The effects of cocaine on microbiota have been scarcely explored. Here, we investigated the gut (GM) and oral (OM) microbiota composition of cocaine use disorder (CUD) patients and the effects of repetitive transcranial magnetic stimulation (rTMS). 16S rRNA sequencing was used to characterize GM and OM, whereas PICRUST2 assessed functional changes in microbial communities, and gas-chromatography was used to evaluate fecal short and medium chain fatty acids. CUD patients reported a significant decrease in alpha diversity and modification of the abundances of several taxa in both GM and OM. Furthermore, many predicted metabolic pathways were differentially expressed in CUD patients' stool and saliva samples, as well as reduced levels of butyric acid that appear restored to normal amounts after rTMS treatment. In conclusion, CUD patients showed a profound dysbiotic fecal and oral microbiota composition and function and rTMS-induced cocaine abstinence determined the restoration of eubiotic microbiota.

Gut microbiota may affect function of the dorsolateral prefrontal cortex (DLPFC). However, there have been a few studies on modification of brain-gut interactions with repetitive transcranial magnetic stimulation (rTMS) to the DLPFC. We hypothesized that stimulation of the right or left DPFC by rTMS modifies the brain-gut interactions in humans. Subjects were 25 healthy males. Viscerosensory evoked potential (VEP) with sham (0 mA) or actual (30 mA) electrical stimulation (ES) of the rectum was taken after sham, low frequency rTMS at 0.1 Hz, and high frequency rTMS at 10 Hz to the right or left DLPFC. Rectal tone was measured with a rectal barostat. Visceral perception and emotion were analyzed using ordinates scale, rectal barostat, and viscerosensory evoked potential. Low frequency rTMS to the right DLPFC significantly reduced the visceral sensation and emotion composite score evoked by ES at 30 mA (p < 0.05). Plasma ACTH was significantly increased by high frequency rTMS to the right or left DLPFC (p < 0.05). Rectal fine contractions were significantly induced by low frequency rTMS to the right or left DLPFC and high frequency rTMS to the right DLPFC (p < 0.05). These results suggest that stimulation of the right or left DPFC by rTMS modifies the brain-gut interactions in humans.

INTRODUCTION:Repetitive transcranial magnetic stimulation (rTMS) is a clinically useful therapy for depression. However, the effects of rTMS on the metabolism of fatty acids (FAs) and the composition of gut microbiota in depression are not well established. METHODS:Mice received rTMS (15 Hz, 1.26 T) for seven consecutive days after exposure to chronic unpredictable mild stress (CUMS). The subsequent depressive-like behaviors, the composition of gut microbiota of stool samples, as well as medium- and long-chain fatty acids (MLCFAs) in the plasma, prefrontal cortex (PFC), and hippocampus (HPC) were evaluated. RESULTS:CUMS induced remarkable changes in gut microbiotas and fatty acids, specifically in community diversity of gut microbiotas and PUFAs in the brain. 15 Hz rTMS treatment alleviates depressive-like behaviors and partially normalized CUMS induced alterations of microbiotas and MLCFAs, especially the abundance of Cyanobacteria, Actinobacteriota, and levels of polyunsaturated fatty acids (PUFAs) in the hippocampus and PFC. CONCLUSION:These findings revealed that the modulation of gut microbiotas and PUFAs metabolism might partly contribute to the antidepressant effect of rTMS.

The microbiota-gut-brain axis (MGBA) refers to the bidirectional communication between the brain and the gut microbiota and recent studies have linked the MGBA to health and disease. Research has so far investigated this axis mainly from microbiota to brain but less is known about the other direction. One approach to examine the MGBA from brain to microbiota is through understanding if and how neuromodulation might impact microbiota. Neuromodulation encompasses a wide range of stimulation techniques and is used to treat neurological, psychiatric and metabolic disorders, like Parkinson's Disease, depression and obesity. Here, we performed a systematic review to investigate whether neuromodulation is associated with subsequent changes in the gut microbiota. Searches in PsycINFO and MEDLINE were performed up to March 2022. Included studies needed to be clinical or preclinical studies comparing the effects of deep brain stimulation, electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or vagal nerve stimulation on the gut microbiota before and after treatment or between active and control groups. Seven studies were identified. Neuromodulation was associated with changes in relative bacterial abundances, but not with (changes in) α-diversity or β-diversity. Summarizing, currently reported findings suggest that neuromodulation interventions are associated with moderate changes in the gut microbiome. However, findings remain inconclusive due to the limited number and varying quality of included studies, as well as the large heterogeneity between studies. More research is required to more conclusively establish whether, and if so, via which mechanism(s) of action neuromodulation interventions might influence the gut microbiota.

