Fermented foods: Harnessing their potential to modulate the microbiota-gut-brain axis for mental health

suggest solutions that can advance understanding of the therapeutic merit of fermented foods to modulate the microbiota-gut-brain axis.


Introduction
"Long is the calm brain active in creation; Time, only, strengthens the fine fermentation".

Johann Wolfgang von Goethe
Keeping the brain active in creation as referenced by Goethe relies on a variety of intrinsic and extrinsic signals.Over the past two decades, there has been a growing appreciation that the gut microbiota is a key mediator with respect to responding to external signals and triggering intrinsic functions within the body.The microbiota-gut-brain axis consists of a diverse microbial community contained in the intestinal environment that is in constant communication with the central nervous system, and vice versa.The gut microbial community is influenced by a variety of factors ranging from diet (Latorre-Pérez et al., 2021;Qin et al., 2022;Asnicar et al., 2021), age (Yatsunenko et al., 2012;Ghosh et al., 2022), medication use (Ghosh et al., 2022), sex (Cuesta-Zuluaga et al., 2019), ethnicity (Ang et al., 2021;Dwiyanto et al., 2021) and geographical location (Bai et al., 2022;Kabwe et al., 2020) and other factors, with diet playing a particularly important role in influencing the microbiota and the metabolites they produce.These microbes and their metabolites influence the hosts intestinal (Del Bo et al., 2021;Peron et al., 2021), immunological (Longhi et al., 2021;Wastyk et al., 2021;Bisgaard et al., 2016;Li et al., 2016) and neural components (Shi et al., 2021;Tessier et al., 2021;Ribeiro et al., 2022) of the microbiota-gut-brain axis.In parallel, meta-analyses examining the relationship between mental health and dietary patterns have hinted at the promise of dietary intervention strategies to influence the cognitive wellbeing of an individual (Abbott et al., 2019;Ocklenburg and Borawski, 2021;Taylor et al., 2021).Thus, as a consequence of a combination of these advances, there is a growing interest in targeting the microbiota via diet so as to confer mental health benefits to the host (Berding et al., 2021b).The majority of microbiota-targeted interventions involve probiotics (Long-Smith et al., 2020), prebiotics (Mörkl et al., 2020), fibres (Berding et al., 2021a), polyphenols (Rodríguez-Daza et al., 2021), fatty acids (Silva et al., 2020), or, more broadly via changes in habitual dietary consumption (Ghosh et al., 2020;Millman et al., 2021;Valls-Pedret et al., 2015).Whole food based dietary interventions are increasingly applied to study mental health (Berding et al., 2021a).These interventions are usually lifelong and are integrated into the habitual diet of the patient.Recently studies have investigated fermented foods as a potential avenue of microbiota-targeted intervention strategy (Marx et al., 2020).Although ancient in origin, fermented foods are now seen as conduits for introducing beneficial microbes and molecules.Moreover, fermented foods are applicable therapeutics across various socioeconomic sectors given their potential affordability and cross-cultural accessibility.
Food fermentation was traditionally employed to enable longer storage/shelf-life of food substrates that would otherwise spoil quickly, which was crucial in times of scarcity (Amato et al., 2021;Borremans et al., 2020;Ross et al., 2002), whilst concurrently enhancing flavour profile (Liu et al., 2019b;Cai et al., 2019;Mandha et al., 2022;Peraza and Perron, 2022), reducing the toxicity of raw materials/controlling pathogenic microorganisms and simultaneously allowing for their digestion (Reddy and Pierson, 1994;Maixner et al., 2021).Fermented foods are mainly classified into categories based on the substrate used, e. g., cereal, dairy, meat, fish, vegetable and legume (Tamang et al., 2020), which differ with respect to their primary food substrate and type of fermentation (e.g., defined starter culture, spontaneous or back-slopped culture).Table 1 in this review highlights the diverse nature of fermented foods that is referred to in this review along with the substrate category and the nature of fermentation employed in its production.The microbial community present in a fermented food is associated with a number of factors, including the type of substrate (Achi and Asamudo, 2019;Leech et al., 2020), geographical location (Van Reckem et al., 2019;Jung et al., 2018;Zhong et al., 2016;Li et al., 2017), pH (Yang et al., 2020) and method of preparation (Lee et al., 2021;Van Reckem et al., 2019) (See Fig. 1).Fermented foods are a rich source of beneficial microorganisms (potential probiotics) (Okada et al., 2018;Wang et al., 2022) as well as bioactive peptides (Chaudhary et al., 2021), phytochemicals and vitamins (Septembre-Malaterre et al., 2018;Shahbazi et al., 2021b).As researchers increasingly investigate the impact of different dietary intervention strategies and habitual dietary practices on sculpting the gut microbiota (Losasso et al., 2018;Tanes et al., 2021;Stege et al., 2022) and, consequently, their metabolites (Wu et al., 2016;Chen et al., 2022), it is not surprising that fermented foods receive particular attention.This is in no small way related to their capacity to modulate the composition and/or diversity of the gut microbiota (Bellikci-Koyu et al., 2019;Le Roy et al., 2022;Wastyk et al., 2021) and/or the production of microbial metabolites, such as short chain fatty acids (SCFA), polyphenolic (Johnson et al., 2019;Zorraquín-Peña et al., 2021), tryptophan and bile metabolites (Scott et al., 2020) and, as a result, can modulate the pathways that relay information from gut to the brain.Table 2 provides a primer on the nomenclature of various microbial components and bioactive components along with consensus statement that aptly captures their function.The frequent, yet incorrect, description of fermented food-associated microorganisms as probiotics in the literature and by industrial stakeholders has led the International Scientific Association for Probiotics and Prebiotics (ISAPP) to establish a consensus statement regarding terminology that is frequently used in microbiota based therapeutic strategies.
Here, we review the components of fermented foods that can exert beneficial effects to the individual with a particular focus on mental health.We also summarise existing literature from preclinical and clinical research relating to the impact of fermented foods on individual components of the microbiota-gut-brain axis.Lastly, we discuss the current challenges associated with preclinical and human studies aimed at understanding the beneficial effects of fermented foods as a potential intervention strategy targeting mental health.

Fermented food and the microbiota-gut-brain axis
The microbiota-gut-brain axis facilitates a constant bidirectional relay of information from the intestine via the enteric nervous system (ENS) and from the intestinal milieu consisting of microbial communities, microbial metabolites, gut associated lymphoid tissue (GALT), peripheral immune cells and cytokines to the brain and vice versa via the sympathetic/parasympathetic nervous system, neurotransmitters and the circulatory immune system (Cryan et al., 2019).Fermented foods are rich in microbes and their metabolites.In addition to the phytochemicals, these metabolites can take the form of neurotransmitters, neuroactives and neuromodulators (Yu et al., 2020), and thereby stimulate the connecting pathways of the microbiota-gut-brain axis: immune, neuroendocrine, enteric nervous and circulatory system.Upon digestion, they can result in the production of microbial metabolites that can modulate the permeability of the intestinal barrier (Scott et al., 2020) and the blood brain barrier (BBB) (Stachulski et al., 2022;Angelino et al., 2019).Before we discuss the effects of fermented food supplementation on mental health, we outline the current evidence of the ability of fermented foods to modulate the individual components of the microbiota-gut-brain axis so as to exploit them for future microbiota-targeted therapeutics.

Fermented food and the immune system
Microbial metabolites are capable of regulating the immune system (Lavelle and Sokol, 2020) via systemic circulation (Colombo et al., 2021) or by the vagus nerve (Bluthe et al., 1996;Namgung et al., 2022;Huffman et al., 2019).Growing evidence on the presence of receptors for bacterial cell wall components and immunostimulants such as peptidoglycan and lipopolysaccharides in the brain depict the far reaching ability of the gut microbiota on the brain and behaviour of the host (Wheeler et al., 2023;Arentsen et al., 2017;Tillinger and Mravec, 2021).

