of alcohol. Or it may arise as a coincidence of schizophrenia in individuals addicted to alcohol.^{[ 60 ]}

Studies have suggested that patients who have bipolar disorder and simultaneously have a history of alcohol use have a higher risk of developing neurocognitive issues when compared with patients who do not have bipolar disorder.^{[ 61} , ^{62 ]} Bipolar disorder has been seen to have a genetic disposition and may be inherited in families; therefore, it could be hypothesized that AUD may seem to have been causing a trigger to bipolar disorder, though the evidence obtained is much less.^{[ 22} , ^{62 ]}

2.1.5. Wernicke−Korsakoff syndrome

Caused by thiamine deficiency, this syndrome has been listed as lethal under neuropsychiatric conditions.^{[ 63 ]} This particular syndrome has been seen to have occurred frequently in patients who have chronic alcoholism and includes both Wernicke encephalopathy and Korsakoff syndrome and hence the name.^{[ 64 ]} But, this could also happen due to infections, malnutrition, certain GI tract diseases, or certain psychiatric disorders such as schizophrenia.^{[ 63 ]} In a majority of patients, this WKS syndrome is not diagnosed properly. The symptoms of Wernicke encephalopathy include those of ataxia and ophthalmoplegia; these have been observed in as less as 30% of the patients and leading to death in almost 20% of the patients observed.^{[ 65 ]} The diagnosis may be done based on the change in the mental state or abnormalities in the oculomotor function, or any deficiency in the diet.^{[ 64 ]} Wernicke encephalopathy progresses to Korsakoff syndrome, which could be managed with the early treatment of Wernicke encephalopathy with high thiamine dosage, given parenterally, which will help in the improvement of the prognosis and reduction in the progression toward the Korsakoff syndrome.^{[ 66 ]} Korsakoff syndrome usually follows after an episode of Wernicke encephalopathy, which may be regarded as a permanent neuropsychiatric condition characterized by amnesia.^{[ 67 ]} According to a study conducted, it was seen that in 3 patients out of 4, various other comorbidities might indicate a state of confusion in the patient, such as dementia, heart disease, and so on; this could be inconclusive to WKS alone. Hence, treatment with thiamine helped better understand the prognosis of the disease, but more insights are required.^[ 68, 69 ^]

3. WHOLE‐BODY EFFECTS OF ALCOHOL

3.1. Positive effects of alcohol on the body

The effects of moderate amounts of alcohol on reducing stress are beneficial. It has been shown that decreased and low dosages of alcohol intake would augment the level of expression such as euphoria, happiness, pleasant, and conviviality with carefree feelings. A study found that an equal dose of the drug attenuates self‐consciousness, tension, and depression. Along with the low dosage of alcohol consumption would decrease cognitive performance inclusive of short‐term memory, problem‐solving, and geropsychiatric problems.^{[ 70 ]} It is proven that decreased intake or moderate intake of alcohol would reduce cardiovascular risk. Alcohol intake (30 g/day) would increase the level of HDL thereby it protects from 17% of the coronary heart disease. Along with that, alcohol affects antioxidants in LDL, further, it reduces the generation of atherosclerotic plaque.^{[ 71 ]} Moderate intake of alcohol reduces the risk of cardiovascular via an antithrombotic mechanism. In addition to that, it decreases the fibrinogen concentration in plasma and further attenuates the agreeability of the platelets. In the case of diabetes, moderate intake of alcohol augments the sensitivity of the insulin in skeletal muscles, which would defend from obesity and its associated diabetes.^{[ 72 ]} A meta‐analysis study by Corrao et al. shows that there is a difference in the alcohol protective effect based on gender. The intake of alcohol from 10 to 31 g/dL would have a high protective effect in women than men. In the case of men, the intake of alcohol from 25 to 87 g/dL has an increased protective effect. This shows that alcohol intake has a protective effect at low dosages in women compared to men.^{[ 73 ]} Thereby protecting from coronary heart diseases. Moderate intake of alcohol in humans would decrease the inflammatory process at monocyte and suppresses the level of Nf‐kb and IL‐10.^{[ 74 ]}

3.2. Alcohol hepatitis

Intake of alcohol beyond a certain limit (10 g/day) was seen to be an associated increase in the levels of viral RNA of HC in the serum.^{[ 75 ]}

It has been seen in patients having HC virus infection, more pronounced fibrosis, and an increase in the cirrhosis rate is associated with alcohol abuse, which is mediated by a rise in oxidative stress. It has also been seen that the HCV is present in a higher amount in alcoholics.^{[ 76 ]} Studies have also shown that in the event of alcohol abuse in chronic HC patients, a significant increase occurs in the risk value of All‐Cause (ac) type mortality.^{[ 77 ]} Viral hepatitis and alcohol consumption has been seen to cause alterations at the molecular level in the liver ranging from oxidative stress, weakening in the immune system functioning to cytotoxicity. Alcohol has been found to cause an enhancement in the progression of the same.^{[ 78 ]} In patients with hepatitis B virus cirrhotic patients, alcohol abuse led to an increase in HC cancer^{[ 79 ]}

Alcohol intake from less and up to moderate levels (average intake of alcohol: 15 g/day) has increased HC cancer in events related to HC virus‐related cirrhosis. The risk of HC cancer has been seen to rise with intake levels of alcohol.^{[ 80 ]}

3.3. Alcoholic cirrhosis

A study found that regular drinking among men led to an increase in the alcoholic cirrhosis risk with recent alcohol consumption compared to consumption in an earlier life was linked to alcoholic cirrhosis risk.^{[ 81 ]} Alcoholic cirrhosis patients are prone to infections that may be linked to an innate type of immune response being defective or a reply to inflammation maybe not be proper in them.^{[ 82 ]} In studies, it has been seen that cirrhosis‐related mortality is due to several complications ranging from hepatic encephalopathy, bacterial infections, variceal bleeding, and hepatorenal syndrome, to HC carcinoma. It has also been seen that it promotes the occurrence of numerous comorbidities as well.^{[ 83 ]} Alcoholic cirrhosis is said to present the end stage of alcoholic LD.^{[ 53 ]} Another study showed that in alcoholic cirrhosis cases, vitamin D deficiency is prevalent.^{[ 84 ]}

3.4. Variceal bleeding

Alcohol abuse has been found to cause variceal bleeding and has been found seen to be one of the reasons for death in alcoholic cirrhosis patients.^{[ 85 ]} Consumption of alcohol has been seen to cause variceal bleedings, which also explains the increase in portal pressure due to alcohol intake.^{[ 86 ]} In patients with alcoholic cirrhosis, it has been found that the mortality rate in the initial 6 weeks after the occurrence of variceal bleeding has been quite high.^{[ 87 ]}

3.5. Ascites

Studies on a patient with ascites showed alcoholic cirrhosis is one of the major reasons for its occurrence.^{[ 88 ]} Approximately half of the patients diagnosed with “compensated” cirrhosis, which means they have not developed one of these complications, developed ascites for 10 years of the observation period. Another study has shown that approximately half of the individuals with alcoholic cirrhosis had ascites development during a period of observation for 10 years.^{[ 89 ]} It was seen that there had been a higher complication risk in patients associated with alcoholic cirrhosis. Patients with alcoholic cirrhosis saw numerous complications being present in a study on a Danish population. The presence of ascites is one of them, which can be considered a mortality predictor.^{[ 90 ]} It has been seen that within 10 initial years of cirrhosis being diagnosed, half of the patients were seen to have developed ascites, and its development is associated with a bad prognosis.^{[ 91 ]}