While the impact of the gut microbiota on brain and behavior is increasingly recognized, human studies examining this question are still scarce. The primary objective of the current study was to explore the potential relationships between the gut microbiota composition, motor cortical excitability at rest and during inhibitory control, as well as behavioral inhibition, in healthy volunteers and in patients suffering from alcohol use disorder. Motor cortical excitability was examined using a range of transcranial magnetic stimulation (TMS) measures probed at rest, including the recruitment curve, short and long intracortical inhibition, and intracortical facilitation within the primary motor cortex. Moreover, TMS was applied during a choice reaction time task to assess changes in motor excitability associated with inhibitory control. Finally, behavioral inhibition was investigated using a neuropsychological task (anti-saccade). Overall, our results highlight several interesting correlations between microbial composition and brain measures. Hence, higher bacterial diversity, as well as higher relative abundances of UGC-002 and Christensenellaceae R-7 group were correlated with stronger changes in motor excitability associated with inhibitory control. Also, higher abundance of Anaerostipes was associated with higher level of corticospinal excitability. Finally, relative abundances of Bifidobacterium and Faecalibacterium were positively related to performance in the neuropsychological task, suggesting that they might have a positive impact on behavioral inhibition. Although correlation is not causation, the present study suggests that excitatory and inhibitory brain processes might be related to gut microbiota composition. This article is part of the Special Issue on 'Microbiome & the Brain: Mechanisms & Maladies'.

Currently, gut microbiota living in the gastrointestinal tract, plays an important role in regulating host's sleep and circadian rhythms. As a tool, gut microbiota has great potential for treating circadian disturbance and circadian insomnia. However, the relationship between gut microbiota and circadian rhythms is still unclear, and the mechanism of action has still been the focus of microbiome research. Therefore, this article summarizes the current evidences associating gut microbiota with factors that impact host circadian rhythms neurology sleep disorder. Moreover, we discuss the changes to these systems in sleep disorder and the potential mechanism of intestinal microbiota in regulating circadian rhythms neurology sleep disorder via microbial metabolites. Meanwhile, based on the role of intestinal flora, it is provided a novel insight into circadian related insomnia and will be benefit the dietary treatment of circadian disturbance and the circadian related insomnia.

Physical activity (PA) can improve functional abilities, well-being, and independence in older adults with insomnia. Studies have shown that PA may be linked to changes in the gut microbiota composition and its metabolites' concentrations. This association among older adults with insomnia, however, is yet to be determined. We explored the relationships between physical activity (PA) levels, gut microbiota composition, and short-chain fatty acid (SCFA) levels in this population. Forty-nine community-dwelling adults with insomnia symptoms, aged 65 and older, participated in this study. Their average daily step-count and sleep continuity measures over a two-week period were calculated based on Actigraphic recordings. Each participant provided fecal samples for the microbiome and SCFA analyses, anthropometric measures, and information via questionnaires on medical history and food consumption. The gut microbiota composition and SCFA concentrations were determined by next-generation sequencing and Gas chromatography-mass spectrometry, respectively. Participants were divided into two groups (more and less active) according to their median step/day count. We compared the microbiota abundance and SCFA concentrations between groups and performed correlation analysis between gut microbiota abundances and study variables. Different microbiota taxa in each PA group and increased SCFAs in feces of less active individuals were found. Changes in step counts were positively or negatively associated with the relative abundance of 19 ASVs, 3 microorganisms at the family level, and 11 microorganisms at the genus level. Furthermore, significant associations were discovered among physical activity, gut microbiota, SCFAs, and sleep parameters. Our findings provide new insights on the relationship between PA, gut microbiota composition, and primary metabolites in older adults with insomnia.

