Neuroinflammation

Neuroinflammation is a key mediator in the pathophysiology of AUD, and the gut microbiota plays a central role in its regulation. Chronic alcohol consumption triggers neuroinflammation through multiple pathways. Ethanol metabolites (e.g. acetaldehyde) promote NOD-, LRR- and pyrin-domain-containing protein 3 (NLRP3) inflammasome signalling in microglia, as shown in post-mortem human brain tissue.^{Reference Guo, Roodsari, Cheng, Dempsey and Hu19} Peripheral cytokine infiltration, particularly tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), disrupt blood–brain barrier integrity via matrix metalloproteinase-9 (MMP-9) activation, allowing cytokine entry into the CNS.^{Reference Xiao, Ge, Feng, Li, Luo and Dong20} Additionally, gut-derived LPS activate the vagus nerve, which transmits pro-inflammatory signals to the nucleus tractus solitarius, further amplifying neuroinflammatory cascades.^{Reference Bonaz, Bazin and Pellissier21} These interconnected pathways contribute to the sustained neuroimmune dysregulation observed in people with AUD, reinforcing alcohol-seeking behaviours.

Chronic alcohol consumption disrupts the gut barrier, resulting in increased intestinal permeability. This dysfunction allows bacterial endotoxins to enter systemic circulation. LPS activates Toll-like receptor 4 (TLR4) pathways, triggering the release of pro-inflammatory cytokines, including TNF-α and IL-6.^{Reference Li, Chen, Kumar, Zhang, Zhong and Zhang5} These cytokines cross the blood–brain barrier, where they activate microglia, the brain’s resident immune cells.

Once activated, microglia perpetuate neuroinflammation by producing additional inflammatory mediators that disrupt neural plasticity and impair synaptic function. This inflammatory environment contributes to alterations in reward circuitry within the mesolimbic pathway, particularly in areas such as the ventral tegmental area (VTA) and nucleus accumbens. Dysregulated reward signalling reinforces alcohol-seeking behaviour, creating a feedback loop that exacerbates addiction.^{Reference Rodriguez-Gonzalez and Orio7} Furthermore, neuroinflammation has been implicated in cognitive deficits and mood disorders, both of which are common comorbidities in AUD.

Animal studies provide compelling evidence for the link between gut dysbiosis and neuroinflammation. In murine models, alcohol-induced dysbiosis was associated with elevated systemic LPS levels and increased activation of brain microglia.^{Reference Leclercq, Stärkel, Delzenne and de Timary6} Interventions such as faecal microbiota transplantation (FMT) from healthy donors reversed these effects, reducing neuroinflammatory markers and improving cognitive outcomes. Translating these findings into human studies is a critical step in validating the therapeutic potential of targeting neuroinflammation through gut microbiota modulation.

Stress axis dysregulation

The hypothalamic–pituitary–adrenal (HPA) axis, a central regulator of the body’s stress response, is intimately connected to gut–brain communication. Dysbiosis induced by chronic alcohol consumption has been shown to exaggerate HPA axis activity, leading to heightened cortisol levels and increased stress reactivity.^{Reference García-Cabrerizo and Cryan22} This dysregulation creates a vulnerability to stress-induced alcohol consumption, as individuals often turn to alcohol as a maladaptive coping mechanism.

The bidirectional communication between the gut and the HPA axis involves multiple pathways. Gut microbiota influence the production of stress-modulating molecules, such as corticotropin-releasing hormone (CRH), which initiates the HPA axis cascade. Dysbiosis alters this balance, resulting in excessive CRH release and sustained HPA axis activation. Elevated cortisol levels, in turn, further disrupt gut microbiota composition, creating a vicious cycle that perpetuates dysbiosis and stress axis dysregulation.^{Reference Rusch, Layden and Dugas23}

Preclinical studies have demonstrated the impact of gut microbiota on stress responses. In germ-free mice, absence of gut microbiota was associated with exaggerated HPA axis activation in response to stress. Restoring microbiota through probiotic supplementation or FMT normalised HPA axis activity, reducing anxiety-like behaviours and alcohol preference.^{Reference Frankiensztajn, Elliott and Koren24} These findings suggest that modulating gut microbiota could serve as a therapeutic strategy for mitigating stress-related triggers in AUD.