4. EFFECT OF ALCOHOL ON NEUROTRANSMITTER

Alcohol has significant effects on various neurological pathways, such as GABA, dopaminergic, glutamate pathways, and serotonergic.^{[ 92 ]}

4.1. Interaction of neurotransmitters with alcohol

Alcohol has been seen to have caused acute reinforcing effects because of its interaction with the brain's neurotransmitter system. The addiction rate of an individual toward consuming alcohol increases. It has been observed that alcohol relapse and symptoms related to alcohol withdrawal were because of a decrease in dopamine functioning in individuals dependent on alcohol.^{[ 92 ]} Furthermore, studies have shown that an increase in alcohol consumption and alcohol craving is associated with the DRD2 gene in alcoholic patients.^{[ 93 ]}

4.2. Alcohol and secondary psychological conditions

Ethanol's high consumption has a major and direct effect on the brain affecting its functions at both chemical and hormonal levels, which work as the basic cause of multiple disorders associated with an individual's mental health.^{[ 94 ]} Some common diseases associated with heavy alcohol‐consuming people are:

4.2.1. Depression

Mood swings that are not too intense to be named as a disorder are found to be very familiar symptoms described to psychiatric patients showing effects to most of the alcoholic population.^{[ 95 ]} Mood swings are quite prominent and common symptoms in the lives of the population. These difficulties with mood handling may show some further problems with either affecting the brain or provoking more symptoms describing disorders that are close to classified as Depression and finally may also lead to a condition that has a probability to coexist with other disease features, which is commonly observed in 30%−40% of the alcoholism‐related cases. Although it's still an arguable discussion to conclude the exact relation depression has with alcoholism.^{[ 96 ]}

4.2.2. Bipolar disorder

The epidemiology department has surveyed this disorder as the second highly occurring one when it comes to alcoholism in the previous 20 years. It marks second in the conditions measured by axis I disease, usually related to alcohol or any drug abuse cases. It was reported that most maniac patients tend to submit themselves to addiction to some drugs or alcohol at some part of their ill lifestyle. The familiarity between the symptoms of bipolar disorder and other mood‐related disorders such as mood swings makes a diagnosis of this disorder quite challenging, decreasing the efficiency of the diagnosis results. Although it's a common feature to see people with bipolar disorder show alcohol abuse, it's also observed that these patients tend to show addiction toward drugs like cocaine and others, too, thereby increasing the complications that come when diagnosing the disease.^{[ 95 ]}

4.2.3. Anxiety

Disorders associated with anxiety are not much of a common occurrence in people when compared to others. It's highly crucial to separate anxiety disorders that originate through alcohol intake from those that occur for several other reasons. These can be differentiated with the period the last for. Furthermore, it appears to see people with a habit of chronic alcohol intake show greater symptoms of panic attacks, social anxiety, and PSTD.^{[ 97 ]} The symptoms associated with alcohol addiction in patients usually range between anxiety or depression or antisocial activities and psychosis seen during or after their alcoholic period. Sometimes these behavioral patterns may all occur together, and the patient may show signs of psychiatric disorders, which are mostly based on alcohol intake leading to syndromes. These disorders happen to decline in their occurrence when the patient has not been exposed to intoxication for some time. The existing commonality between these disorders to other psychiatric conditions increases the possibility of errored diagnosis. Therefore it's important to understand the patient's history and have a proper understanding of the symptoms of each disorder while diagnosing patients with complaints of panic attacks, mood swings, anxiety, and many other commonly shared symptoms.^{[ 98 ]}

5. SIGNALING PATHWAYS AFFECTED BY ALCOHOLISM

5.1. Serine‐threonine kinases

These enzymes are considered a major class with similar heterogeneous phosphorylation substrates of different proteins on serine or threonine sediments.^{[ 99 ]} Few of these are receptors, while greater classes of these are kinases of proteins. Some of these are calmodulin or calcium‐dependent protein kinases and mitogen‐activated protein kinases.^{[ 96 ]}

5.2. Protein kinases—cAMP‐dependent

Protein kinase A shows an important part in response to abuse of drugs at a behavioral level, in memory as well as learning.^{[ 96} , ^{97 ]} PKA is activated when cAMP binds to various regulatory subunits, leading to the dissociation of these subunits from their catalytic subunits, causing them to become activated.^{[ 99 ]}

5.3. Ethanol regulation of AC

It has been observed that drugs that are easy to get addicted drastically enhance the dopamine concentration in the extracellular region of NAc, which was followed to be the same with the ethanol consumption table. It's reported to activate AC and PKA by activating the receptor of D1 dopamine, which works together with Golf and Gs. Furthermore, it also activates other receptors of dopamine like D2, which work together with Gi/o, thereby inhibiting multiple isoforms of AC. This follows a chain reaction of activation of different channels and finally leads to a decline in the excitability rate of neurons. Still, the response changes when NAc neurons need simultaneous activity/stimulation of two receptors D1 and D2.^{[ 100 ]}

In rats, it was observed that in the limbic area and also in subcortical motor areas, the concentration of dopamine in the extracellular region was enhanced because of alcohol by a mechanism in which many signaling pathways of AC/PKA/DARPP‐32 in NAc were activated.^{[ 101} , ^{102 ]} In rats, ethanol caused the increase in dopamine neuron firing in the brain's VTA region, which was observed when a dosage of 0.5 and 2 g/mg was given.^{[ 103} , ^{104 ]} In mice, AC activation was observed, which resulted from the enhancement of a receptor called dopamine D1. This enhancement of a receptor called dopamine D1 was due to alcohol.^{[ 105 ]} When alcohol was added to the cell culture of the rat's brain, we observed that the reuptake of adenosine was inhibited by alcohol. Therefore it showed indirect activation of A2a receptors which are Golf coupled adenosine in nature. This inhibition involves nucleoside transporters which caused adenosine concentration enhancement extracellularly.^{[ 106} , ^{107 ]} When NG108‐15/D2 cells and primary neurons of the nucleus accumbens were administered with addictive drugs via cell culture (transfection), it was observed emission of Gβγ subunits happens with activation of Golf as well as D2 dopamine receptor, which is done by the stimulation of ACs working together with A2a receptor stimulated by the intake of addictive drugs at minute concentrations.^{[ 108} , ^{109 ]} In S49 cells of the whole body, it was observed that a dosage of 2.4 mg/mL caused this activation of the subunits lead to a unique CRE conveyed expression of genes which is observed in both NAc as well as in a variety of different limbic areas of the brain^{[ 110 ]} (represented in Table 1).

Table 1.

Showing ethanol regulation of AC in different animal models.