Sleep plays a fundamental role in maintaining good psycho-physical health, it can influence hormone levels, mood, and weight. Recent studies, focused on the interconnection between intestinal microbiome and sleep disorders, have shown the growing importance of a healthy and balanced intestinal microbiome for the hosts health. Normally, gut microbiota and his host are linked by mutualistic relationship, that in some conditions, can be compromised by shifts in microbiota's composition, called dysbiosis. Both sleep problems and dysbiosis of the gut microbiome can lead to metabolic disorders and, in this review, we will explore what is present in literature on the link between sleep pathologies and intestinal dysbiosis.

Insomnia is a type of sleep disorder which has negative impacts on the quality of life, mood, cognitive function and health of humans. The etiology of insomnia may be related to many factors such as genetics, biochemistry, neuroendocrine, immune, and psychosocial factors. However, the detailed pathological aspects of insomnia remain unclear. Recent investigation of the microbiome-gut-brain axis enhances our understanding of the role of the gut microbiota in brain-related diseases. Gut microbiome has been shown to be associated with insomnia. However, the available data in this field remain limited and the relevant scientific work has only recently begun. This review aims to summarize the recent literature as an aid to better understanding how the alteration of gut microbiota composition contributes to insomnia while evaluating and prospecting the therapeutic effect of modulating gut microbiota in the treatment of insomnia based on previous publications.

PURPOSE:The major purpose of this study was to detect the changes in gut microbiota composition and inflammatory cytokines production associated with acute and chronic insomnia. This study also evaluated the relationship between gut microbiota changes and increased inflammatory cytokines in insomnia patients. PATIENTS AND METHODS:Outpatients with acute and chronic insomnia (aged 26-55 years; n=20 and 38, respectively) and age/gender-matched healthy controls (n=38) were recruited from a southern China region. Participants' gut microbiome, plasma cytokines, and self-reported sleep quality and psychopathological symptoms were measured. RESULTS:The gut microbiomes of insomnia patients compared with healthy controls were characterized by lower microbial richness and diversity, depletion of anaerobes, and short-chain fatty acid (SCFA)-producing bacteria, and an expansion of potential pathobionts. and were signature bacteria for distinguishing acute insomnia patients from healthy controls, while and were signature bacteria for distinguishing chronic insomnia patients from healthy controls. Acute/chronic insomnia-related signature bacteria also showed correlations with these patients' self-reported sleep quality and plasma IL-1β. CONCLUSION:These findings suggest that insomnia symptomology, gut microbiota, and inflammation may be interrelated in complex ways. Gut microbiota may serve as an important indicator for auxiliary diagnosis of insomnia and provide possible new therapeutic targets in the field of sleep disorders.

Sleep is a universal physiological need in all species and is essential for the maintenance and recovery of various physiological functions of the body. In late years, the gut microbiota (GM), a vast and extraordinarily complex ecosystem located in human gastrointestinal tract that oversees an array of critical bodily functions, has become a popular focus among researchers. Accumulated evidences in this field have revealed that it exerts important roles in the regulation of some biological characteristics, especially metabolic, immunological and neurobehavioral functions. With the increasing comprehension of brain-gut axis, a bidirectional communication channel linking the brain and gut, the roles of GM in sleep are paid much attention to. Evidences have shown that the GM is essential for the maintenance of normal sleep physiology. In turn, it has also been demonstrated that the abnormal sleep patterns and duration affect the composition, diversity and function of the GM through the brain-gut-microbiota axis (BGMA). Present contributions have described several underlying factors that could be involved in the BGMA in sleep, such as the immune system, the vagus nerve, the neuroendocrine system, and bacterial metabolites. Furthermore, several interventions targeting the GM have been proved to be beneficial for amelioration of sleep problems. On this basis, in this review, we aim to explore the interaction between sleep and GM, and elucidate the therapeutic microbiota manipulations with potential promoting effects on sleep quality.