Table 1
Compilation of fermented foods that are frequently referred to in this review and the type of fermentation process most commonly employed in their production.The methods of fermentation might be subjected to variation in their production, geographical location, cultural practices and are not strictly confined the method specified in the table.This microbiota-gut-immune-brain connection is influenced by different dietary and lifestyle choices across lifespan (Bostick et al., 2022;Ratsika et al., 2023).Fermented foods, a subset of dietary intervention strategies can therefore be leveraged to boost this bidirectional communication.
Several components of fermented foods are being individually studied for their ability to modulate the immune system.The bacterial cellular components of fermented foods have shown the ability to instigate the release of IL-10 from dendritic cells and CD4 + T cells (Kim et al., 2019).Other components, such as fermented food exopolysaccharides (EPS) are also being explored for their modulatory effects on the immune system, as seen with kefiran, an EPS product produced by Lactobacillus kefirofaciens (Bourrie et al., 2016).Microbial metabolites produced in fermented food also have immunomodulatory abilities.For example, oleamide, a microbial metabolite produced by Penicillium candidum, is present in products such as camembert cheese.Oleamide has been shown to suppress TNF-α release from microglia by acting as an agonist for the P2Y and cannabinoid receptors (Kita et al., 2019).
A potential mechanism by which fermented foods are able to exert immunomodulatory effects is through activation of the hydrocarboxylic acid receptor (HCA3R), as a consequence of consuming lactic acid bacteria (LAB) fermented food.Sauerkraut, also rich in LAB upon consumption is shown to elicit a chemotactic response from monocytes via D-Phenylacetic acid, a potent HCA3R receptor agonist (Peters et al., 2019).Large scale genome wide association analysis have revealed the LAB found in human gut likely to be from foods (Pasolli et al., 2020).Interestingly, a human observational study on the TwinsUK cohort showed elevation in B. animalis subsp.lactis with yogurt consumers that positively correlated with 3-hydroxyoctanoate levels, which is an agonist for HCA3 and could be potentially implicated in host immunoregulation (Le Roy et al., 2022).Further studies on the hydrocarboxilic receptor revealed only humans and great apes to possess three hydrocarboxylic receptors, as opposed to the two (HCA1R, HCA2R) seen in other organisms, indicating the development of evolutionary adaptations to accommodate the consumption of fermented foods (Peters et al., 2019).

Fermented food on inflamed barrier integrity
Microbial surface molecules and microbial metabolites are implicated in the integrity of the intestinal epithelial barrier (Spiljar et al., 2017;Liu et al., 2020b) and the blood brain barrier (Knox et al., 2022a).SCFA (Knox et al., 2022b), methylamines (Hoyles et al., 2021), bile acid metabolites (Lajczak-Mcginley et al., 2020) and amino acid metabolites (Scott et al., 2020;Stachulski et al., 2022) are some of the metabolites produced by the host microbiome that can influence the intestinal and BBB integrity of the host.Fermented foods are a rich source of microorganisms and on consumption can result in production of microbial metabolites that can elicit an immunological response, thereby influencing the integrity of these physiological barriers.
Several studies have examined the impact of fermented food products on intestinal integrity in the context of Inflammatory Bowel Disease (IBD).Murine models of IBD when supplemented with Bacillus subtilis Fig. 1.Fermented foods are diverse in their preparation, substrate category and type of fermentation.This can influence the microbiota and the molecular composition of fermented foods.Subsequently, these components can influence the communication between the gut and the brain resulting in modulation of the intestinal barrier and blood brain barrier, peripheral and central immune system and nervous system and thereby modulating the intestinal mileu, general gut and brain health.Created with BioRender.com.
R. Balasubramanian et al. fermented milk showed rescue in intestinal morphology as well as elevation in tight junction protein level as opposed to the disease control (Zhang et al., 2021b).This restoration of intestinal tight junction proteins has also been observed using in-vitro and murine models of IBD supplemented with fermented barley and soybean (Woo et al., 2016c).Studies have also measured rescue of intestinal integrity via measurement of bacterial translocation.As the microbial community resides within the gut, translocation can indicate a compromise to intestinal integrity.The translocation of microbes and their cellular components can activate the peripheral immune system resulting in the release of cytokines that can ultimately trigger altered BBB integrity and neuroinflammation (Maes et al., 2013;Vujkovic-Cvijin et al., 2022).Indeed, pre-treatment of mice with milk fermented using Lacticaseibacillus paracasei subsp.paracasei lowered intestinal permeability as visualised by the reduced translocation of Salmonella typhimurium (Acurcio et al., 2020).Although less frequently studied, downstream reinforcing effects of fermented food on BBB integrity was observed following kimchi and kefir supplementation, which increased expression of BBB tight junction proteins along with a sex-specific reduction of mRNA levels of IL-1β and TNFα in the pre-frontal cortex and hippocampus in murine models (Kim et al., 2022b;Murray et al., 2019).

Fermented food and central/peripheral inflammation
Beyond their influence on barriers, fermented foods are also studied with respect to their role on central/peripheral immunomodulation.Preclinical studies assessing the impact of fermented foods on the immune system have either studied effects on the baseline unperturbed immunological state of the host or when the host is subjected to an immune challenge that mimics a pathological condition.For instance with respect to the latter, Lactobacillus delbrueckii and Streptococcus thermophilus fermented yogurt supplementation in a recurrent model of IBD in murine models, decreased levels of TLR4 + and IL-17 along with elevation of IL-10 and TLR9 + cells in the colon (Chaves et al., 2011).
Similar reductions in the levels of inflammatory cytokines, especially IFN-γ and TNF-α, were observed in the colon of mice receiving milk kefir post-infection with Giardia intestinalis (Franco et al., 2013).These effects could be due to the ability of some kefirs to upregulate mRNA levels of IL-17 and downregulate IL-6, TNF-α, and IFN-γ when subjected to immune challenge in mice (Acurcio et al., 2020).Moreover, repeated treatment with other milk kefirs in mice has been shown to increase levels of Treg and IL-10 cells coupled with an attenuation of the elevated neutrophils and CXCL1 levels induced by the stress of repeated oral gavage (Van De Wouw et al., 2020).Further studies have highlighted that this potential peripheral immunomodulation observed in kefir could be attributed to IgA-stimulating Lactobacillus kefiri that reduces expression of pro-inflammatory cytokines in the mesenteric lymph nodes and increases anti-inflammatory cytokines, CXCL-1 and expression of mucin-6 genes.Other strains of the same species were also associated with a lowered expression of IL-6 in the ileum and colon post-LPS exposure (Carasi et al., 2015).It should be noted that studies focusing on a single strain isolated from fermented food aid in the discovery of potential probiotic strains and can give insights into the mechanisms via which a fermented food may confer a health benefit.However, these studies do not capture the broader bioactive potential of fermented foods that include more complex mixtures of bacterial strains, bioactive peptides, microbial metabolites, fibres and other components that can impart beneficial biological effects on the individual (Vieira et al., 2021).
Studies are increasingly shifting towards understanding the farreaching effects of fermented foods on neuroinflammation.A spatial observation of the immunomodulatory effects of fermented foods on the brain revealed that hippocampal and cortical regions of the brain exhibit lower levels of mRNA expression pertaining to IL-6, TNF-α, TLR4 receptor and MCP1 protein, which was significantly upregulated in mice fed a high-fat diet (Kim et al., 2022b).This was also observed in the hypothalamic regions of the brain and serum in mice subjected to chronic unpredictable mild stress when supplemented with fermented rice germ (Batsukh et al., 2022).Future work is needed to explore the impact of fermented foods at each compartment of the microbiota-gut-brain-immune axis, particularly the effects of microbial metabolites on the intestinal barrier, peripheral immune system, BBB and central immune system.This information would provide valuable insight into understanding the molecular underpinnings of the microbiota-gut-brain-immune axis.
Importantly, some of the aforementioned findings relating to the immunomodulatory effects of fermented foods have translated to human studies, albeit only a few studies have also concurrently looked at the gut microbiome profile.For instance, in a study conducted with healthy volunteers, a 10-week fermented food-based intervention resulted in decreased circulating cytokine levels, especially IL-6, IL-10 and IL-12b, along with a concurrent reduction of activation proteins from 4 major immune cell types: CD4 + , CD8 + , T and B cells (Wastyk et al., 2021).The study also revealed a correlation between faecal butyrate and lower circulating B cells (Wastyk et al., 2021), mirroring the preclinical findings of an interplay between microbial metabolite and host immune status.Furthermore, a reduction in circulating cytokine levels such as IL-4, IL-10, IL-12 and MCP-1 was observed in IBS patients supplemented with kimchi for a period of 12 weeks (Kim et al., 2022a).This is however not replicated in other studies that have looked at the impact of fermented, unfermented and pickled vegetables for 6 weeks (Galena et al., 2022).The study showed no difference in their serum C -reactive protein (CRP) and TNF-α profile, when measured at the end of the intervention.Similarly, a fermented food enriched diet, when administered for a duration of 4 weeks, did not show any alteration in serum cytokines (Berding et al., 2023).Epidemiological studies have also revealed no associations between the consumption of fermented and unfermented dairy with circulating CRP levels (Voutilainen et al., 2022).It is therefore surprising that a recent meta-analysis on fermented dairy products such as yogurt, fermented milk and kefir revealed lowered CRP and