Serial no	Animal model	Organ studied	Substance involved	Dose given	Mode of administration	Result	References
1	Rats	Limbic area, subcortical motor area	Dopamine	0.5 mL/100 g and 0.1 mL/100 g	Surgery (via tubes)	Alcohol enhances dopamine concentration in the extracellular region by activating many signaling pathways of AC/PKA/DARPP‐32 in NAc.	101,102
2	Rats	Brain	Dopamine	0.5 and 2 g/mg	NA	Ethanol increases the dopamine neuron firing of the VTA region.	103,104
3	Mice	Brain	Dopamine	50 µg/mL	Transfection	Alcohol furthermore motivates the AC activation conveyed by the enhancement of a receptor called dopamine D1.	105
4	Rat	Brain	Adenosine	NA	Cell culture	Alcohol also inhibits adenosine reuptake, thereby indirectly activating receptors called A2a, which are Golf coupled adenosine in nature. This inhibition occurs by nucleoside transporters which are type one equilibration, thus enhancing adenosine concentration extracellularly.	106,107
5	NG108‐15/D2 cells and primary neurons (cell culture)	Nucleus accumbens	Dopamine D2 receptor	NA	Cell culture (transfection)	Emission of Gβγ subunits happens with activation of Golf and D2 dopamine receptor, which is done by stimulating ACs working togetherly with the A2a receptor produced by the intake of addictive drugs at minute concentrations.	108,109
6	Whole‐body	S49 cells (cell line)	Adenosine	Adenosine	NA	The activation of the subunits causes a unique CRE conveyed expression of genes in both NAc as well as in varied different limbic areas of the brain.	110

5.4. Anxiety and ethanol consumption‐regulation by PKA and CREB

Much research was done to understand the importance of PKA in alcohol intoxication. One of the works was done on rats to explain how inhibiting PKA by administering specific inhibitors by ICV mode can decline the phenotypic effects similar to ataxia or hypnosis.^{[ 111 ]} Similarly, a decline in these effects of alcohol consumption was observed when the RIIβ knockout mouse was used to study. It showed you decreased PKA action majorly promoted by the cAMP mechanism.^{[ 112 ]} Another study on knockout of PACAP in mice mostly assumed to have a deficiency in the signaling of PKA reported a decline of the above‐mentioned clinical features as a response to alcohol, alongside regulating the intake of alcohol done by the signaling of PKA as well as changing the response at behavioral level toward alcohol. Therefore, it can be said that these mice, which have RIIβ knockout in them, manifest declination in PKA action, which is promoted by cAMP and increasing the intake of alcohol.^{[ 112 ]}

5.5. Protein kinase C

PLC has many isoforms from which β and γ are widely discussed. The isoform β becomes active when ligands are bound by the receptors that are G‐coupled in nature. This stimulation of tyrosine kinase receptors recruits its phosphorylation (tyrosine) alongside activating PLCγ. PKC on becoming active usually causes PKC translocation between the cellular compartments, which possess activators of lipids and proteins that link with kinase, which is dynamic and present close to substrates.^{[ 111} , ^{113 ]}

5.6. Extracellular signal‐regulated kinases (ERKs)

Antibodies that are phospho‐specified can be used to measure the MEK phosphorylation process done on ERKs, which helps in assaying the ERK considering the MEK phosphorylation shows activation of ERK1 as well as ERK2. It has been seen that various research have been done to understand this correlation, thereby offering a possibility that when some conditions are maintained there is a possibility to see that ERK1 and ERK2 can be activated when alcohol stimulates the dopamine signaling pathway.^{[ 114 ]} At this point, it can be said that alcohol shows incidental activation of both ERK through upregulation of BDNF accompanying signaling pathways in the dorsal cranium region. However, the exact mechanism of ERK inhibition by alcohol is still unknown. A study in the cortex, cerebellum, and hippocampus of adult rats with a greater concentration of alcohol dosage for 1 h via vapors showed an inhibiting effect on ERK signaling in the regions mentioned above of the brain.^{[ 115 ]} A regular or sporadic alcohol dosage showed inhibition in ERK in the amygdala, PFC, and dorsal stranium areas in the brain.^{[ 116 ]} Alcohol dosage in NAc via sporadic but systematic manner in coronal sections of the forebrain region of C57BL/6 mouse showed that it did not alter the phosphorylation of ERK.^{[ 117 ]} When NAC, BNST, and CeA were treated with alcohol dosage, there was ERK activation seen. It was also observed that dopamine D1 receptors could prohibit ERK action at basal and ethanol stimulated levels as antagonists.^{[ 118 ]} In rats, alcohol via injection led to an observation that the nucleus accumbens was shown to be effective at low levels and the cortex (medial prefrontal) showed simultaneous and temporary ERKs dephosphorylation in AA rats who prefer alcohol no effect in alcohol not choosing ANA rat.^{[ 119 ]} In the cerebellum, dorsal striatum, and amygdala (greatly affected), we observed an enhancement in ERK action while there is an alcohol withdrawal.^{[ 116 ]}

When a drastic intake of alcohol dosage was administered in male Wistar rats, it was observed in many regions that early gene c‐fos could undergo transcription upon activation of ERK. Thus, alcohol can promote c‐fos. NAC shell, cortex region (frontal orbital) of rats (dependent on alcohol) inhibition of c‐fos is observed via an ERK signaling pathway. This demonstrates the possibility that ERK could act as a homeostatic response. Thus, it represses the alcohol‐stimulated c‐fos expression via various signaling mechanisms.^{[ 120 ]} When mice (C57BL/6J) were orderly administered with alcohol dosage, it was observed that MEK inhibitors SL327 on administration could enhance effectual self‐administration of alcohol. Finally, it can be said that the effect of alcohol on the signaling process of ERK is a dependent process mostly on brain regions under study and understanding the dependency state of animals on alcohol. Therefore, it can be assumed that the BDNF pathway shows an inhibitory effect over alcohol consumption and also through ERK signals^{[ 114 ]} (represented in Table 2).

Table 2.

Showing the effect of different dosages of alcohol in ERK signaling in animal models.

Serial no	Animal model	Regions involved in the study	Alcohol dosage	Mode of exposure	A time period of exposure	Outcome	References
1	Adult rats	Cortex, cerebellum and hippocampus	Greater concentration	Vapors	1 h	On severe exposure inhibiting effect on ERK signaling at the cortex, cerebellum, and hippocampus regions of the brain.	112
2	Adult rats	The amygdala, PFC, and dorsal stranium	Regular or sporadic	Vapors	12 days	Subjection shows inhibition of ERK in other regions of the brain.	113
3	C57BL/6 mouse	Coronal sections of the forebrain, NAc	Around 2 g/kg	In NAc	Sporadic but systematic	Exposure has not altered phosphorylation of ERK.	114
4	SD‐rats	NAc, BNST, CeA	1 g/kg	‐	15 min	ERK was activated and shown that dopamine D1 receptors can prohibit ERK action at basal and ethanol, stimulated level acting as an antagonist.	115
5	AA rats	Low level and cortex (medial prefrontal), NAc	Alcohol‐ 25% v/v‐ 1.5 g/kg—body weight	Injection	20−45 min	Nucleus accumbens is shown to be effective at a low level, and cortex (medial prefrontal) showed simultaneous and temporary ERKs dephosphorylation in AA rats which prefers alcohol while showing no effect in alcohol not selecting ANA rat.	116
6	Wistar rats	Cerebellum, dorsal striatum, and amygdala (greatly affected)	‐	‐	‐	ERK action is enhanced while alcohol withdrawal.	113
7	Male Wistar rats	Many regions	Many regions	‐	‐	Immediate‐early gene c‐fos can undergo transcription upon activation of ERK. Of alcohol can promote c‐fos.	117
8	Rats (dependent on alcohol)	NAC shell, cortex region (frontal orbital)	‐	‐	‐	Inhibition of c‐fos is observed via an ERK signaling pathway. Explains the possibility that ERK could act as a homeostatic response which represses the alcohol stimulated c‐fos expression through various signaling mechanisms.	117
9	Mice (C57BL/6J)	‐	‐	‐	Orderly administered	MEK inhibitors SL327 on administration can enhance effectual self‐administration of alcohol.	111

Abbreviation: ERKs, extracellular signal‐regulated kinases.