Studies have confirmed that insomnia is related to gut microbiota. Previous research suggests that immunity and metabolism are also associated with insomnia. However, to our knowledge, the integration of these factors has not been investigated in insomnia. Here, we explored the correlations across gut microbiota, serum metabolism, and inflammatory factors in insomnia. Our results showed that the composition and structure of gut microbiota and metabolism in insomnia patients were different from healthy controls. Compared to healthy controls, the relative abundances of , Streptococcus, and Lactobacillus crispatus were significantly increased in insomniacs. There were five metabolic pathways in insomniacs (glycerophospholipid metabolism; glutathione metabolism; nitrogen metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis) significantly different between the two groups. Moreover, we found that IL-1β levels were significantly higher in insomnia patients while TNF-α was significantly reduced. We further identified that the changes in the level of IL-1β and TNF-α were associated with some specific bacteria and metabolites, such as Prevotella amnii, Prevotella buccalis, Prevotella timonensis, and Prevotella colorans. Mediation analysis further determined that the immune factors and metabolites could mediate the relationship between gut microbes and insomnia. Our study indicated that systematic inflammation and metabolites might be a pathway linking the gut microbiome with insomnia. These findings provide new insights and a better understanding of gut microbiota's role in insomnia as well as potential novel microbiome-related etiologies for insomnia.

Sleep is a complex physiological process and is a critical determinant of physical and mental health. In the past decades, significant progress has been made in understanding the neural mechanisms of sleep and awakening. However, the initiation and maintenance of the sleep-wake cycle is regulated not only by the central system but is also affected by signals from peripheral tissues. Growing evidence shows that the microbiota-gut-brain axis contributes to the regulation of sleep behavior both directly and indirectly and may play a critical role in the etiology and pathogenesis of sleep disorders. Sleep deprivation leads to dysfunction of gut microbiota and sleep disorders are accompanied by altered gut microbiota composition. In this review, we describe the bidirectional relationships between sleep and gut microbiota and summarize the abnormal characteristics of gut bacteria in distinct conditions including sleep disturbances, sleep disorders and sleep disorders comorbid with neuropsychiatric disorders. We also examine the potential routes of microbiota-gut-brain axis in sleep and gut microbiome interactions, including metabolic, immune, and neural pathways, and propose microbiota-targeted interventions for improving sleep. Manipulating gut microbiota may be a promising avenue for the development of novel interventions for sleep disorders.

BACKGROUND:Alcohol abuse has deleterious effects on human health by disrupting the functions of many organs and systems. Gut microbiota has been implicated in the pathogenesis of alcohol-related liver diseases, with its composition manifesting expressed dysbiosis in patients suffering from alcoholic dependence. Due to its inherent plasticity, gut microbiota is an important target for prevention and treatment of these diseases. Identification of the impact of alcohol abuse with associated psychiatric symptoms on the gut community structure is confounded by the liver dysfunction. In order to differentiate the effects of these two factors, we conducted a comparative "shotgun" metagenomic survey of 99 patients with the alcohol dependence syndrome represented by two cohorts-with and without liver cirrhosis. The taxonomic and functional composition of the gut microbiota was subjected to a multifactor analysis including comparison with the external control group. RESULTS:Alcoholic dependence and liver cirrhosis were associated with profound shifts in gut community structures and metabolic potential across the patients. The specific effects on species-level community composition were remarkably different between cohorts with and without liver cirrhosis. In both cases, the commensal microbiota was found to be depleted. Alcoholic dependence was inversely associated with the levels of butyrate-producing species from the Clostridiales order, while the cirrhosis-with multiple members of the Bacteroidales order. The opportunist pathogens linked to alcoholic dependence included pro-inflammatory Enterobacteriaceae, while the hallmarks of cirrhosis included an increase of oral microbes in the gut and more frequent occurrence of abnormal community structures. Interestingly, each of the two factors was associated with the expressed enrichment in many Bifidobacterium and Lactobacillus-but the exact set of the species was different between alcoholic dependence and liver cirrhosis. At the level of functional potential, the patients showed different patterns of increase in functions related to alcohol metabolism and virulence factors, as well as pathways related to inflammation. CONCLUSIONS:Multiple shifts in the community structure and metabolic potential suggest strong negative influence of alcohol dependence and associated liver dysfunction on gut microbiota. The identified differences in patterns of impact between these two factors are important for planning of personalized treatment and prevention of these pathologies via microbiota modulation. Particularly, the expansion of Bifidobacterium and Lactobacillus suggests that probiotic interventions for patients with alcohol-related disorders using representatives of the same taxa should be considered with caution. Taxonomic and functional analysis shows an increased propensity of the gut microbiota to synthesis of the toxic acetaldehyde, suggesting higher risk of colorectal cancer and other pathologies in alcoholics.