Neurotransmitter imbalances

The gut microbiota plays a pivotal role in the synthesis and regulation of neurotransmitters that influence brain function and behaviour. For example, gut bacteria are involved in producing GABA, serotonin, dopamine and noradrenaline, all of which are critical in regulating mood, cognition and reward processing.^{Reference Chen, Xu and Chen14} Chronic alcohol consumption disrupts microbial populations responsible for these processes, contributing to neurotransmitter imbalances that exacerbate addiction behaviours.

One of the most well-studied examples is serotonin. Approximately 90% of the body’s serotonin is synthesised in the gut, with gut bacteria such as Lactobacillus and Bifidobacterium playing essential roles in its production.^{Reference Akram, Faisal, Irfan, Shah, Batool and Zahid25} Dysbiosis reduces serotonin availability, which is associated with depressive symptoms commonly observed in individuals with AUD. Depressive symptoms, in turn, increase the risk of relapse, further perpetuating the cycle of addiction.

Similarly, dopamine, a key neurotransmitter in the brain’s reward system, is influenced by gut microbial metabolites such as SCFAs. Dysbiosis impairs dopamine signalling, leading to anhedonia (reduced ability to experience pleasure) and increased alcohol-seeking behaviour as a compensatory mechanism. Studies in rodent models have shown that restoring gut microbial balance through probiotics can enhance dopamine signalling, reducing alcohol intake and improving motivation.^{Reference García-Cabrerizo, Carbia, Riordan, Schellekens and Cryan26}

Finally, GABA, the primary inhibitory neurotransmitter in the brain, is modulated by gut microbiota through pathways involving specific bacterial strains. Alcohol disrupts these pathways, contributing to heightened anxiety and irritability during withdrawal. Probiotic interventions targeting GABA production have shown promise in reducing these withdrawal symptoms, highlighting the therapeutic potential of restoring gut–brain neurotransmitter balance in AUD.^{Reference Tette, Kwofie and Wilson15}

Probiotics and prebiotics

Probiotics, which are live microorganisms that confer health benefits when consumed in adequate amounts, represent one of the most extensively studied therapeutic options for AUD. Specific strains such as Lactobacillus rhamnosus and Bifidobacterium bifidum have demonstrated efficacy in preclinical studies, where they were shown to restore gut barrier function, reduce systemic inflammation and modulate neuroinflammatory responses.^{Reference Varela-Trinidad, Domínguez-Díaz, Solórzano-Castanedo, Íñiguez-Gutiérrez, Hernández-Flores and Fafutis-Morris27,Reference Mazziotta, Tognon, Martini, Torreggiani and Rotondo28} Probiotics modulate gut barrier function, potentially reducing systemic inflammation and alcohol-induced neurotoxicity. For instance, Zhang et al^{Reference Zhang, Zhang, Deng, Cui, Li and Yang29} reported that Lactobacillus casei supplementation reduced serum zonulin (a marker of gut permeability) by 25% in a 12-week randomised controlled trial (RCT). However, the extent of probiotics’ impact remains debated.

Prebiotics, non-digestible fibres that promote the growth of beneficial microbiota, complement the effects of probiotics. Compounds such as inulin and fructo-oligosaccharides have been shown to increase SCFA production, particularly butyrate, which exerts anti-inflammatory effects and supports gut barrier integrity.^{Reference Facchin, Bertin, Bonazzi, Lorenzon, De Barba and Barberio30} In preclinical models, prebiotic supplementation reversed alcohol-induced dysbiosis and reduced alcohol-seeking behaviour.^{Reference Fan, Wei, Lu, Sun, Wang and Zhang31} Combining probiotics with prebiotics into symbiotic formulations offers a synergistic approach, enhancing microbial diversity and metabolic activity while addressing the multifaceted disruptions caused by AUD.