6. INVOLVEMENT OF SCAFFOLD PROTEIN

Scaffold proteins are necessary for multiple binding proteins together at the same time, lining up the binding partners so that they look like a functional unit resulting in a structured signaling cascade.^{[ 121 ]} Scaffold protein directs many essential signaling pathways and is many. Inside the cell, large complexes are formed when signaling molecules associate with each other and stay attached to the cell membrane, unlike others which eventually move to the cytoplasm. The large complex is termed a signalosome. Signalsome is made up of several components, among which one is scaffold protein which uniquely has no enzymatic activity.^{[ 122 ]} By function, it lays out a framework for other members and hence helps them to work efficiently. It provides a central point for the interaction of signaling proteins, their respective substrate, plasma membrane, cytoskeletal network, and intracellular organelles. It also aids in giving a medium that can carry out spatially and temporally divided events. They are core regulators of signaling pathways as they order negative and positive feedback signals. Alteration in the interaction pattern of scaffold proteins or with respective binding partners is observed in neuroadaptations in ethanol.^{[ 123 ]} Neuroadaption is the process wherein the body reimburses the presence of a chemical and adapts to function in a usual manner.^{[ 124 ]}

6.1. RACK 1

The receptor of activated protein C kinase 1 (RACK 1), which was observed in high amounts in the human central nervous system, was discovered as an anchoring protein.^{[ 125 ]} It is coded by the GNB2L1 gene, which has seven introns and eight exons categorized as a relatively smaller gene. Structurally, the ORF region of the gene is 1142 bp. RACK 1 protein has 317 amino acids. It has a significant role in the subcellular distribution and function of various proteins and regulates essential signaling pathways.^{[ 126 ]} To date, more than 80 binding partners of RACK 1 have been recorded; however, many of them do not associate with RACK 1 directly. RACK 1 has a different role in distinct cell types though the basic nature of expression has not changed.^{[ 106 ]}

RACK 1 has a seven‐bladed β propeller structure, and it allows the various protein to associate with multiple binding partners along with enzymes' intracellular tails of the receptor.^{[ 117 ]} However, the internal structure of RACK 1 undergoes alteration upon interaction with a stimulus. Ethanol exposure to a cell may result in modifications in intracellular localization. Interestingly, translocation induced by ethanol of RACK 1 to the nucleus results in heightened expression of BDNF in some parts of the brain.^{[ 127 ]} Recent research suggests that when BDNF is highly expressed, stimulated by RACK 1 has a role in the homeostatic pathway^{[ 128 ]} (represented in Figure 2).

Figure 2.

This diagram shows the effect of ethanol exposure on cells which results in the alteration in the intracellular localization. This alteration leads to RACK 1 translocation into the nucleus, with a subsequent increase in the expression of BDNF depicted by a black arrow, which leads to changes in the homeostatic pathway.

6.2. Homer

Homer proteins are basic linked scaffolding proteins. They are produced by genes‐ Homer 1, Homer 2, and Homer 3.^{[ 129 ]} They generate essentially expressed extended isoforms‐ Homer 1b, Homer c, Homer d, Homer 2a, b, Homer 3, and a short isoform—Homer 1a.^{[ 130 ]} Structurally, the long isoform accommodates—the coil domain and leucine zipper motif. This structure permits them to appear as multimers.^{[ 131 ]} Homer protein holds the protein−protein interaction binding motif enabled vasodilator‐stimulated phosphoprotein homology 1, which implements the immediate interaction of homers with numerous proteins. They attach ion channels and receptors intracellular calcium storage, and cytoskeleton, to multiple signaling cascades.^{[ 132 ]}

A diverse study shows that Homer 2 isoform is essential for the action of ethanol. Higher‐level consumption of ethanol results in an increase in the expression levels of HOMER 2 in mice NAc. This rise continues post 2 months after the last episode of ethanol consumption.^{[ 133 ]} Research has proven that an elevated amount of ethanol consumption increases the expression of homer protein, provided the increase lasts for 2 months following the last drinking session. Earlier research groups have concluded that an elevated amount of ethanol ingestion enlarges Homer proteins in the NAc through mTORC1, likely to issue a structure for ethanol interfered induction of protein levels of Homer 2.^{[ 134 ]} Ingestion of ethanol in Homer 2 knockout mice is observed to be reduced compared to mice of wild type in a 2‐bottle choice continuous access paradigm. It is not seen to grow ethanol place preference or locomotor sensitization toward ethanol. Homer 2 knockout mice rather display disinclination toward ethanol place and an enhanced hypotonic response to the elevated amount of ethanol in contrast to wild‐type mice. Furthermore, Homer 2 knockout mice never display definite feature neurochemical modification correlated with replicated ethanol management.^{[ 135 ]} Excitingly, the donation of the Homer gene to measure the Ethanol has also been distinguishing in Drosophila, requiring the Homer gene to display enhanced sensitivity to sedative steps ethanol and never mature critical tolerance to ethanol.^{[ 136 ]}

6.3. PSD‐95

The postsynaptic density protein of 95 KDa congregates NMDARs located at glutamatergic synapses attaching the receptor to the cytoskeleton and subsequently signaling proteins to control the channel functioning.^{[ 137 ]} The protein PSD 95 is incriminated in synaptic plasticity basic learning. Current studies tell us that PSD‐95 knockout mice demonstrate a considerable amount of intoxication of Ethanol and appear smaller voluntary ethanol ingest compared to other littermates of the wild type. Even though the pair of genotypes display homogenous ethanol levels, partially the wild type other than PSD 95 knockout mice continued their inclination toward Ethanol post 14 days. Remarkably, the deficiency allocated to PSD 95 deletion never appears to require the modified function of NMDAR antagonist increased intoxication of ethanol to a related degree in a couple of genotypes.^{[ 138 ]}

7. HUMAN GUT MICROBIOMES

7.1. Dysbiosis

Alcohol addiction is linked to the disability of absorption in the duodenum region, resulting in a reduction of storage of thiamine in the liver and malnutrition. Though alcohol liver disorder is a lifestyle disease, it can be avoidable as other conditions such as fibrosis and alcohol hepatitis.^{[ 139 ]} But despite the fact still, alcohol disorder prevails to be one of the most usual sources of death.^{[ 140 ]} The relationship between alcohol liver disorder and gut microbiota has been established in early research. For patients who are suffering from alcoholism, it is often observed that ingestion of alcohol collapses the gut microbiome function, termed a leaky gut.^{[ 141} , ¹⁴² , ^{143 ]} The main components of the intestinal barrier are goblet cells, enterocytes, substances antimicrobial in nature which influence the microbiome of the intestinal region inside a layer of mucus, and various cells of the immune system in lamina propria.^{[ 144 ]} The research behind the occurrence of leaky gut is still understudied.