RATIONALE:Gut microbiota communicates information to the brain. Some animals are born with a gut microbiota that predisposes to high alcohol consumption, and transplantation of fecal material from alcoholics to mice increases animal preference for ethanol. Alcohol-use-disorders are chronic conditions where relapse is the hallmark. A predictive animal model of relapse is the "alcohol deprivation effect" where ethanol re-access is allowed following chronic alcohol intake and a long alcohol deprivation. The present study evaluates the effect of gut microbiota modification on relapse, as an adjunct to N-acetylcysteine + Acetylsalicylic acid administration, which inhibits the alcohol-induced hyper-glutamatergic condition. METHODS:Rats bred as heavy alcohol consumers (UChB) were allowed ethanol intake for one month, were deprived of alcohol for two-weeks and subsequently offered re-access to ethanol. Prior to ethanol re-access animals received orally either (i) vehicle-control, (ii) Lactobacillus-rhamnosus-GG after antibiotic treatment (LGG); (iii) N-acetylcysteine+Acetylsalicylic acid (NAC/ASA) or (iv) both treatments: LGG+ (NAC/ASA). RESULTS:Marked binge drinking (1.75 g ethanol/kg in 60 min) and blood alcohol levels exceeding 80 mg/dl were observed in the control group upon ethanol-re-access. Lactobacillus-GG or (NAC+ASA) treatments inhibited alcohol intake by 66-80%. The combination of both treatments virtually suppressed (inhibition of 90%) the re-access binge-like drinking, showing additive effects. Treatment with NAC+ASA increased the levels of glutamate transporters xCT and GLT-1 in nucleus accumbens, while Lactobacillus-GG administration increased those of the dopamine transporter (DAT). CONCLUSIONS:The administration of a well-accepted probiotic may be of value as an adjunct in the treatment of alcohol-use-disorders.

BACKGROUND:Alcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is known about commensal fungi therein. METHODS:We studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples. RESULTS:Patients with AUD had significantly increased abundance of the genera , , , , and , and of the species and compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera , , , , , and the species and . This was mirrored by significantly higher specific anti- immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti- IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease. CONCLUSION:In conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of and , and lower serum anti- IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.

Recent studies have revealed that the gut microbiota participates in the psychiatric behavior changes in disorders associated with alcohol. But it still remains unknown whether alcoholism is involved in changes in gut microbiota and its underlying mechanism is also not clear. Here, we tested the gut microbiota of patients with alcoholism and conducted fecal microbiota transplantation (FMT) from patients with alcoholism to C57BL/6J mice whose gut microbiota had been sharply suppressed with antibiotics (ABX). Then we evaluated their alcohol preference degree, anxiety, and depression-like behaviors and social interaction behaviors, together with molecular changes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Our data indicated that the gut microbiota of patients with alcoholism was drastically different from those of the healthy adults. The abundance of p_Firmicutes was significantly increased whereas p_Bacteroidetes was decreased. Compared to mice transplanted with fecal microbiota from healthy male adults, the mice accepting fecal microbiota from patients with alcoholism showed (a) anxiety-like and depression-like behaviors, (b) decreased social interaction behaviors, (c) spontaneous alcohol preference, and (d) decreased brain-derived neurotrophic factor (BDNF), alpha 1 subunit of GABA type A receptor (α1GABA R) in mPFC and decreased metabotropic glutamate receptors 1 (mGluR1), protein kinase C (PKC) ε in NAc. Overall, our results suggest that fecal microbiota from patients with alcoholism did induce a status like alcohol dependence in C57BL/6J mice. The decreased expression of BDNF, α1GABA R, and mGluR1/ PKC ε may be the underlying mechanism.