Terminology Description Reference
Fermented foods "Foods made through desired microbial growth and enzymatic conversion of food components" (Marco et al., 2021) Probiotic "Live microorganisms, which when administered in adequate amounts confer a health benefit on the host, and a general benefit could either be by supporting a healthy digestive tract or healthy immune system" (Hill et al., 2014) Prebiotic "A substrate that is selectively utilised by host microorganisms conferring a health benefit" (Gibson et al., 2017) Postbiotic "Preparation of inanimate microorganisms and/or their components that confer a health benefit on the host" (Salminen et al., 2021a;Salminen et al., 2021b) Synbiotic "A mixture comprising live microorganisms and substrate(s) selectively utilised by host microorganisms that confers a health benefit on the host" (Swanson et al., 2020) Cryptic peptide Bioactive peptides that require enzyme hydrolysis to release the bioactive portion and hence are encrypted in the protein molecule (Guo et al., 2023) Psychobiotic "Live organism that which when ingested in adequate amounts, produces health benefit in patients suffering from psychiatric illness that has evolved to "Microbiota-targeted intervention that has a positive effect on mental health" (Dinan et al., 2013;Long-Smith et al., 2020) R. Balasubramanian et al. elevated IFN-γ with no significant effect on IL-12, IL-10 and IL-6 (Zhang et al., 2023).It is clear that the effects of fermented foods on circulatory inflammatory cytokines cannot be generalised given the varied responses observed with intervention strategies.A potential reason for this could be due to the heterogeneity of food substrates and microorganisms present in the fermented food and duration of the dietary intervention.The immunological response observed is highly tailored to the fermented food that is being studied and could be influenced by the microbial community it hosts (Spindler et al., 2022) and is addressed in greater detail in the final section of the review.It is also to be acknowledged that sex plays a critical role in modulating microbiota-gut-brain-immune axis communication (Jaggar et al., 2020;Klein and Flanagan, 2016).Some studies have only looked at fermented food supplementation in male (Schoen et al., 2009;Bourrie et al., 2023) and female volunteers (Han et al., 2015;Galena et al., 2022).One study, however, examined sex differences on moderate beer consumption and observed that women had higher CD3 + counts than male volunteers, with both groups showing an overall reduction in the IFN-γ/IL-10 ratio when compared to their baseline abstinent phase (Romeo et al., 2007).However, there is a general dearth of human studies that explore sex-selective immunomodulatory responses associated with the consumption of fermented foods and its effects on the overall health of the individual.

Fermented food and the hypothalamic-pituitary adrenal (HPA) axis
The HPA axis is a key regulator of mood and behaviour and forms the neurohormonal component of the microbiota-gut-brain axis.Dysregulation of the HPA axis and its interplay with the immunological system is implicated in multiple neuropsychiatric disorders (Wingenfeld and Wolf, 2011;Rinne et al., 2002;Cruz-Pereira et al., 2020).Cortisol, the main stress hormone of the HPA axis, has been shown to modulate the immune system (Bellavance and Rivest, 2014), BBB permeability (Varanoske et al., 2022) and intestinal barrier integrity (Zhao et al., 2019;Karl et al., 2017).The latter is responsible for sustaining homoeostasis in the gut micro-environment (Amini-Khoei et al., 2019;Uren Webster et al., 2020) and can be influenced by the neurological state of the host.
In murine models, the impact of the HPA axis on various behavioural parameters such as appetite, aversion and cognition are studied by using a multitude of tests such as forced suspension, and immobilisation (despair related behaviour), sucrose water preference (depression-like behaviour), elevated plus maze (anxiety-like behaviour) and startle reflex (responsiveness) and many others (Packard et al., 2016).Consumption of fermented foods including red bean tempeh, cheese and fermented plant (Laminaria japonica) as assessed by murine models, was shown to reduce anxiety-like behaviours and corticosterone levels when subjected to stress (Chen et al., 2020;Chen et al., 2021b;Fourman et al., 2021;Jung et al., 2020).Similar attenuations in depression and anxiety-like phenotype accompanied by lowered plasma corticosterone and inflammatory markers such as NF-Κb, TNF-α and IL-6 were observed in the colon of mice supplemented with fermented ginseng extract for a period of 5 days (Han et al., 2020).In a comparable manner, fermented porcine placenta supplementation for a 21-day period, which showed lowered cortisol along with creatinine kinase and lactate.The study also showed concurrent lowering of circulating cytokines-IL-6, TNF-α, IL-1β, IL-4 and IFN-γ (Kim et al., 2016).All of the mentioned studies report a strong interplay between the immune system and the HPA axis.A potential mechanism by which fermented foods are able to modulate cortisol release could be via blunting the response peripheral immune challenge by causing a reduction in circulating cytokines and other inflammatory markers which are responsible for activating neuronal projectionsinto the PVN (Bellavance and Rivest, 2014).Interestingly, a study on mice subjected to restraint stress and receiving milk kefir treatment, reported the probiotic containing fermented food was able to block HPA axis dysregulation by attenuating the altered expression of glucocorticoid receptors in the PVN, when compared to mice receiving unfermented milk.The study also hinted at the HPA axis dysregulation to be highly sex specific and a potential connection between IL-6 and glucocorticoid receptor expression (Smith et al., 2021).Such interesting exploratory efforts could shape our understanding of the multifaceted role played by fermented foods in modulating the microbiota-gut-immune-brain axis.
Fermented food interventions in human cohorts have been limited and conflicting.An 8-week intervention of fermented porcine placenta resulted in lower serum cortisol levels along with concurrent reduction in the mRNA expression of IL-1β following treadmill stress testing (Yoon et al., 2020).Similarly, reductions in salivary cortisol was observed in students receiving Lacticaseibacillus casei strain Shirota and subjected to examination stress.The same strain was also shown to blunt the release of corticosterone in rats subjected to water avoidance stress (Takada et al., 2016).Conversely, some studies reported no effects of fermented foods on post-stress cortisol levels (Jaatinen et al., 2014;Marcos et al., 2004), potentially due to the small quantity, diverse nature of fermented food being consumed, and short duration of intervention.

