Carnitine in Alcohol Use Disorders: A Scoping Review.

Recent studies in alcohol use disorders (AUDs) have demonstrated some connections between carnitine metabolism and the pathophysiology of the disease. In this scoping review, we aimed to collate and examine existing research available on carnitine metabolism and AUDs and develop hypotheses surrounding the role carnitine may play in AUD. A scoping review method was used to search electronic databases in September 2019. The database search terms used included "alcohol, alcoholism, alcohol abuse, alcohol consumption, alcohol drinking patterns, alcohol-induced disorders, alcoholic intoxication, alcohol-related disorders, binge drinking, Wernicke encephalopathy, acylcarnitine, acetyl-l-carnitine, acetylcarnitine, carnitine and palmitoylcarnitine." The inclusion criteria included English language, human-based, AUD diagnosis and measured blood or tissue carnitine or used carnitine as a treatment. Of 586 studies that were identified and screened, 65 underwent abstract review, and 41 were fully reviewed. Eighteen studies were ultimately included for analysis. Data were summarized in an electronic data extraction form. We found that there is limited literature available. Alcohol use appears to impact carnitine metabolism, most clearly in the setting of alcoholic cirrhosis. Six studies found carnitine to be increased in AUD, of which 5 were conducted in patients with alcoholic cirrhosis. Only 3 placebo-controlled trials were identified and provide some support for the use of carnitine in AUD to decrease cravings, anhedonia, and withdrawal and improve cognition. The increase in plasma carnitine in alcoholic cirrhosis may be related to disordered fatty acid metabolism and oxidative stress that occurs in AUD. The multiple possible therapeutic effects carnitine could have on ethanol metabolism and the early evidence available for carnitine supplementation as a treatment for AUD provide a foundation for future randomized control trials of carnitine for treating AUD.

Improvement of Alcohol-Poisoning Symptoms in Mice by the Oral Administration of Live Lactobacillus plantarum SN13T Cells.

A clinical study carried out previously by our group has demonstrated that yogurt manufactured with a plant-derived lactic acid bacterium, Lactobacillus plantarum SN13T, significantly reduces the γ-glutamyl transpeptidase (γ-GTP) level as a liver-function parameter. In the present study, we show that with the oral administration of live SN13T cells, alcohol-poisoning symptoms in mice are improved, and the condition does not become fatal. However, prior to the simultaneous administration with ethanol, when the cells were heat-killed or sonicated, the improvement was not observed, and almost all of the mice died. In addition, the dysbiosis of the intestinal microbiota observed in the mice administered with ethanol was restored by simultaneous administration with live SN13T cells. Furthermore, by analyzing the metabolites detected in contents from the mouse cecum, it was demonstrated that the increase in nonvolatile putrefactive amines observed in the ethanol-administration group was reduced by simultaneous administration with live SN13T cells. Judging from these results, the lactic acid bacterial cells capable of reaching the living bowels prevent ethanol-induced poisoning and restore the intestinal microbiota.

Restoring an adequate dietary fiber intake by inulin supplementation: a pilot study showing an impact on gut microbiota and sociability in alcohol use disorder patients.

Alcohol use disorder (AUD) is a chronic relapsing disease associated with malnutrition, metabolic disturbances, and gut microbiota alterations that are correlated with the severity of psychological symptoms. This study aims at supplementing AUD patients with prebiotic fiber during alcohol withdrawal, in order to modulate the gut microbiota composition and to evaluate its effect on gastrointestinal tolerance, metabolism, and patient's behavior. A randomized, double-blind, placebo-controlled study included 50 AUD patients assigned to inulin versus maltodextrin daily supplementation for 17 days. Biological measurements (fecal microbial 16S rDNA sequencing, serum biology), dietary intake, validated psychological questionnaires, and gastrointestinal tolerance assessment were performed before and after the intervention. Inulin significantly decreased the richness and evenness and induced changes of 8 genera (q < 0.1) including Bifidobacterium and Bacteroides. Prebiotic had minor effects on gastrointestinal symptoms and nutritional intakes compared to placebo. All patients showed an improvement in depression, anxiety, and craving scores during alcohol withdrawal regardless of the intervention group. Interestingly, only patients treated with inulin significantly improved the sociability score and had an increased serum level of brain-derived neurotrophic factor. This pilot study shows that inulin is well tolerated and modulates the gut microbiota and the social behavior in AUD patients, without further improving other psychological and biological parameters as compared to placebo. Gut2Brain study, clinicaltrial.gov: NCT03803709, https://clinicaltrials.gov/ct2/show/NCT03803709.

Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice.

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body's metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion.

BACKGROUND: Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40-60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N-acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. METHODS: After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. RESULTS: Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. CONCLUSIONS: These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection.

The gut microbiota: A new target in the management of alcohol dependence?