Alcohol use disorders (AUD) is characterized by persistent or intermittent alcohol cravings and compulsive drinking. The functional changes in the central nervous system (CNS) after alcohol consumption are alcohol-associated cognitive impairment and mood disorders, which are major health issues reported in AUDs. Studies have shown that transferring the intestinal microbiota from AUDs patients to germ-free animals causes learning and memory dysfunction, depression and anxiety-like behavior, indicating the vital role of intestinal microbiota in development of neuropsychiatric disorders in AUD. Intestinal flora composition of AUD patients are significantly different from normal people, suggesting that intestinal flora imbalance orchestrate the development of neuropsychiatric disorders in AUD. Studies suggests that gut microbiome links bidirectional signaling network of the enteric nervous system (ENS) to central nervous system (CNS), forming gut-microbe-brain axis (brain-gut axis). In this review, we discussed pathogenesis and possible treatment of AUD-induced cognitive deficits, anxiety, and depression disorders. Further, we described the mechanism of intestinal flora imbalance and dysfunction of hippocampus-amygdala-frontal cortex (gut-limbic circuit system dysfunction). Therefore, we postulate therapeutic interventions of gut-brain axis as novel strategies for treatment of AUD-induced neuropsychiatric disorders.

Many patients with alcohol use disorder (AUD) consume alcohol chronically and in large amounts that alter intestinal microbiota, damage the gastrointestinal tract, and thereby injure other organs via malabsorption and intestinal inflammation. We hypothesized that alcohol consumption and subsequent abstinence would change the gut microbiome in adults admitted to a treatment program. Stool and oral specimens, diet data, gastrointestinal assessment scores, anxiety, depression measures and drinking amounts were collected longitudinally for up to 4 weeks in 22 newly abstinent inpatients with AUD who were dichotomized as less heavy drinkers (LHD, <10 drinks/d) and very heavy drinkers (VHD, 10 or more drinks/d). Next-generation 16 S rRNA gene sequencing was performed to measure the gut and oral microbiome at up to ten time points/subject and LHD and VHD were compared for change in principal components, Shannon diversity index and specific genera. The first three principal components explained 46.7% of the variance in gut microbiome diversity across time and all study subjects, indicating the change in gut microbiome following abstinence. The first time point was an outlier in three-dimensional principal component space versus all other time points. The gut microbiota in LHD and VHD were significantly dissimilar in change from day 1 to day 5 ( = .03) and from day 1 to week 3 ( = .02). The VHD drinking group displayed greater change from baseline. The Shannon diversity index of the gut microbiome changed significantly during abstinence in five participants. In both groups, the Shannon diversity was lower in the oral microbiome than gut. Ten total genera were shared between oral and stool in the AUD participants. These data were compared with healthy controls from the Human Microbiome Project to investigate the concept of a core microbiome. Rapid changes in gut microbiome following abstinence from alcohol suggest resilience of the gut microbiome in AUD and reflects the benefits of refraining from the highest levels of alcohol and potential benefits of abstinence.

Alcohol use is a leading cause of chronic liver disease worldwide, and changes in the microbiome associated with alcohol use contribute to patients' risk for liver disease progression. Less is known about the effects of alcohol use on the intestinal viral microbiome (virome) and interactions between bacteriophages and their target bacteria. We studied changes in the intestinal virome of 62 clinically well-characterized patients with alcohol use disorder (AUD) during active alcohol use and after 2 weeks of alcohol abstinence, by extracting virus-like particles and performing metagenomic sequencing. We observed decreased abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages in patients with active AUD when compared with controls, whereas after 2 weeks of alcohol abstinence, patients with AUD demonstrated an increase in the abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages. The intestinal virome signature was also significantly different in patients with AUD with progressive liver disease, with increased abundance of phages targeting Enterobacteria and Lactococcus species phages compared with patients with AUD with nonprogressive liver disease. By performing moderation analyses, we found that progressive liver disease is associated with changes in interactions between some bacteriophages and their respective target bacteria. In summary, active alcohol use and alcohol-associated progressive liver disease are associated with changes in the fecal virome, some of which are partially reversible after a short period of abstinence. Progression of alcohol-associated liver disease is associated with changes in bacteriophage-bacteria interactions.