Fermented foods influencing serotonin secretion and receptor expression
The enterochromaffin cells in the intestine are major producers of serotonin (Lund et al., 2018).Gut-derived serotonin is shaped by host diet (Bruta et al., 2021;Horn et al., 2022), baseline microbiota composition (Reigstad et al., 2015a;Yano et al., 2015;Hata et al., 2017) and microbial metabolites produced as a consequence (Reigstad et al., 2015;Yano et al., 2015).Although serotonin cannot pass the BBB, it can influence fundamental aspects of the gastric system, such as regulating secretion, motility and tonicity.There are a growing number of studies focusing on the influence of fermented foods on serotonin secretion with special emphasis on tryptophan metabolites.Tryptophan metabolites are critical precursors for serotonin and melatonin biosynthesis and also lead to the production of indole and kynurenine-related metabolites, all of which are increasingly being appreciated for their neuroactive role in addition to maintaining gut health.
Preclinical studies report lowered serotonin turnover in the colon of mice supplemented with milk kefir compared to unfermented controls (Van De Wouw et al., 2020), which was also reflected in mice subjected to immobilisation stress and supplemented with fermented Chinese medication such as fermented Mentha arvensis and fermented Cornus officinalis (Tian et al., 2018;Tian et al., 2020).Other preclinical models have demonstrated the ability of fermented soy-based food such as tempeh to modulate the level of serotonergic genes.Tempeh-fed zebrafish showed upregulation in genes involved in transportation, synthesis and signalling of serotonin, namely tph1b, tph2 and slc6a4a genes in the brain (Chen et al., 2021b).The ability of fermented foods to modulate peripheral serotonin levels could be attributed to the presence of endogenous bacteria within the food, which are capable of producing these metabolites as a result of the fermentation process (Jeong et al., 2021;Gallardo-Fernández et al., 2022;Kumar et al., 2022).The ability of fermented foods to modulate gut health could also be credited to synbiotic components present in the food.A study of a murine model of constipation employed a synbiotic yogurt containing konjac mannan oligosaccharide (prebiotic) and Bifidobacterium animalis spp lactis (probiotic).The study reported an increase in levels of acetylcholine, substance P and upregulation of motilin, vasoactive intestinal peptide receptor (VIPR-4) and 5-HT4 receptors in colonic tissue upon intervention with the synbiotic containing yogurt (Li et al., 2021b).
Despite these developments, there remains a shortage of human studies that have extensively explored the involvement of fermented foods in modulating the serotonergic landscape.In one instance, daily consumption of a fermented milk product containing Lactobacillus casei for 8 weeks showed increased faecal serotonin and decreased abdominal discomfort without changes in serum tryptophan, kynurenine, salivary cortisol and IgA levels compared to participants receiving unfermented controls (Kato-Kataoka et al., 2016).Other studies on white wine consumption have shown lowered myogastric electrical activity, variation in plasma serotonin and dopamine profiles (Boyer et al., 2004;Levanon et al., 2002).Peripherally produced serotonin cannot cross the BBB but downstream metabolic products of tryptophan metabolism can cross the BBB and influence neurological state of the host.In recent years, research has been dedicated towards understanding the effects of tryptophan metabolism, especially the kynurenine pathway, on host behaviour and health.A meta-analysis of prebiotic and probiotic supplementation on tryptophan metabolism revealed significant decrease in kynurenine and kynurenine:tryptophan ratio with probiotic supplementation (Purton et al., 2021).Indeed, metabolomic analyses of fermented foods have revealed that they are reservoirs for tryptophan metabolites (Yılmaz and Gökmen, 2020), revealing that it could be interesting to see how peripheral supplementation of tryptophan metabolites can affect mood and behaviour modulated by the gut microbiota.

Fermented food modulating enteroendocrine signalling
The enteroendocrine system (EES) is capable of secreting molecules that can influence the afferent vagus nerve, and receptors of these molecules are expressed higher up in the nucleus tractus solitarius (NTS) and hypothalamic regions of the brain.These regions undermine energy expenditure, food preferences and satiety of the host thereby mediating feeding behaviour (Latorre et al., 2016;Holst, 2013).Functioning of the EES is also influenced by microbial metabolites that are introduced through dietary intake.The EES primarily hosts a network of gut hormones such as serotonin, neuropeptide-Y, GLP-1, ghrelin, peptide YY (PYY), motilin and somatostatin that continuously relay information to the enteric nervous system (ENS).The impact of each of these gut hormones and peptides on the microbiota-gut-brain axis has been described in detail across multiple extensive reviews (Richards et al., 2021;Wachsmuth et al., 2022;Sun et al., 2020).In brief, the hormones of the EES regulate motility, appetite, release of insulin and bile acids (Sun et al., 2020).The submucosal and the myentric plexsus of the ENS communicate with each other via a small collection of neurotransmitters and neuropeptides, which can be secreted and modulated by the fermented food microbiome, microbial metabolites and co-occurring active principles.

Fermented food and gut hormone secretion
The enteroendocrine cells (EEC) receive multiple stimuli ranging from nutrients, toxins and microorganisms present in fermented and unfermented food and respond by releasing peptides and hormones.Modulating the levels of GLP-1 is being used to attain improved glucose homoeostasis (Yadav et al., 2013) as well as to target obesity (Aldawsari et al., 2023) resulting in the development of wide array of GLP-1 analogues aimed at managing obesity (Dailey and Moran, 2013) and type 2 diabetes mellitus (Maselli and Camilleri, 2021).Dietary intervention strategies are also being employed to target circulating levels of GLP-1 peptides in patients diagnosed with type 2 diabetes (Di Mauro et al., 2021) and abdominal obesity (Fuglsang-Nielsen et al., 2021).This recent exploration in the use of dietary strategies to combat type 2 diabetes mellitus has resulted in the identification of microbial metabolites, predominantly SCFA that can improve production of GLP-1 and peptide YY, both of which are implicated in regulation of insulin release.(Zhao et al., 2018).Fermented foods as a potential source of prebiotics and probiotics to shape the gut microbiota and its metabolites are also being explored to manipulate the levels of gastric peptides that are implicated in satiation and insulin release (Manaer et al., 2015;Fallah et al., 2018).
Both unfermented and fermented foods contain bioactive components that can influence the secretion of incretins such as GLP − 1, a gut hormone implicated in satiety (Johnson and De Mejia, 2016).It is therefore necessary for studies focusing on the impact of fermented foods on the enteric environment to concurrently account for the effect of unfermented controls on EEC secretion profiles.The patterns of endogenous and exogenous release of GLP-1 have been well reported in murine models and human studies (Flint et al., 1998;Terrill et al., 2019;Chen et al., 2021a) and therefore can be adopted to study the effects of fermented foods on satiation.Interestingly, in-vitro studies on kippuku-cha, a fermented Japanese beverage, was found to activate GPR-120 and stimulate the release of GLP-1 via phosphorylation of the Erk1/2 (p42/44 MAP kinase) pathway (Nagasawa et al., 2020).Similarly, phenol and polysaccharide extracts from quinoa yogurt fermented with starter cultures of S. thermophilus and Lactobacillus bulgaricus stimulated the release of GLP-1 and influenced expression of proglucagon mRNA, CCK and c-FOS along with DDP-1 V inhibitory potential (Obaroakpo et al., 2020).The study revealed that the fermented product elevated concentrations of GLP-1 and proglucagon than the unfermented controls.Such studies assessing the incretin release profile using in-vitro studies must be interpreted with caution, as their effects can be inflated when compared to in-vivo conditions.For example, fermented dairy-based products such as whey possess the ability to stimulate the release of GLP-1 and CCK (Chaudhari et al., 2017;Sánchez-Moya et al., 2020), however these effects were not translated to in-vivo studies (Kondrashina et al., 2018).The study stated that this lack of translatability between in-vitro to in-vivo models could be due to the action of gastrointestinal enzymes, which may reduce the GLP secretogogue capacity of fermented dairy products unless enterically protected (Kondrashina et al., 2018).
Human studies often adopt self-reported questionnaires to gauge the effect of intervention strategy on satiety and hunger.In humans, fermented dairy, fermented dairy alternates and fermented bread are predominantly studied for their ability to modulate satiety in the individual, but only a few studies investigated circulating GLP profiles.For example, consumption of sourdough bread by Swedish adults resulted in pronounced satiety compared to consumption of unfermented whole grain and yeast fermented controls.However, the effects of sourdough on insulin release and satiety has not been replicated in two other clinical trials (Shah et al., 2020;Iversen et al., 2018).The GLP-1 release profiles across all the cohorts were unaffected, suggesting fermented foods enhance satiety via mechanisms independent of GLP-1 (Zamaratskaia et al., 2017).Apart from sourdough, high levels of vinegar supplementation has been associated with increased satiety and lower postprandial blood glucose (Ostman et al., 2005).Researchers have hypothesised that the satiating effect of vinegar and some sourdough could be due to the acid content of the fermented product.The inconsistent results observed on satiety profiles across studies could be attributed to factors such as sex, sample size, duration of intervention, method of sourdough preparation (including species and strain level differences) and quantity of sourdough consumed (Ribet et al., 2023).