Nonetheless, intestinal dysbiosis is considered to be a major contributing factor to leaky guts.^{[ 145 ]} Any type of variation in gut microbiota is termed intestinal dysbiosis. This is distinguished by any modification of intestinal bacterial taxa—which can be either a diminishing level of anti‐inflammatory bacteria or maybe an escalated level of proteobacteria.^{[ 146} , ^{147 ]} Several in vivo studies have confirmed that development in intestinal barrier unity can improve liver damage affected by alcohol consumption.^{[ 148} , ¹⁴⁹ , ^{150 ]} The above research lays a foundation for the treatment involving the alteration of gut microbiota to cure alcoholism. Constant utilization of alcohol can alter the pH of fecal matter, encouraging excess growth of pathogens. If observed for a long time, it also modifies the functionality of the gut microbiome. The modification of functionality involves interchanging particular secretions of metabolite engaged in gut barrier dysfunction.^{[ 151} , ^{152 ]} Patients suffering from AUD/alcoholism frequently display increased levels of plasma cytokines—TNF alpha, CRP. This demonstrates long‐term, low‐grade, systemic inflammation.^{[ 153 ]}

Besides, studies are establishing a relationship between psychiatric disorders and systemic inflammation.^{[ 154} , ^{155 ]} An assumption for the relationship between alcoholism and systemic inflammation can be that products of intestinal bacteria trigger the peripheral blood mononuclear cells along with cytokines. They pass on to the bloodstream causing low‐grade systemic inflammation in the patient's body suffering from alcoholism.^{[ 153 ]} Alcoholism is linked to various disorders of the mind such as bipolar disorder, and major depressive disorder.^{[ 156 ]} Sometimes mood disorders often follow the beginning of alcoholism. Systemic inflammation gives rise to inflammation of the gut and liver and gut microbiome imbalance. This may give rise to peripheral inflammation and brain inflammation, where the brain cells (microglia) are affected directly.^{[ 156 ]}

7.2. Importance of homeostasis, eubiosis, necrobiosis

The human body's gut is a very complicated and strong network with a continuous interplay between the host and gut microbiota^{[ 157 ]}—the interaction among the two forms a symbiotic, balanced, and cooperative relationship. The homeostasis of the gut is essentially the condition of acceptance and defiance of internal and external changes.^{[ 130 ]} Commensal microbiota is responsible for maintaining and regulating gut homeostasis. Gut microbiota has incorporated all microorganisms inside the GI tract.^{[ 158 ]} The microorganism in the gut ranges from bacteria, eukaryotes, viruses, and fungi. Microbiome implies the complete assembly of microbial genes in a specific habitat.^{[ 159 ]} By NGS, metagenomics made it possible to know the factors causing disturbances in the human microbiome (HM), essentially contributing to the disease phenotype. The previous estimation of microorganisms in the GI tract showed that approximately 10¹³ to 10¹⁴ bacteria are present.^{[ 160 ]} The main factors that affect the composition of microbiota are the host's genotype, the person's diet, and the environment around the person. Motility, digestion, and the harvest of energy mucosal immunity are directly influenced by signaling molecules and metabolic products.^{[ 161 ]} Sometimes the elements of gut microbiota penetrate the bodily circulation. They get transferred to several important organs such as the brain and liver, which causes dysfunction of the organs. When it enters the brain, the person experiences impairment in cognitive functions. Dysfunction of lipid metabolism is observed when the liver gets affected by the elements of gut microbiota.^{[ 162 ]} A healthy microbial system in the body is essential for a healthy human being. The microbial ecosystem of the intestine is called eubiosis.^{[ 163 ]} The intestinal microbiota is classified as richness and evenness, meaning the type of microbe present and their amount, which forms the ecological diversity terms. The physiology of the host and intestinal microbiota are very closely linked.^{[ 164 ]}

This is supported by the fact that. When their physicochemical condition distinguishes different anatomical regions in the GI tract, the situation changes. It applies selective pressure to the microbial community. Normobiosis is the state where the microbiota lives in a relative balance in an individual's body.^{[ 165 ]}

7.3. Factors supporting microbiota development

The gut microbiota is formed at an early stage of development, but it is sensitive to many factors that influence its diversity and development.^{[ 166 ]} The microbiota present in the placenta and amniotic fluid is responsible for colonizing intestinal microbiota inside the uterus.^{[ 167 ]} Several studies described the presence of bacteria and bacteria products in meconium, placenta, and amniotic fluid. Once the child is born, the mode by which they are delivered influences the early life development of gut microbiota. The gut microbiota of children changes to adult microbiota at age 3.^{[ 102 ]} Vegetarian diets are observed to keep the gut microbiota healthy and varied. This is determined by the gut microbiome species, which dominates and metabolizes the insoluble carbohydrates.^{[ 141 ]}

On the other hand, a nonvegetarian diet is linked to the production of short‐chain fatty acids and can even result in the generation of harmful compounds.^{[ 168 ]} When a person consumes an antibiotic, it destroys the pathological, disease‐causing bacteria, and beneficial microbes that are part of the gut microbiome. This results in the loss of essential gut microbiota, leading to dysbiosis.^{[ 169 ]}

7.4. Metagenomic study of the gut microbiome

Recent metagenomic sequencing has described that the bacteria make up the maximum portion of gut microbiota in a healthy individual. In 90% of healthy individuals have two types of gut bacteria—bacteroides and firmicutes.^{[ 170 ]} A study involving samples of 124 Europeans examined 3.3 million nonredundant genes of microbes. A total of 18 species of the microbiome are present in every individual; approximately 57 and 75 species were seen in >75% and >50%.^{[ 171 ]} In another study, Turnbaugh et al. analyzed the human gut houses a functional, core microbiome.^{[ 172 ]} To maintain homeostasis, gut microbiota acts in performing critical metabolic and immunological functions. It has been identified by studies on separate groups that the conservation at the superkingdom level quickly vanishes as we go down the phylogenetic hierarchy leading to “a microbiota fingerprint” of a person at various levels such as the genus level, species level, and strain level.^{[ 173 ]}

It is observed that the gut microbiome is healthier when the person is disease‐free, whereas when the person is in a diseased condition, the gut microbiome tends to get disturbed. At the time of disease, the diversity of the gut microbiome in the human body goes down. For disease development, the proportion of pathological (potential) to beneficial commensal microbes is more important than a particular organism or a group.^{[ 174 ]} Nevertheless, one pathobiont, a commensal transformed as a pathogen, also has disease‐causing potential when favorable genetic and environmental conditions are present. In a more recent discovery, the metagenome has also unleashed the gut virome, which consists of viral species present in the gut. In an experiment, Reyes et al. collected fecal matter samples from twins of monozygotic nature and their mothers. Upon analysis, they sequenced the viromes, which were compared with total fecal DNA. Based on this, it was considered that the gut microbiome, especially the bacteria, was very similar in the mother and monozygotic twins.