The gastrointestinal tract is the natural habitat for a huge community of microorganisms, comprising bacteria, viruses, fungi and yeast. This microbial ecosystem codevelops with the host throughout life and is subject to a complex interplay that depends on multiple factors including host genetics, nutrition, life-style, stress, diseases and antibiotics use. The gut microbiota, that refers to intestinal bacteria, has profound influence on the host immune system, metabolism and nervous system. Indeed, intestinal bacteria supply the host with essential nutrients such as vitamins, metabolize bile acids and undigested compounds, defend against pathogen invasion, participate to the development of the intestinal architecture and the intestinal immune system and play an important role in the maintenance of the gut barrier function. More recently, the gut microbiota has been shown to influence brain functions, such as myelin synthesis, the blood-brain barrier permeability and neuroinflammatory responses but also mood and behavior. The cross-talk between microbes and the host implicates a vast array of signaling pathways that involve many different classes of molecules like metabolites produced by the bacteria from dietary or endogenous sources of carbohydrates and proteins (i.e. short-chain fatty acids (SCFAs), indole), neurotransmitters and inflammatory cytokines. This review will focus on the involvement of the gut microbiota in the pathophysiological aspects of alcohol dependence related to the gut barrier function, liver damage and psychological disturbances. We will also discuss the possibility to create new and realistic humanized animal models of alcohol dependence by the use of fecal transplantation.

Effects of stress on emotional reactivity in hostile heavy social drinkers following dietary tryptophan enhancement.

AIM: Because individuals high on hostility may be at risk for alcohol abuse due to serotonergic dysfunction and greater reactivity to stress, we examined the effects of acute dietary tryptophan enhancement and stress on mood and craving for alcohol in low-hostile (LoH) and high-hostile (HiH) individuals. METHODS: Thirty-four LoH and 33 HiH heavy social drinkers [selection based on the Hostility scale from the Buss and Perry Aggression Questionnaire (1992)] received either tryptophan-enriched or control diet and underwent a stress-induction procedure. Trait differences between the two hostile groups were explored using personality, anxiety, and depression questionnaires. Mood, craving for alcohol, and salivary cortisol levels (CORT) were measured before and after tryptophan and after stress-induction. Heart rate (HR) was measured during stress-induction. RESULTS: HiHs compared to LoHs scored higher on the depression and anxiety trait scales as well in the character dimension Harm Avoidance and reported more of stress exposure over the past month. They also showed more negative mood and higher craving for alcohol. Diet alone did not produce any subjective or physiological effects. Stress increased CORT, HR, negative mood, and craving for alcohol. HiHs displayed higher CORT increase and lower cardiovascular reactivity in response to stress compared to LoHs. Opposite to the predictions, tryptophan enhancement selectively facilitated stress-induced increase in craving in the HiHs. CONCLUSION: Among heavy drinkers HiHs report higher craving for alcohol and show greater reactivity to stress as measured by CORT and negative mood. The effects of stress on craving in HiHs may be mediated by a serotonergic mechanism.

The galanin receptor-3 antagonist, SNAP 37889, inhibits cue-induced reinstatement of alcohol-seeking and increases c-Fos expression in the nucleus accumbens shell of alcohol-preferring rats.

INTRODUCTION: This study aimed to investigate the effects of the galanin-3 receptor antagonist, SNAP 37889, on c-Fos protein expression after cue-induced reinstatement of alcohol-seeking in the brains of alcohol-preferring rats. METHODS: Eighteen alcohol-preferring rats were trained to self-administer 10% v/v ethanol in the presence of response-contingent cues, which was followed by extinction. Rats were then treated with SNAP 37889 (30 mg/kg, i.p.) or vehicle, before being tested for cue-induced reinstatement. Administration of SNAP 37889 reduced cue-induced reinstatement of ethanol-seeking behaviour. To examine the effect of SNAP 37889 and cue-induced reinstatement on neuronal activation, c-Fos expression was measured in subregions of the medial prefrontal cortex and nucleus accumbens. RESULTS: SNAP 37889 administration increased c-Fos immunoreactivity in the nucleus accumbens shell, but was without effect in the nucleus accumbens core and the medial prefrontal cortex. Dual-label Fos/tyrosine hydroxylase immunohistochemistry was used to examine the effects of SNAP 37889 on dopamine neurons in the ventral tegmental area; however, no differences between SNAP 37889 and vehicle-treated rats were found. CONCLUSIONS: These data support previous findings of galanin-3 receptor involvement in cue-induced reinstatement of alcohol-seeking behaviour, and provide novel evidence that the ability of galanin-3 receptor antagonism to attenuate cue-induced reinstatement relates to activation of the nucleus accumbens shell.

Increased rate of alcohol removal from blood with oral fructose and sucrose.