Impact of fermented food consumption on ghrelin and leptin levels
Desacyl ghrelin and acyl ghrelin are orexigenic hormones that are the predominant forms of circulating ghrelin and are implicated in the regulation of appetite and its neuroprotective effects (Lach et al., 2018;Rhea et al., 2018;Huang et al., 2019).Unlike serotonin, ghrelin is released in the periphery and can cross the BBB, thereby binding to several targets associated with food reward including corticolimbic, amygdala, insula and orbitofrontal cortex (Zanchi et al., 2017;Farokhnia et al., 2019).Leptin, an anorexigenic hormone produced by adipocytes and enterocytes, is shown to activate several regions of the brain such as the brain stem, parahippocampal gyrus, middle frontal gyri, middle temporal gyrus, right hypothalamus and lingual gyrus (Zanchi et al., 2017).Several detailed reviews have highlighted the role of gut hormones in regulating food reward-motivated behaviour in the host and also in contributing towards the conversation between the gut and the brain (Lach et al., 2018;Zanchi et al., 2017;Decarie-Spain and Kanoski, 2021).It is therefore essential to also understand if fermented foods can alter levels of ghrelin/leptin in circulation and consequently affect the food reward-motivated behaviour of the host.
Preclinical murine models have addressed this topic by showing a reduction in plasma ghrelin levels post-intervention with fermented goat and cow milk and mixed results with respect to impacts on plasma leptin and adiponectin levels (Diaz-Castro et al., 2017;Muñoz Alférez et al., 2020).Moreover, rats receiving a fermented whey beverage alongside a high-fat diet showed no difference in leptin and ghrelin profiles, despite a decrease in food intake, compared to high-fat diet controls (Hong et al., 2015).Some studies have included unfermented controls and have reported a greater reduction in serum leptin (Lu et al., 2021) and ghrelin levels (Liu et al., 2019a) upon consuming the fermented counterparts.Such reports serve as an important reminder to interpret other studies that lack critical controls with caution, so as to prevent inflating the potential health benefits associated with fermented food intake.A number of human studies have tried to ascertain if the satiating effects of fermented food are due, at least partially, to protein content.In one randomised crossover study, the diets of participants were supplemented with fermented and unfermented tempeh (protein control) for a period of two weeks.The group receiving the fermented product showed a reduction in circulating acyl-ghrelin levels by 30% with concurrent reduction in circulating insulin compared to unfermented controls (Noer et al., 2021;Diaz-Castro et al., 2017).Other clinical studies have reported varied gastric hormone responses depending on the fermented product consumed.The effects have ranged from an increase in ghrelin after moderate beer consumption without changes in leptin levels (Beulens et al., 2008) to almost no differences in the level of leptin and ghrelin release amongst different fermented dairy products (Hansson et al., 2020) and no effect on sensation of satiety post-intervention with red wine despite lowering of plasma ghrelin levels (Ismail et al., 2022).These results provide evidence of the highly individualistic enteric hormone release profiles towards the consumption of fermented foods along with potential involvement of other pathways/gut hormones, in driving satiation.

Other pathways and mechanisms through which fermented food can influence appetite
Another gut hormone associated with satiety is somatostatin, which has long been implicated in satiety and hunger.Activation of somatostatin positive neurons in the brain shows increased preference towards high-calorie foods and may be implicated in the development of metabolic conditions such as obesity (Kumar and Singh, 2020); but it is important to note that somatostatin has alsobeen shown to regulate the release of gastric enzymes, increased gastric emptying and mediating inflammatory response.The stomatostatin release profile after consumption of fermented soy bean (natto) was demonstrated in mice subjected to gastric mucosal injury.The mice receiving the fermented soy bean showed higher levels of somatostatin, vasoactive intestinal polypeptide, and motilin (Suo et al., 2015) and concurrently showed lowered levels of serum cytokines.Microbial metabolites are also being studied for their participation in modulating satiety of the host.Several studies exploring the effects of SCFAs have shown that feeding behaviour can also be influenced by these bi-products of bacterial fermentation (Brooks et al., 2017).For example, yogurt supplementation to rats reduced weight and elevated faecal SCFAs (Qu et al., 2018).Similarly, a type 2 diabetes model of mice receiving kombucha lowered fasting blood glucose and increased faecal SCFAs compared to unfermented tea (Xu et al., 2022).However, both interventions maintained intestinal permeability and restructured the gut microbiome by increasing the abundance of Lactobacillus, Butyricicococcus and Lachnospiraceae with a concurrent increase in the levels of GLP-1 and PYY secretion.A potential mechanistic explanation for this could be the stimulating action of SCFA on the mRNA for POMC, AgRP, CART in the hypothalamus (regions of the brain implicated in feeding and energy expenditure) (Pichiah et al., 2016), a pattern which is in agreement with targeted peripheral administration of acetate (Frost et al., 2014).Together, these studies hint at a potential crosstalk between gut microbiota, microbial metabolite profiles and the ENS/CNS within the individual.Most of the discussed pre-clinical studies have included only a single time point post-intervention with the fermented food.The analysed parameters include only a subset of the phenotypical traits such as body weight, feeding pattern and adiposity.In addition to this, molecular markers implicated in understanding satiety and feeding behaviour is also being incorporated.This method of experimental design might be insensitive in capturing transient changes in the gut microbiota and microbial metabolite composition, and gut hormone profile, and can therefore be resolved by sampling at multiple time points.