On the other hand, even if the individuals are genetically identical, their gut viromes tend to differ. A year‐long longitudinal study was also conducted, taking samples from fecal matter obtained from the same people at various points in time. The result showed that a high majority of virotypes (95%) remain constant, whereas the maximum population of bacteria modified when observed for a long time.^{[ 175 ]}

7.5. Gut microbiome and its role against incoming bacteria

Normal gut symbionts play an important role by establishing a secured community that combats bacteria that is not native and the growth of symbionts. Such occurrence has been termed colonization resistance which dates back to older times.^{[ 176} , ^{177 ]} There can be conditions such as an immature bacterial community, or one which is disturbed by antibiotics or food, and hence colonization resistance cannot be present. It incorporates various associated aspects: (1) Defiance to initial infection, (2) Better toleration of an already existing infection, (3) Removal of infection.^{[ 9 ]} These are a result of continuous competition among common gut residents (essentially commensals, pathobionts). Bacteria use two mechanisms to compete in the gut—direct and indirect.^{[ 178 ]} The microbiota encourages a direct mechanism of colonization resistance by killing and completing resources.^{[ 141 ]} Due to finite sources of nutrients and space inside the gut, the bacteria compete against each other.^{[ 179 ]} During this time, they tend to develop a series of ordnance to destroy the competitor directly. Bacteria that are alike generally use similar niches and nutrients. With time they have developed targeted killing for competition with the same kind.^{[ 180 ]} Indirect‐killing microbes do not compete against each other; they act on the host. This is done by inducing an innate or adaptive immune system and the participation of nonimmune defense.^{[ 181 ]}

7.6. Pyrosequencing to analyze gut microbiome

Microbial cells that flourish inside the body are 10X more in number as compared to our bodily cells. They consist of 100X more genes than cells. Humans and microbial symbionts are regarded as superorganisms. Existing research shows that the microbiota composition in various human body environments such as skin and oral cavities, and nasal passage plays an important part in development, nutrition, and immunity.^{[ 182 ]} With the help of molecular techniques such as next‐generation high throughput sequencing, new bacterial phylotypes are identified, which were not known before. The taxonomic makeup of the microbial community increases the predisposition to develop inflammatory bowel, cardiovascular diseases, and bacterial vaginosis.^{[ 183 ]} Turnbaugh et al. have reported that experiments involving the Chinese population (healthy individuals) have analyzed specific habitats of the body by administering high throughput sequencing techniques.^{[ 172 ]} The results depict various communities of microbes with distinguishable intra‐individual variations and interindividual variations.^{[ 184 ]} The HM project has examined a large unit and collection of different, clinically applicable body habits taken from healthy adults, particularly from the West, to identify the ecology of microbial communities related to the human body. This examination was carried out using 454 pyrosequencing and Illumina sequencing.^{[ 185 ]}

8. INTERLINK BETWEEN ALCOHOL AND HUMAN GUT MICROBIOME

Recently, a metagenomic survey was conducted for the gut microbiota in a group of patients suffering from liver cirrhosis and has been observed to have notable improvement of the bacteria present in the oral cavity. This event is likely because of impaired liver function.^{[ 186 ]} The total functional potential of gut microbiota was assessed with the help of shotgun metagenomics. Further, the comparison study was carried out among healthy subjects and within an individual group of alcoholic patients. Dubinkina et al. reported alterations in the metabolic potential for the metabolic pathway. Various metagenomic studies have defined the gut microbial constitution of people suffering from ALC and ADS.^{[ 146 ]} Most of the projects were carried out with the use of 16s rRNA amplicon sequencing.^{[ 150 ]}

8.1. Correlation of microbiome and phenotype

The gut microbiome is called our second genome. The main genome is housed in the nuclei of cells and encodes smaller than 1% of the total no. of genes encoded by the gut microbiome.^{[ 152 ]} There are many microbial genes, that help in modifying the ingested food material, but they are unable to digest. Few gut microbes can digest plant polysaccharides, giving out small chain fatty acid, which in turn are important nutrients for enterocytes, which lines our gut and chemical messengers that act on our metabolism through gut−brain or gut−liver link.^{[ 187 ]} The gut microbiome is essential for the transformation of oral drugs; hence pharmacokinetics gets affected. Current studies identify the microbiome as an emergent source for phenotypes of human beings, especially in behavior and neurobiology.^{[ 188 ]}

8.2. Role of probiotics and prebiotics

Elie Metchnikoff proposed the idea that gut bacteria act as a regulator for health and disease. He described that toxins secreted by putrefactive microorganisms located in the colon could prevent the growth of other bacteria.^{[ 189 ]} He noticed that a part of the Eastern European population who consumed large amounts of fermented milk had lived longer. He later suggested that good lactic acid‐producing bacteria are needed to maintain the well‐being of the host. They work by bringing down the number of toxic products produced by other bacteria inside the colon, encouraging homeostasis in the host's body. In his experiment, he separated Bacillus bulgaria. He enhanced its usage in therapy to maintain homeostasis and thereby obstruct ageing, and therefore, yoghurt was advised for consumption. This experiment was the basis of probiotics.^{[ 190 ]} Microbe‐associated molecular pattern obtained signaling has consequences on cytoprotection of epithelial regions and survival pathways.^{[ 191 ]}

Pattern recognition receptors (PRRs), nod‐like receptors, have critical parts for maintaining a constant relationship between the host's gut and their microbiota. Probiotics offer many host‐specific benefits, which have been found true based on information acquired from model animals and various clinical types.^{[ 192 ]} They are proven effective in the treatment or even can prevent diseases such as diarrhea after antibiotic use, inflammatory bowel disease, and pediatric allergic disorders. The discovery of probiotics has been proven a boon to humankind as it also helps in the treatment of irregularities, dysfunction of the GI^{[ 193 ]} (represented in Figure 3).

Figure 3.

This diagram is on the effect of alcohol on the human gut microbiome. The black arrows indicate the normal functioning of the human gut microbiome in the body. The colonies provide resistance against the colonization of other harmful microorganisms. On the other hand, probiotics help treat the gastrointestinal tract's dysfunctions, which help prevent inflammatory bowel disease, pediatric allergic disorders, and avoid diarrhea associated with taking antibiotics. Consumption of alcohol disrupts all these functions.

Prebiotics are defined as food components containing oligosaccharide that is indigestible by the host but is beneficial for the host's health. This is carried out by carefully simulating certain particular gut microbiota members' growth.^{[ 194 ]} In recent times, inulin and galactooligosaccharides are considered prebiotics. They are natural ingredients of food present in the form of storage carbohydrates in plants.^{[ 195 ]} Previously only fermented food components were considered prebiotics. Vieira et al. hypothesized that any kind of dietary supplement which can enhance the growth of bacteria of beneficial nature and simultaneously maintains the gut region's homeostasis of the host should be accepted as a prebiotic even if the supplement is unable to fulfill the required criteria.^{[ 189 ]}

9. ABSOLUTE EPIGENETIC REGULATION

Epigenetics is defined as the genetic changes that influence the expression of genes without changing the underlying sequence of DNA.^{[ 196 ]} DNA methylation, modification of histones, and RNA‐associated silencing are the three mechanisms dependent on one another. They can start and assist epigenetic silencing and hence determine genetic changes in gene expression. Modifications in any of these systems result in defected target gene expression or silencing, resulting in epigenetic regulation of human disorders such as cancer and neurological disorders.^{[ 197 ]} There are many types of epigenetic defects and are mainly tissue‐specific. They occur mostly due to environmental elements such as toxins and drugs.^{[ 198 ]} The primary mode of action is altering the secondary or tertiary structure of DNA not to undergo transcription.^{[ 199 ]}