Despite these promising findings, challenges remain. Variability in probiotic strains and dosages across studies limits the generalisability of results, and long-term clinical trials are needed to establish their efficacy in diverse patient populations. Moreover, adherence to probiotic regimens, particularly in the context of AUD-related cognitive and motivational impairments, poses a practical challenge to widespread implementation.

Faecal microbiota transplantation (FMT)

Faecal microbiota transplantation (FMT) involves the transfer of gut microbiota from a healthy donor to a recipient, with the aim of restoring microbial diversity and functionality.^{Reference Karimi, Shirsalimi, Hashempour, Omran, Sedighi and Beigi32} Although FMT is well-established in treating conditions such as Clostridioides difficile infection, its application in AUD is still in its early stages. Preclinical studies have provided compelling evidence for the efficacy of FMT in reversing alcohol-induced dysbiosis and reducing addiction-related behaviours. In murine models, FMT from healthy donors restored gut barrier integrity, normalised microbial composition and attenuated alcohol-induced neuroinflammation, resulting in decreased alcohol consumption.^{Reference Leclercq, Stärkel, Delzenne and de Timary6}

The therapeutic potential of FMT extends beyond its ability to address dysbiosis. By introducing a diverse microbial community, FMT may also enhance the production of SCFAs and neurotransmitter precursors, thereby improving gut–brain communication. In addition, FMT has been shown to modulate immune responses, reducing the pro-inflammatory state associated with chronic alcohol use. Ezquer et al^{Reference Ezquer, Quintanilla, Morales, Santapau, Munita and Moya-Flores33} reported that FMT from healthy donors reduced LPS levels, restored gut microbiota diversity and decreased alcohol-seeking behaviour in preclinical models. Leclercq et al^{Reference Leclercq, Le Roy, Furgiuele, Coste, Bindels and Leyrolle8} demonstrated in a preclinical murine AUD model that FMT from healthy donors reduced hippocampal TNF-α levels by 60% and restored spatial memory in the Morris water maze.^{Reference Leclercq, Le Roy, Furgiuele, Coste, Bindels and Leyrolle8} However, Bajaj et al^{Reference Bajaj, Gavis, Fagan, Wade, Thacker and Fuchs34} reported mixed results in a human phase 1, double-blind RCT: although FMT was found to be safe and associated with short-term reduction in alcohol craving and consumption with favourable microbial changes versus placebo in individuals with alcohol-associated cirrhosis, microbial diversity reverted to baseline after 12 weeks, highlighting durability challenges. However, these findings remain preliminary and require replication in larger clinical cohorts.

Despite its promise, FMT faces several challenges in clinical translation. Safety concerns related to the potential transmission of pathogens and variability in donor microbiota composition necessitate stringent donor screening and standardised protocols.^{Reference Tian, Wang, Fang, Li, Wu and Bi35,Reference Rasmussen, Mao, Forster, Larsen, von Münchow and Tranæs36} Ethical considerations, particularly regarding informed consent and equitable access, must also be addressed. Furthermore, public perception of FMT as an invasive or unappealing procedure may limit patient acceptance, highlighting the need for effective communication and education.

To advance FMT as a treatment for AUD, rigorous clinical trials are required to establish its efficacy and safety in human populations. Longitudinal studies investigating the durability of its effects and its impact on relapse rates are particularly important. As research progresses, encapsulated forms of FMT, which offer a less invasive alternative to traditional procedures, may enhance its feasibility and acceptance in clinical practice.