Fermented food and gut microbiota
The gut microbial community produces metabolites that can modulate host health and reinforce/reduce the integrity of the intestine and BBB thereby modulating the levels of pro-inflammatory triggers reaching systemic circulation and eventually the brain.It is therefore important to understand the impact of fermented food on the intestinal milieu and intestinal health, as they continuously relay information to the peripheral immune system, enteric and central nervous system.
In addition to the modulation of the gut microbiota, preclinical studies have also looked at the impact of fermented dairy products on intestinal permeability (Putt et al., 2017), microbial metabolites (Gao et al., 2021) and peripheral cytokine profile (Du et al., 2022).Frequently studied microbial metabolites, SCFA's were elevated in interventions containing fermented plant-based products such as fermented carrot juice (Liu et al., 2021;Yu et al., 2022;Ma et al., 2021), fermented beverages containing fruits and vegetables (Wang et al., 2019), and fermented raspberry pomace enriched with lactic acid bacteria (Wu et al., 2021).SCFA's are implicated in the maintenance of intestinal barrier integrity (O'riordan et al., 2022) and might be the driving force in increasing the expression of tight junction proteins thereby reinforcing the permeability of the intestine (Zorraquín-Peña et al., 2021;Taladrid et al., 2021).
It is to be noted that sex is a critical factor that can influence the composition of the gut microbiome (Bridgewater et al., 2017).Studies exploring the sex-selective effects on gut microbiome composition have been conflicting, and this may be due to small sizes of study population, body mass index, xenobiotic use, diverse dietary patterns, pathological condition, inconsistencies in tools and pipelines employed to study microbiota composition, diverse ethnicities and strains of models employed in preclinical studies (Kim et al., 2020).The aforementioned factors influence the gut microbiome to a greater effect than sex in humans (Kolde et al., 2018;Jaggar et al., 2020;Lloyd-Price et al., 2017).Murine models, however, seem to show a much more pronounced difference in gut microbiota profile than human studies (Mcgee and Huttenhower, 2021), which has led to differential responses to dietary intervention strategies (Bridgewater et al., 2017).Considering this sexual dimorphic nature of the gut microbiota, a recent study of dietary fibre supplementation for 20 weeks to mice revealed sex-specific responses in the gut microbiome and faecal metabolome.Female mice on a high inulin-based diet showed increased abundance of Bacteroidota and a decline in Faecalibaculum and Lactococcus, the latter of which is exaggerated in diets rich in dietary fibre (Lloyd-Price et al., 2017).The sexually dimorphic nature of the microbiota in mice along with the differences in the gonadal hormone profile results in a distinct humoral response.As a result, there is a marked increase in genes pertaining to inflammation in the hippocampus and hypothalamus profile in a sex-specific manner when subjected to probiotic intervention (Yahfoufi et al., 2023).Fermented foods being a possible source of prebiotics and probiotics, as previously described, have resulted in a sex-selective response (Murray et al., 2019).Therefore, preclinical murine models should be controlled for sex-selective variations in the gut microbiome and downstream immunological profiles.

Microbiota modulatory components of fermented foods
Several literature works have documented the capacity of fermented foods to restructure the gut environment and modulate host health (Stiemsma et al., 2020;Leeuwendaal et al., 2022;Selhub et al., 2014;Melini et al., 2019;Aslam et al., 2020;Costa et al., 2021;Moreno-Arribas et al., 2020), hinting at the potential capacity of fermented foods to influence microbiota gut-brain-axis communication.Some of the modulatory components are produced as a result of the fermentation process.For instance, fermented beverages can contain a percentage of alcohol and other volatile components that can influence the composition of the gut microbiota.The impact of the alcoholic fraction of fermented food on the gut microbiome has been reported in murine (Lee et al., 2020) and human studies (Marques et al., 2022).The alcoholic portion of the fermented food has to be accounted for as it has been recently implicated for its ability to confer a neurological benefit to the food consumer.A retrospective cohort study analysing the impact of alcohol consumption and changes in their intake frequency with risk of dementia revealed its potential neuroprotective activity.The study reported mild and moderate drinkers had a lower risk of all-cause dementia compared to non-drinkers whereas heavy drinkers were posed to have a higher risk of all cause dementia (Jeon et al., 2023).In fact, recent systematic reviews have revealed that low to moderate percentage intake of alcohol in several of the fermented foods and beverages have been linked with lowered risk of Alzheimer's disease and dementia (Porras-García et al., 2023).For this reason, it is also important to control for the effect of alcohol on the gut microbiota and gut brain communicatory pathways.Fermented foods can also alter metabolite production in the gut even without altering the microbial composition or diversity in some circumstances.This can be due to the presence of dietary fibres and bioactive components that are intrinsically present in the food (Zhou et al., 2019;Wang et al., 2021).Fermented foods can also be rich in phytochemicals and other bioactive agents, though some of these originate from the food substrate and hence are also present at similar concentrations in the unfermented counterparts.In light of this, it is important to include unfermented controls in preclinical and human study design, so as to accurately understand the components of fermented foods driving the change on the intestinal milieu and on cognitive health.Supplementary table 1 provides a non-exhaustive compilation of important phytochemicals present in both fermented and unfermented foods that can influence microbiota-gut-brain communication.Fermented foods also contain a variety of potentially health-promoting microorganisms that can confer better gut health in addition to contributing towards the restructuring of the gut microbiota.Indeed, strains isolated from fermented camels' milk, pickled Chinese cabbage (LAB fermented), fermented yogurt when formulated into a probiotic cocktail (Lactobacillus species) all showed the ability to restore the colonic microbial community in antibiotic-treated mice and shift the gut microbiota at a phyla level from a Pseudomonadota-dominated environment to a profile similar to the control group (Shi et al., 2018).
In other instances, it would seem that the beneficial impacts are not attributable to a single strain but rather a combination of factors, including the introduction of multiple microbes, metabolites and substrates that confer benefit to the host.This was evident in mice receiving fermented barley juice, which resulted in an altered faecal metabolomic profile in a manner that was distinct from the group receiving Lactobacillus plantarum alone (Zhu et al., 2021).It should be noted that the ability of fermented foods to shape the gut microbiome in preclinical models does not necessarily translate to human studies (Nguyen et al., 2015;Hugenholtz and De Vos, 2018).To address this, many studies have explored the impact of fermented foods on the gut microbiome in humans.For instance, observational studies reveal high alpha gut microbiome diversity in Korean participants who habitually consumed high amounts of fermented legumes, fermented vegetables, tea, seaweed and nuts (Noh et al., 2021).Similarly, self-reported fermented food consumption patterns in 130 participants from northern Spain also revealed that fermented dairy consumption correlated with higher levels of Akkermansia and low levels of Bacteroides with concurrent high levels of SCFA such as propionate and butyrate, a pattern that was also observed among cheese consumers when compared to non-consumers (González et al., 2019).Greater beta diversity has been seen in regular fermented food consumers than occasional consumers with the former displaying higher proportions of Faecalibacterium prausnitzii, Prevotella spp, Pseudomonas spp, Clostridiales, Enterobacteriaceae, Lachnospiraceae and Bacteroides spp (Taylor et al., 2020).On the other hand, the effects of fermented foods on gut microbiome diversity are inconsistent between intervention and observational study designs with studies reporting little to no change in the diversity metric after intervention with fermented food (Alvarez et al., 2020;Berding et al., 2023;Le Roy et al., 2022;González et al., 2019).The conflicting nature of these studies could be attributed to the gut microbiome being predominantly resistant to change over time (Faith et al., 2013).It could also be due to the study duration being too short to capture subtle changes, diverse nature of fermented foods being incorporated into the study design, high degree of interindividual-variability of baseline gut microbiome amongst participants warranting need for crossover studies with sufficient washout period.Other factors include studies employing 16 S rRNA gene sequencing as opposed to shotgun metagenomics sequencing, thereby lacking species and further strain level resolution that can significantly contribute towards understanding the subtle changes in microbiota composition along with variation in functional capabilities of microbiome.