The effect of oral glucose, fructose and sucrose on the disappearance rate for intravenously administered alcohol was studied in eight abstinent alcoholic subjects. The three sugars were ingested on separate days in random sequence. alcohol levels were determined at hourly intervals. During sugar ingestion, the mean rates of alcohol disappearance were: 19 plus or minus 1.4 mg/100 ml per hour (plus or minus SE), with glucose, 23.9 or minus 1.4 mg/100 ml per hour with sucrose, and 25.4 plus or minus 1.4 mg/100 ml per hour with fructose. Compared to glucose both fructose and sucrose increased the rate of alcohol from the blood. The blood levels of fructose were similar after the oral dose of 2 g/kg of fructose or 4 g/kg of sucrose.

Alcohol craving in rehabilitation: assessment of nutrition therapy.

If untreated, alcohol abuse, which often results from alcohol craving, causes major metabolic abnormalities, altered life-styles, lost productivity, and eventually death. Biochemical mechanisms that may contribute to alcohol craving include the stress response of the hypothalamic-pituitary adrenal axis, the endogenous opiate beta-endorphin system, neurotransmitter synthesis and release, hypoglycemia, and nutrient deficiencies. The macronutrient ratio of meals, the resulting insulin response, and nutrient blood levels can affect amino acid and nutrient transport across the blood-brain barrier. Researchers have reported that animals increase alcohol intake when fed nutrient-deficient diets or after stressful experience. A pilot study was designed to assess the effects of nutrition therapy added to a traditional rehabilitation program based on the 12-step program of Alcoholics Anonymous. One study group received traditional therapy; the other study group received traditional therapy and nutrition therapy consisting of modified menus and individualized nutrition counseling. Patients who received nutrition therapy reported significantly fewer hypoglycemic symptoms, lower sugar intake, less alcohol craving as well as significantly greater nutrient intakes; a greater number abstained from alcohol. These findings indicate that nutrition therapy can aid in the recovery from alcoholism.

Alcohol-nutrition interaction: 1984 update.

Alcohol remains a prevailing cause of malnutrition resulting in a variety of deficiency states secondary to decreased intake of nutrients. In addition to various well described primary malnutrition syndromes, secondary malnutrition may result from the interaction of ethanol with nutrient digestion, absorption or utilization. Some of the latter alcohol-nutrient interactions have been recently defined and their pathogenesis is discussed in this review. Included are interactions with thiamine, folic acid, vitamin A and disorders secondary to amino acid imbalances. The rationale for various forms of therapy is reviewed, including the treatment aimed at correcting the "hypermetabolic state" in alcoholics ad the pitfalls of excess nutrient administration (particularly as it pertains to pyridoxine, vitamin A and amino acids). The desirability of recognizing early precirrhotic stages of alcoholic fibrosis is emphasized, in order to start therapy prior to the medical and/or social disintegration of the alcoholic.

Antiperoxide effect of garlic protein in alcohol fed rats.

Rats fed ethanol (3.76g/Kg body wt/day) for about 45 days exhibited high levels of tissue malondialdehyde, hydroperoxide and diene conjugates. Activity of tissue superoxide dismutase, catalase, and glutathione content decreased. Administration of water soluble proteins of garlic (500 mg/kg body wt/day) to alcohol fed rats showed significant increase in antiperoxide activity and decrease in the activity of glutathione peroxidase and glutathione s transferase as compared to a standard drug gugulipid (50 mg/kg body wt/day).

[Changes in the fatty acid composition of erythrocyte membranes in patients with chronic alcoholism under the effect of a diet enriched with linoleic acid]. / Izmeneniia zhirno-kislotnogo sostava membran éritrotsitov u bol'nykh khronicheskim alkogolizmom pod vliianiem ratsiona, obogashchennogo linolevoi kislotoi.

The authors have studied the influence of additional introduction into the ration of sunflower oil on fatty-acid composition of erythrocytic membranes in chronic alcoholics. The computerized discriminant analysis has evidenced that additional introduction of sunflower oil into the ration of the patients normalizes the fatty-acid spectrum of erythrocytic membranes. Besides that, enrichment of the ration with linoleic acid improves the parameters characterizing the liver function (bilirubin, alanine aminotransferase of blood serum).

Possible role of prostaglandin E1 in the affective disorders and in alcoholism.

Prostaglandin (PG)E1 may play an important part in the affective disorders, with an excess being present in mania and a deficiency in depression. Platelets from manic patients produce more PGE1 than normal while those from depressive patients produce less. Ethyl alcohol stimulates PGE1 production whereas lithium inhibits it. Alcoholics will tend to have raised PGE1 concentrations while drinking, but, because precursor supplies are limited, when alcohol concentrations fall PGE1 concentrations may fall sharply leading to depression. PGE1 biosynthesis may be affected by nutritional factors including essential fatty acids, pyridoxine, vitamin C, and zinc. Nutritional approaches may be of value in both depression and alcoholism.