9.1. Histone acetylation

Histone acetylation is controlled by histone acetyltransferase and histone deacetylases by their opposing actions.^{[ 200 ]} The electrostatic affinity between DNA and histone proteins is reduced due to histone acetylation. This enhances a chromatin structure which is freer for transcription of gene.^{[ 201 ]} Histone proteins are one of the main targets of epigenetic changes. A group of specific enzymes can alter them. These enzymes conciliate covalent bonding and transfer chemical groups such as methyl, acetyl, ubiquitin, and phosphate.^{[ 202} , ^{203 ]}

Major studies are concentrating on two types of histone modification: (1) H3K4me3—trimethylation of histone 3, at lysine four residue (2) acetylation of many residues of histone H3 and H4. Long use of alcohol may affect histone acetylation by the gene‐specific increase in H3K4me3, especially in the brain cortex.^{[ 204 ]} Long‐term alcohol use can lead to DNA hypomethylation through various methods such as vitamin B deficiencies. Histone acetylation is increased by acute exposure to alcohol. On the other hand, chronic alcohol addiction elevates the deacetylation of histones.^{[ 205 ]}

9.2. DNA methylation

DNA methylation is an epigenetic process that starts with the covalent transfer of a methyl group to the C5 position of the cytosine ring in the DNA. The whole process is regulated by the enzyme DNA methyltransferases.^{[ 206 ]} There are many pathogenetic mechanisms for carcinogenesis, which are alcohol stimulated.^{[ 207 ]} Recent studies describe that alcohol causes epigenetic alteration, especially abnormal DNA methylation. This is an essential factor for alcohol‐induced carcinogenesis.^{[ 208 ]} The risk of colon cancer increases with excessive alcohol consumption. This is characterized by hypomethylation or hypermethylation of DNA.^{[ 209 ]}

9.3. Role of micro‐RNA

Elizabeth et al. illustrate that alcohol consumption modifies the transcriptional profile of brain region‐specific, studied in human alcoholics and animal models.^{[ 210 ]} Their research group has reported time‐dependent alteration in mRNA expression, seen in mice. The mice are exposed to chronic intermittent ethanol exposure. microRNA is known to change the expression of various target genes.^{[ 211 ]} Multiple studies are showing that upon exposure to alcohol consumption in humans, miRNA expression is modified. The changes in microRNA, which are alcohol‐induced, are linked with cellular tolerance to alcohol and effects on antianxiety.^{[ 212 ]}

10. TREATMENTS

10.1. Treatments using drugs

10.1.1. Drug used to treat AWS and DT

The DT is the most common disease occurring in alcoholics. It's usually seen as the result of withdrawal symptoms, ranging from minor termers to major like causing death.^{[ 41} , ^{213 ]} Few studies done by European scientists showed that the prevalence of this disease is 0.7% and 0.2% in the general population^{[ 214} , ^{215 ]} There are 14% of people around the globe who can be categorized as heavy drinkers and are victims of multiple AUD.^{[ 39 ]} A person can be called as they are suffering from this disorder if they show two main features, that is, they should be a heavy alcoholic undergoing withdrawal, and the person must be suffering from delirium.^{[ 216 ]} The specific symptoms of delirium include clouding of consciousness where the patient is observed to have very little concentration and is most of the time unaware of their surrounding environment, partial cognitive impairment, and increased psychological disturbances.^{[ 41 ]}

While these features are specific to DT, the patient usually first shows some general symptoms about the body's usual reaction toward alcohol withdrawal. These symptoms like hallucinations, tremors of arms, eyelids, nausea, and headache are the first signs of AUD. Identification of DT includes characteristics like how severe it is: alcohol withdrawal, delirium, and other factors related to high and continuous consumption of alcohol.^{[ 41 ]} Due to its ability to cause death in severe cases, DT should be taken as an emergency disease and should be treated in ICU.^{[ 39 ]} Usually, alcohol withdrawal symptoms are not served and hence are advised to get treated as early as possible to prevent progression into more severe symptoms.^{[ 217 ]} Although this diazepam is given to patients to control the agitation rate in patients.^{[ 218} , ^{219 ]} it has been observed to show a reduced effect on patients who are constantly exposed to its consumption. It is assumed to be due to constant doses of these that might cause conformational changes in the GABA receptors, making them less effective with each amount given.^{[ 220 ]}

10.1.2. Alcohol syndromes

The most recurrent manifestations of this syndrome are lack of sleep (insomnia), seizure, a habit of hallucinating, and various preliminary manifestations at the start but grow highly when not treated in time.^{[ 41 ]} When the intake of alcohol is stopped after its consumption was very high a person, it causes a physiological loss of balance amongst GABA and NMDA receptor activities leading to a showing of the symptoms mentioned above, caused due to decrease of neurotransmission in GABA and increasing of the same in NMDA.^{[ 217} , ²²¹ , ^{222 ]} The normal assessment of this syndrome is done through the alcohol withdrawal scale (AWS), whose scale has 11 contents in total covering a wide range of symptoms mentioned above of alcohol syndrome.^{[ 223 ]}

Although the AWS scale was well furnished to carry out the preliminary assessment of alcohol withdrawal in a patient, it still needed a few modifications, later called Clinical Institute Withdrawal Assessment for Alcohol (CIWA‐Ar).^{[ 224} , ^{225 ]} Treatment of AWS usually includes high usage of the drug benzodiazepines (BDZ). It's the drug used in treating alcohol withdrawal before the patient enters the DT stage, where it can still be used to treat DT on its onset as drugs like diazepam. The major goal of treating Alcohol withdrawal is to prevent its proceeding from causing DT onset.^{[ 41 ]}

Amongst diazepam, a high preference is given to benzodiazepine. Still, there are exceptions when the person has severe liver dysfunction or lack of access through intravenous mode since its absorption at the intramuscular level is highly erratic.^{[ 226 ]} Therefore, in the circumstances like these, lorazepam is recommended considering it can bypass hepatic metabolism.^{[ 217 ]} The overall aim of drug use is to sedate the patient and make sure the person can be aroused. Therefore a drug with longer activity at a higher dose is recommended, that is, benzodiazepine.^{[ 227 ]} Although it's used as a good sedation drug, it has been reported that it could cause respiratory problems, recommending to use it in places where ventilation facilities are available.^{[ 217 ]} It is advisable to prevent the use of this drug in probable head injury and liver dysfunction. Though it can be tried to handle symptoms, the dosage and time of its usage vary depending upon the severity of manifestations measured in the standard withdrawal scale.^{[ 226 ]}

10.1.3. Importance of GABA

GABA is among the most important inhibitory neurotransmitters of the central nervous system (CNS). This GABA gets enhanced in its function when a huge amount of alcohol is taken by a person. This high intake of alcohol causes indigestion resulting indirectly improving the action of GABA, thereby indirectly decreasing the CNS function.^{[ 33} , ^{228 ]} It is observed that continuous alcohol intake affects the CNS and causes multiple adaptive changes in the neurotransmitter systems. The major one affected is GABA and several other methods, therefore successfully influencing the pathway mostly resulting in destabilization.^{[ 229} , ^{230 ]} Thus, to overcome this destabilization and get back the equilibrium, this neurotransmitter undergoes conformational changes. This change is an adaptive change the CNS system undergoes to induce tolerance.^{[ 231} , ^{232 ]} This tolerance decreases the number and sensitivity of GABA receptors; therefore, its inhibitory action toward CNS is downregulated to minimum levels.^{[ 220} , ²³³ , ^{234 ]}