Preclinical and clinical landscape: application of fermented foods to study microbiota-gut-brain axis communication
The ability of fermented foods to influence the major communication pathways involved in gut to brain signalling has been foundational in its adoption to target mental health.To identify fermented foods that modulate the microbiota-gut-brain axis, it is important to know the current ways by which fermented foods are able to alter communication pathways that are involved in relaying information from the gut to the brain.The priming of the immune system and the restructuring of the gut microbiota and microbial metabolites via fermented food supplementation has been extensively studied.In addition to the immune system, the ENS, along with its gastric peptides and hormones, is also being shaped by fermented food supplementation.Table 3 provides a summary of the current understanding of fermented foods on communication pathways between the gut and brain derived from Section 2.
Several preclinical studies have explored the ability of fermented foods to shape multiple gut to brain communicatory pathways, in addition to obtaining cognitive readouts (Table 4).These studies provide a comprehensive understanding of the how the components of the fermented foods influence the gut microbiota and their metabolites, and eventually the brain, in addition to highlighting promising fermented foods that require further investigation.Other preclinical studies only provide cognitive readouts without mechanistic data (Table 5).
Evidence from human studies, however, needs to be bifurcated by study design for a more detailed understanding.Interventional studies (Table 6) are of superior merit for their monitoring of adherence and consumption patterns and their ability to yield causal insights.Despite their correlational nature and reliance on self-reported intake, observational studies (Table 7) capture a wider demographic and can aid in the identification of trends, which can lead to detailed inquiries on a given fermented food category.
Preclinical models used to study the modulation of microbiota-gutbrain axis by fermented foods typically include drosophila, zebrafish, murine and porcine models.Each of these models possess different advantages ranging from being high throughput to having a gut anatomy that resembles that of humans, thereby increasing the likelihood that R. Balasubramanian et al.Table 3 Summary of the potential mechanisms of how fermented foods modulate microbiota-gut-brain signalling.See Section 2 for details.beneficial impacts, if observed, could be translated.Fermented dairy products have been studied most extensively using these preclinical approaches.Indeed, different fermented dairy products have impacted the gut microbiome, microbial metabolites, inflammatory profile and behavioural phenotypes, resulting in distinct variations compared to normal controls.Behaviourally, administration of specific fermented dairy products has resulted in attenuated anxiety (Oh et al., 2020;Han et al., 2020) and depressive-like (Van De Wouw et al., 2020;Chen et al., 2021c) phenotypes and improved performance in memory associated tasks (Van De Wouw et al., 2020;Van De Wouw et al., 2021;Liu et al., 2020a).These studies have also reported, in some but not all instances, differences between the microbial communities of groups administered fermented food and those that were administered unfermented controls (Han et al., 2020;Van De Wouw et al., 2020;Van De Wouw et al., 2021).Fermented soy foods in the forms of tofu, tempeh, miso, fermented soy milk, natto and chungkookjang were the next most extensively studied food in pre-clinical models.Fermented soy-based products were found to alter the gut microbiome at family level, modulate the levels of various molecular messengers involved in maintenance of permeability (Chen et al., 2020;Singh et al., 2021;Dai et al., 2019), raise the level of anaerobes (Bedani et al., 2010) and improve intestinal integrity (Kawahara et al., 2015;Jeong et al., 2020a).Notably with respect to this review, the studies also revealed that interventions with fermented soy were associated with significant improvements in memory (Kridawati et al., 2016;Woo et al., 2016b;Go et al., 2016;Yang et al., 2015).
Fermented sugar-based products such as kombucha and other fruit juices have shown the ability to improve exploratory behaviour, hippocampal memory as well as reinforce intestinal barrier by increasing the levels of SCFA, tight junction proteins and lowering expression of inflammatory cytokines (Cataldo et al., 2020;Chen et al., 2019;Pakravan et al., 2019;Zorraquín-Peña et al., 2021;Hartmann et al., 2000).The longest duration of an intervention involved the administration of a specific wine to mice for 28 weeks, which resulted in attenuation of cognitive decline.Importantly, the effects of alcohol were accounted for through the use of an ethanol control.They reported no difference in behavioural tests (Barnes maze) and amyloid plaque formation pattern between control and ethanol controls, indicating the neurological benefit of wine was independent of alcohol percentage (Wang et al., 2006).Other substrate categories include diverse fermented plant products such as fermented seaweed, fermented peanut meal, fermented Chinese herbs such as C. lanceolata, spirulina maxima and rice peptides, which have shown improvements in learning and memory in murine models (Reid et al., 2018b;Ding et al., 2021;Weon et al., 2014;Corpuz et al., 2019;Choi et al., 2018).

Human Studies
Fermented dairy intervention in humans have yielded mixed results, ranging from an absence of differences between the intervention and placebo groups in mini-mental status exam (MMSE) scores (Beauchet et al., 2019;Suzuki et al., 2019) to a mixed trend with respect to circulating BDNF (Chung et al., 2014;Suzuki et al., 2019;Nevé et al., 2021) and CRP (Chen et al., 2019;Kuroda et al., 2007;González et al., 2019) levels.Similarly, when a fermented food enriched diet is considered, especially while employing multiple fermented foods of varied substrate categories, an increased gut microbiota diversity was observed (Wastyk et al., 2021), a feature that was not observed in a 4 week fermented food based dietary intervention study when compared to the arm receiving control diet (Berding et al., 2023).A potential explanation for this could be the variation in fermented foods categories employed in both studies along with duration of the dietary intervention.
In general, observational studies relating to the consumption of fermented dairy products on the gut microbiome mirrored longitudinal intervention based human studies (Tessier et al., 2021;Le Roy et al., 2022;Suzuki et al., 2017).Observational studies that analysed the consumption of a broad collection of fermented food in participants showed a clear separation of gut microbiota profiles between consumers and non-consumers, along with lowered anxiety in the former (Taylor et al., 2020;Hilimire et al., 2015;Karbownik et al., 2022b).Moreover, observational studies investigating the impact of fermented soy-based products such as tofu, tempeh, miso, natto and soy sauce revealed that higher consumption of soy-based products correlated with better cognitive function in women (Nakamoto et al., 2018b) and was also associated with attenuation of age-associated memory (Porras-García et al., 2023) and cognitive decline (Lin et al., 2018).The isoflavone components of fermented soy products can exert oestrogen-like protective effects and may contribute to the neuromodulatory effects of fermented soy-based products in women (Nakamoto et al., 2018a).Studies have also have reported negative consequences associated with the consumption of tofu, which is implicated in worse cognitive outcomes in several cross sectional observational studies (Xu et al., 2015;Hogervorst et al., 2008a;White et al., 2000).It has been hypothesised that the formaldehyde used in the production of tofu for maintaining freshness could cause oxidative damage thereby contributing to cognitive decline (Hogervorst et al., 2008a).When we look at meta-analysis on microbiota targeted intervention strategies on global cognition, fermented food based intervention strategies revealed a greater degree of promise than prebiotics and probiotics.The study also reported no significant alteration in memory by prebiotics, probiotics and fermented food intervention (Marx et al., 2020).The study attributed these findings to heterogeneity in cognitive tasks included in the analysis and studies being under-powered to test a hypothesis, in addition to an overall lack of studies (N = 22) that are geared towards understanding the impact of microbiota-targeted interventions with cognitive readouts.