Psychobiotics

Psychobiotics, a subclass of probiotics with specific effects on mental health, have garnered attention as a potential therapeutic strategy for AUD. These agents influence the gut–brain axis by modulating neurotransmitter production, reducing systemic inflammation and neuroinflammation, and normalising HPA axis activity.^{Reference Oroojzadeh, Bostanabad and Lotfi37} For instance, strains such as Bifidobacterium longum and Lactobacillus helveticus have been shown to alleviate anxiety and depressive symptoms in preclinical models, both of which are common comorbidities in AUD.^{Reference Dziedzic, Maciak, Bliźniewska-Kowalska, Gałecka, Kobierecka and Saluk38}

In the context of addiction, psychobiotics may offer dual benefits by addressing the psychological and physiological dimensions of AUD. By enhancing the production of serotonin and GABA, psychobiotics can regulate mood and reduce stress reactivity, which are critical factors in relapse prevention.^{Reference Skowron, Budzyńska, Wiktorczyk-Kapischke, Chomacka, Grudlewska-Buda and Wilk39} Additionally, their anti-inflammatory properties may mitigate neuroinflammation, thereby improving cognitive function and reward processing.

The mechanistic basis of psychobiotics extends beyond AUD to other psychiatric disorders, such as depression and schizophrenia, where gut dysbiosis similarly disrupts neurotransmitter balance (e.g. serotonin, GABA), gut barrier integrity and neuroimmune signalling.^{Reference Rodriguez-Gonzalez and Orio7,Reference Dicks11,Reference Mhanna, Martini, Hmaydoosh, Hamwi, Jarjanazi and Zaifah12,Reference Chen, Xu and Chen14} Critically, conventional psychotropic medications (e.g. antidepressants, antipsychotics) may themselves induce dysbiosis or alter microbial metabolism,^{Reference Chen, Xu and Chen14,Reference Oroojzadeh, Bostanabad and Lotfi37} creating a therapeutic paradox. This underscores the need for integrated approaches that consider microbiota–medication interactions – particularly in AUD, where comorbidities often necessitate polypharmacy.

Preliminary clinical studies investigating psychobiotics in AUD populations have yielded promising results. Patients receiving psychobiotic supplementation reported improvements in emotional well-being, reduced alcohol cravings and better adherence to abstinence protocols. Although there was a general agreement on the effectiveness of psychobiotics, the variability in treatment approaches and clinical presentations limits the comparability and generalisation of the findings.^{Reference Mosquera, Lizcano Martinez and Liscano40} Larger-scale trials are needed to validate these findings and identify the specific strains and dosages that are most effective.

The integration of psychobiotics into AUD treatment frameworks offers a unique opportunity to address the gut–brain axis as a therapeutic target. Future research should explore the combined use of psychobiotics with behavioural and pharmacological therapies to maximise their efficacy and ensure comprehensive care.

Dietary interventions

Dietary interventions are a practical and non-invasive approach to improving gut health in AUD populations. Diets rich in fibre, fermented foods and polyphenols have been shown to enhance microbial diversity, support gut barrier function and reduce systemic inflammation.^{Reference Zhang41} For example, a high-fibre diet promotes the growth of beneficial bacteria that produce SCFAs, which play a critical role in maintaining gut–brain communication.

Fermented foods, such as yogurt, kefir and kimchi, naturally contain probiotics that can supplement microbial diversity. Polyphenol-rich foods, including berries, tea and dark chocolate, exhibit anti-inflammatory and antioxidative properties that support gut and brain health. These dietary components may counteract the detrimental effects of alcohol-induced dysbiosis, thereby improving overall health outcomes.

Integrating dietary counselling into AUD treatment programmes could provide a cost-effective and accessible adjunct to existing therapies. By empowering patients with knowledge about the impact of diet on gut health, clinicians can encourage sustainable lifestyle changes that support recovery. However, dietary interventions should be tailored to individual needs and preferences, particularly in populations with coexisting conditions or dietary restrictions.

Further research is needed to establish evidence-based dietary guidelines for people with AUD, with a focus on optimising microbial diversity and function. Longitudinal studies examining the impact of dietary interventions on relapse rates and psychological outcomes would provide valuable insights into their long-term efficacy.