Therefore, a balance is finally created in the system, but this tolerance can be deranged when there is a sharp or immediate block in alcohol intake. This sudden stop in alcohol intake disrupts the balance created by the CNS. These unbalance are due to an abrupt decrease in GABA activity and the promotion of other signaling actions. The complete blunt concern results in hyperexcitability and, therefore, finally leads to AWS. The unbalance created so high that its results can be seen within a few hours of stopping alcohol consumption.^{[ 230 ]} Other pathways are affected too, which are responsible for major key symptoms of AWA like hallucinations and hyperactivity.^{[ 235 ]}

10.1.4. Pharmacological therapies

In a cohort study of 617 people suffering from AWS and hospitalized, it was observed that there was a reduction in AWS symptoms when these patients were exposed to gabapentin as well as subsequently to benzodiazepine at a higher dosage. This gave out a possibility of quick symptom stabilization and may lead to a shorter stay period at hospitals.^{[ 221 ]}

10.2. Psychological treatment

When AWS is observed for its impact on the mental state, it can be said that continuous withdrawals may disturb cognitive functions, control over motivation and inhibition, and decision‐making, and reduce social interactions in general.^{[ 236} , ^{237 ]} Therefore, it becomes important to treat these impairment issues and cause long‐lasting effects of therapeutics, as they might reduce therapeutics' efficiency. The major aims should be 1. They are making withdrawal time pleasant as much as they can, and 2. Plan an aftercare schedule.^{[ 236 ]}

10.2.1. Nonpharmacological therapies

It's important to make aftercare an important factor for a long‐lasting effect to avoid its recurrence, which is highly likely to happen postdischarge.^{[ 238 ]} But it's reported that almost 40%−50% of withdrawal patients do not opt for posttreatment care once they complete their detoxification period.^{[ 239 ]} Therefore, it's always recommended that making plans or scheduling an aftercare process post‐therapeutic treatment can make the withdrawal last long and increase the success rate of withdrawal. Abstinence Preparation Groups can explain it (APG) play an important role in enrolling around 80% of withdrawal patients for post‐therapeutic aftercare.^{[ 239} , ^{240 ]} While therapeutic methods are carried out, it should be made sure that the consumption is minimized, which can be done through motivation and counseling.^{[ 241 ]} There is a high advantage in minimizing alcohol consumption or having possible control over it, which involves strengthening self‐esteem and motivation along with a decline in consumption rate, which relates to a reduction in ethanol‐associated mortality and morbidity.^{[ 242 ]} This helps patients reduce the damage caused due to the consumption of alcohol along with high improvisation in the quality of life of hospitalized patients and those who need hospital care but need time to get admitted.

Another reason that causes social anguish is the lack of a house for the AUD treatment.^{[ 243 ]} Therefore it is studied that patients before AUD treatment should make permanent housing facilities available living independently according to “Housing First” theory.^{[ 244 ]}

11. ROLE OF PRRs AND IMMUNE SYSTEM IN ALCOHOLISM

Usually, the foundation of addiction or depression, which are neurologically similar, may be due to the increasing negativity formed due to the brain's innate immune system.^{[ 245 ]} Recent studies on microglia have discovered that it plays an important part in brain homeostasis, especially in neurocircuitry, neuronal differentiation, and synapsis formation.^{[ 246} , ^{247 ]} These microglia originating from mesoderm are reported to show high involvement in receptors and molecular expression of innate immune signaling. A very important microglia that plays a part in this receptor pathway is the TLR receptor superfamily, a Toll‐like receptor. By sensing huge molecules with high content of sugars, lipids, and nucleic acids, this receptor initiates and promotes inflammation against these foreign organisms (pathogens). In the beginning, it was assumed that only microglia played a role in Toll‐like receptor signaling activity, but in new studies, it was found otherwise. It states that almost all brain cells play a significant role in this signaling process.^{[ 248 ]}

A study was done to understand how the innate immune receptors respond to particular agents (pathogens) helped in the identification of new receptor patterns called PRRs, which caused the change from studying specific organisms to studying the complete signaling process in the brain of the innate immune system. By now, there are five types of PRRs identified: (i) Toll‐like receptors, (ii) C‐type lectin receptors, (iii) NOD‐like receptors, (iv) RIG‐like receptors, and (v) AIM2‐like receptors. New findings reported that the induction of TLRs is caused by alcohol consumption and toll‐like receptor agonists in the brain (endogenous). A peak in the signaling process in this TLR system may cause effects on the behavior, coupled with an escalation in ventral striatal response.^{[ 249 ]} Therefore, these PPRs are believed to show recognition toward the unique molecular pattern present in pathogens.^{[ 250 ]}

12. CONCLUSION

This review discusses the effects of alcohol intake on the human body and involves a range of disorders affecting the brain, liver, and whole body. It includes deadly diseases such as alcoholic hepatitis, where different study groups have reported patient demise within 90 days after detection of this disorder. Alcoholism has an association with neural conditions, and the presence of some molecules such as GABA, and opioid peptides are essential. Consumption of alcohol beyond a limit leads to certain whole‐body effects such as alcoholic cirrhosis, alcohol hepatitis, variceal bleeding, and ascites, which can cause multiple complications and are sometimes fatal.

Alcohol is a powerful drug, that disturbs major neurological pathways such as the glutamate pathway. Consuming a high amount of alcohol can also give birth to a secondary psychological condition in a person. The review also describes the negative effect of alcohol on major signaling pathways such as protein kinase C, serine‐threonine kinases, and so forth. It contributes to establishing an association between alcoholism and the human gut microbiome, for which the concept of leaky gut and dysbiosis in alcoholic patients is marked out. The microbiota present in the amniotic fluid and placenta is responsible for influencing the colonization of the initial intestinal microbiota of the uterus. After childbirth, the delivery mode affects the gut microbiota development in the initial stage of life. Despite the common belief that the colonization of a newborn's microbiome by microorganisms begins only after birth, several studies have shown that this process begins while the infant is still in the womb, via the placenta and the vertical transmission of maternal microbiota by the uterus.^{[ 167 ]} Analytical approaches like metagenomic sequencing and pyrosequencing of the gut microbiome reveal the major microbe present in the human body. Gut microbiota is called the second genome, and it affects behavior and neurobiology; hence the correlation between microbiota and phenotype is explained briefly. Human gut microbiota has delivered the idea of prebiotics and probiotics, and its essential contribution to maintaining healthy human life is discussed. A major health crisis caused due to alcohol is inevitable. Still, several different treatment options using drugs, therapies, psychological treatments, and nonpharmacological therapies to manage and treat the disease are also available. Alcoholism is a lifestyle disorder, but it does affect PRRs and the body's immune system.

The progress in human gut microbiome research and its association with multiple diseases is booming over the last few years. The alteration of human gut microbiota concerning disorders is a potential biomarker for detection and therapy in the future. More signaling pathways in alcoholism need to be studied. The involvement of proteins in alcoholism needs to be found out, all of which will provide a breakthrough and better therapeutic approach to treating disorders related to alcoholism.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Renu K., Myakala H., Chakraborty R., Bhattacharya S., Abuwani A., Lokhandwala M., Vellingiri B., Gopalakrishnan A. V., J. Biochem. Mol. Toxicol. 2023;37::e23502. 10.1002/jbt.23502

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.