: A growing body of evidence highlights the role of the intestine in the development of various alcohol use disorder (AUD) complications. The intestinal microbiome has been proposed as an essential factor in mediating the development of AUD complications such as alcoholic liver disease.: To provide a comprehensive description of alcohol-induced intestinal microbiome alterations.: We conducted a systematic review of studies investigating the effect of alcohol on the intestinal microbiome using the PRISMA checklist. We searched the Medline database on the PubMed platform for studies determining the effect of alcohol on microbiota in individuals with AUD. The manual search included references of retrieved articles. Only human studies examining the intestinal bacterial microbiome using 16S ribosomal RNA sequencing were included. Data comparing relative abundances of bacteria comprising intestinal microbiota was extracted.: We retrieved 17 studies investigating intestinal microbiome alterations in individuals with AUD. Intestinal microbiome alterations in individuals with AUD included depletion of and and an increase of Enterobacteriaceae. At the phylum level, a higher abundance of Proteobacteria and lower of Bacteroidetes were found. Mixed results regarding were obtained. Several species of short-chain fatty acids producing bacteria had a lower abundance in individuals with alcohol use disorder.: Intestinal microbiome alterations associated with dysbiosis in individuals with AUD are generally consistent across studies, making it a promising target in potential AUD complications treatment.

Alcohol use disorder (AUD) is a high-risk psychiatric disorder and a key cause of death and disability in individuals. In the development of AUD, there is a connection known as the microbiota-gut-brain axis, where alcohol use disrupts the gut barrier, resulting in changes in intestinal permeability as well as the gut microbiota composition, which in turn impairs brain function and worsens the patient's mental status and gut activity. Potential mechanisms are explored by which alcohol alters gut and brain function through the effects of the gut microbiota and their metabolites on immune and inflammatory pathways. Alcohol and microbiota dysregulation regulating neurotransmitter release, including DA, 5-HT, and GABA, are also discussed. Thus, based on the above discussion, it is possible to speculate on the gut microbiota as an underlying target for the treatment of diseases associated with alcohol addiction. This review will focus more on how alcohol and gut microbiota affect the structure and function of the gut and brain, specific changes in the composition of the gut microbiota, and some measures to mitigate the changes caused by alcohol exposure. This leads to a potential intervention for alcohol addiction through fecal microbiota transplantation, which could normalize the disruption of gut microbiota after AUD.

The etiology of alcohol dependence is not completely understood. Increasing evidence reveals that gut microbiota dysbiosis is associated with certain psychiatric disorders, including alcoholism, through the "microbiota-gut-brain" axis. The aims of this study were to evaluate the effect of alcohol abuse on the gut microbiota, intestinal permeability and serum metabolic profile and to determine whether alcohol-induced alterations in gut microbiota are correlated with gut permeability and serum metabolic phenotype changes. 16S rRNA gene high-throughput sequencing and nontarget metabolomics techniques were applied in an alcohol-dependent rat model in the present study. The results showed that alcohol intake altered the composition and structure of the colonic microbiota, especially the relative abundances of commensal microbes in the families and , which were significantly decreased. Alcohol-dependent rats developed gut leakiness and a serum metabolic phenotype disorder. The valine, leucine and isoleucine biosynthesis pathways and arginine and proline metabolism pathways were obviously influenced by alcohol intake. Moreover, alcohol consumption disturbed the brain's neurotransmitter homeostasis. Regression analysis showed that alcohol-induced colonic microbiota dysbiosis was strongly associated with increased intestinal permeability and serum metabolic phenotype and neurotransmitter disorders. These results revealed that gut microbiota dysbiosis and serum metabolite alteration might be a cofactor for developing of alcohol dependence. Gut microbiota dysbiosis is associated with certain psychiatric disorders through the "microbiota-gut-brain" axis. Here, we revealed that alcohol consumption induced colonic microbiota dysbiosis, increased intestinal permeability, and altered the serum metabolic phenotype in rats, and there was a strong correlation between gut microbiota dysbiosis and serum metabolite disorders. Thus, gut microbiota dysbiosis and serum metabolite alteration may be a cofactor for development of alcohol dependence.

A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

Since the mid 1980's, the impact of gastrointestinal (GI) microbiome changes during alcohol use disorder has been an area of significant interest. This work has resulted in the identification of specific changes in the abundance of certain members of the GI microbiome and the role these changes play in a variety of alcohol related disorders ( alcoholic liver disease). Interestingly, some findings suggest a possible role for the GI microbiome in alcohol addiction or withdrawal. Unfortunately, there is a significant gap in knowledge in this area. Here we describe differences in the GI microbiome of alcoholic and non-alcoholic individuals and discuss the possible impact of microbes on the gut-brain axis, which could impact alcohol related behaviors ( addiction). Understanding the role of the GI microbiome in alcohol related disorders will potentially lead to the development of successful microbiome-targeted therapeutics to help mitigate these disorders.

Alcohol addiction is a leading risk factor for personal death and disability. In 2016, alcohol use caused 2.2% of female deaths and 6.8% of male deaths, and disability-adjusted life years (DALYs) were 2.3% in female and 8.9% in male. Individuals with alcohol use disorder are at high risk of anxiety, depression, impaired cognition performance, and illicit drug use and are comorbid with liver disease, such as alcoholic hepatitis and liver cirrhosis, which is a major cause of personal death and disability worldwide. Psychological interventions, such as cognitive behavior therapy and motivational interviewing, as well as medical treatments, such as disulfiram, naltrexone, acamprosate, and nalmefene, are used for the treatment of alcohol addiction in Europe and the United States. However, the effect of current interventions is limited, and the need for additional interventions is substantial. Alcohol use impairs the intestinal barrier and causes changes to the intestinal permeability as well as the gut microbiota composition. Emerging studies have tried to reveal the role of the gut-brain axis among individuals with alcohol use disorder with or without alcohol liver disease. Bacterial products penetrate the impaired intestinal barrier and cause central inflammation; changes to the gut microbiota impair enterohepatic circulation of bile acids; alcohol abuse causes shortage of vital nutrients such as thiamine. Several studies have suggested that probiotics, through either oral administration or fecal microbiota transplantation, increased intestinal levels of potentially beneficial bacteria such as bifidobacteria and lactobacilli, improving the levels of liver-associated enzymes in patients with mild alcoholic hepatitis, and demonstrating beneficial psychotropic effects on anxiety and depression. In addition to medications for alcohol addiction, gene editing therapy such as clustered regularly interspaced short palindromic repeats (CRISPRs) may be another potential research target. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are associated with ADH and ALDH genes, are major enzymes involved in alcohol metabolism, and gene editing approaches may have the potential to directly modify specific genes to treat alcoholism caused by genetic defects. Further research is needed to study the effect of the combined treatment for alcohol addiction.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of β-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.

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 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 and . 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.

BACKGROUND:Emerging evidence highlights that targeting the gut microbiota could be an interesting approach to improve alcohol liver disease due to its important plasticity. This study aimed to evaluate the effects of inulin supplementation on liver parameters in alcohol use disorder (AUD) patients (whole sample) and in a subpopulation with early alcohol-associated liver disease (eALD). METHODS:Fifty AUD patients, hospitalized for a 3-week detoxification program, were enrolled in a randomized, double-blind, placebo-controlled study and assigned to prebiotic (inulin) versus placebo for 17 days. Liver damage, microbial translocation, inflammatory markers and 16S rDNA sequencing were measured at the beginning (T1) and at the end of the study (T2). FINDINGS:Compared to placebo, AST (β = 8.55, 95% CI [2.33:14.77]), ALT (β = 6.01, 95% CI [2.02:10.00]) and IL-18 (β = 113.86, 95% CI [23.02:204.71]) were statistically significantly higher in the inulin group in the whole sample at T2. In the eALD subgroup, inulin supplementation leads to specific changes in the gut microbiota, including an increase in Bifidobacterium and a decrease of Bacteroides. Despite those changes, AST (β = 14.63, 95% CI [0.91:28.35]) and ALT (β = 10.40, 95% CI [1.93:18.88]) at T2 were higher in the inulin group compared to placebo. Treatment was well tolerated without important adverse events or side effects. INTERPRETATION:This pilot study shows that 17 days of inulin supplementation versus placebo, even though it induces specific changes in the gut microbiota, did not alleviate liver damage in AUD patients. Further studies with a larger sample size and duration of supplementation with adequate monitoring of liver parameters are needed to confirm these results. Gut2Brain study: https://clinicaltrials.gov/ct2/show/NCT03803709 FUNDING: Fédération Wallonie-Bruxelles, FRS-FNRS, Fondation Saint-Luc.