Challenges relating to standardisation of fermented food
The production of fermented foods is influenced by various environmental conditions and processing parameters.Indeed, the analysis of a large collection of fermented milk samples, predominantly yogurt, koumiss, cheese and fermented yak milk from Mongolia, China and Russia, shows a distinct clustering based on geographical origin (Zhong et al., 2016).The presence of a region-specific microbiota was also observed in Mongolian fermented cow milk samples from Chita and Kalmykia in Russia (Liu et al., 2015) and Airag samples from Mongolia (Choi, 2016).The genetic polymorphisms of starter cultures containing Saccharomyces cerevisiae obtained from Manipur (Indo-Burma) and Sikkim (Himalayan) also varied in a manner that reflected geographical origins (Jeyaram et al., 2011).Scale of production and manufacturing conditions could partially explain the variation in fermented food microbiome as a consequence of geographical location, as was the case with fermented meat products obtained from France, Italy and Spain compared to products obtained from Belgium and Germany.The fermented meat product showed distinct LAB communities segregated by geographical zone of production and the use of different starter cultures (Van Reckem et al., 2019).This was mirrored in other fermented foods, such as Kochujang (Nam et al., 2012;Bal et al., 2017) and also on LAB fermented pickles from China, wherein foods made through commercial fermentation contained more LAB than those generated through artisanal fermentation (An et al., 2021).Emerging research suggests the presence of a distinct core mycobiota, as seen with Chinese traditional dough starters, fermented rice wine and Chinese grape wine (Huang et al., 2021;Bartram et al., 1994;Liu et al., 2020d) and even the viral community being more indicative of geographical location in kimchi samples (Jung et al., 2018).However, this does not hold true across all studies of fermented foods.Indeed, a large study of sourdough starter cultures (n = 500) revealed homogeneity and only weak influence of geography on shaping the fermented food microbiome (Landis et al.,

Table 4
Compilation of various fermented foodsexplored for their ability to modify the microbiota-gut-brain axis under a preclinical lens.The table provides a detailed breakdown of the preclinical models and fermented food employed in studying the impact of latter on the microbiota-gut-brain axis.The table also provides an in-depth breakdown of studies that have accounted for unfermented and positive controls and their lack thereof, thereby providing studies of superior merit.

Table 5
Preclinical studies that study the neuromodulatory effect of fermented foods.The table highlights various categories of fermented foods that have the potential to be harvested for an in depth analysis of the ways by which they modulate the microbiota-gut-brain axis.These studies focus on either the behavioural changes or neuromolecular changes observed in the brain but lack of information pertaining to the modulation of the gut microbiota, gut environment or other communicatory pathways and therefore require further investigation to better understand the pathways of gut to brain signalling.

2021
).Nonetheless, geographical location and scale of production are of critical importance as artisanal/traditionally fermented foods may possess a different microbial community that is critical for the production of bioactive metabolites, which may be absent from commercially produced strains.An example of this is observed in milk kefir, wherein traditionally fermented kefir shows the potential to lower cholesterol in metabolic models of obesity in mice.Consequently, the same effects were not observed in specific commercial kefir beverages (Bourrie et al., 2018).The taxonomic composition driving variation in biological effect is also observed in kombucha samples sourced from artisanal and commercial sources (Villarreal-Soto et al., 2020).In fact, these subtle variations in taxonomic compositions between commercial and traditionally prepared fermented foods have recently been revealed to elicit different circulatory cytokines profile in a randomised crossover trial in humans in that, traditionally prepared kefir showed a greater reduction in CRP, sVCAM, IL-18 and TNF-α compared to commercial kefir (Bourrie et al., 2023).It is important to consider such factors when implementing fermented food based interventions targeting microbiota-gut-brain-axis modulation.
Another feature that has a driving influence in shaping fermented food microbiota is the type of substrate that constitutes the fermented food.Various substrate categories of fermented foods are highlighted in Table 1.An extensive study on fermented food showed dominance of LAB in brine, Acetobacter in sugar-based fermented foods and similarities in the microbiotas across dairy based fermented food (Leech et al., 2020).The driving influence of substrate on fermented food microbiome has been shown to also be reflected in the community composition profiles of naturally fermented milk samples, namely koumiss, which differed in the type of milk used (Zhong et al., 2016).Similar observations were made in a study analysing the effect of different sugar substrates in the production of Argentinean kefir (Gamba et al., 2021) and fermented meat products obtained from the Inuit community (Campbell et al., 2022).Preparatory conditions such as duration of fermentation, fermentation salinity, pH (Lülf et al., 2021) and moisture content (Chen et al., 2023) also influence the microbiome of fermented food.Processing conditions such as ripening time influences the microbial community present in fermented food (Rezac et al., 2018;Jingkai et al., 2020), and these changes were attributed to lowering of the pH and changes in the active enzymes present in the fermented food.In the case of one such example, Taga cheese showed a gradual lowering of mesophilic and psychotropic bacteria at the end of the ripening process.This was accompanied by an increase in the levels of yeasts and moulds along with a gradual increase in long chain fatty acids (Criste et al., 2020).Shaping of the microbial community by such environmental factors manifest also into shaping the functional capabilities of food, with certain food substrates and fermentation production practices enriching for the presence of biosynthetic gene clusters (BGCs) (Du et al., 2023).BGCs are increasingly being studied for their ability to produce specialised metabolites that can influence the health of the host.All of these factors could be exploited in the manufacturing process to coincide with harvest times when foods possess the greatest bioactive potential.
The highly malleable microbial community present in fermented foods is difficult to standardise and poses a critical challenge (Mukherjee et al., 2022).Although the Codex Alimentarius aids in providing guidelines and standards, with a considerable focus on fermented dairy products (Alimentarius, 2003), other fermented food categories have not been extensively explored.However, such consensus or regulatory guidelines require an element of cultural sensitivity that is considerate of the origin and traditional practices involved in fermented food production (Campbell et al., 2022).The increased application of next generation 'omics' techniques has aided the process of standardisation by identification of various community members and their complex relationships.This has led to the development of extensive data archives (Zinno et al., 2022;Whon et al., 2021;Chaudhary et al., 2021).These repositories are valuable sources of information and can be used as reference sources to obtain a preliminary hypothesis on the type of

Table 6
Human studies focusing on the interventional outcomes of fermented foods.These studies also explore the impact of fermented food intervention on the gut and the brain communicatory pathways that form the microbiota-gut-brain axis.microbial community or bioactive molecule(s) that could be present in the fermented food, which could be harvested for therapeutic benefit.However, there is much that is left to be explored given the diverse nature of fermented foods.

Challenges in setting up a human study design targeting fermented food intervention
Human studies aiming to understand the impact of microbiotatargeted therapy need to consider a few key points that are discussed in this section, which can add value with respect to investigating the impacts of fermented food consumption on microbiota-gut-brain axis communication.
Accounting for controls: Fermented foods can contain a variety of components with bioactive properties.However, these agents are also present in unfermented controls.Supplementary table 1 contains information from a non-exhaustive collection of studies relating to the bioactive agents present in fermented foods and the corresponding unfermented substrates.This is of particular importance as the beneficial effect conferred may not always be a result of the fermentation process.Ultimately, studies assessing the effects of fermented foods require the inclusion of suitable unfermented controls.This is also highlighted in the Tables 2 and 3 (preclinical) and Tables 4 and 5 (clinical), which focus on the delineation of cohorts to account for the effect of unfermented controls.Ideally, the participant should be blinded, though this is not always possible and depends somewhat on the fermented food under investigation.
Measuring fermented food intake: One of the challenges in employing fermented foods as a supplementation strategy in human studies is to accurately and conveniently quantify intake, especially when participants are asked to increase their fermented food consumption.This is a challenge when patients are recommended to incorporate a diverse range of fermented foods with their diet as opposed to single food/beverage, which can be consumed as an entire serving.Non-invasive methods of measuring dietary adherence by the participant include employment of 24-hour food recall (Karbownik et al., 2022a,b), food diaries and food frequency questionnaires that are geared towards capturing the diverse nature of fermented foods (Taylor et al., 2020;Li et al., 2020).These methods are often disadvantaged by not being all-encompassing, subject to respondent fatigue, limited to human memory (Das et al., 2022) but are low cost and easy in their employment, thereby being commonly used for reporting the consumption of fermented food (Ribeiro et al., 2022).Fermented food frequency questionnaires (FFQ's) must also be tailored to different environments to account for ethnic/racial minorities and must accommodate various culturally distinct populations so as to accurately capture their consumption.The information provided by FFQ can be supplemented with other methods of measuring dietary intake, albeit their respective shortcomings of being logistically and economically difficult to implement.These methods include: evaluation of biomarkers in plasma and urine, digitalised assessment of dietary compliance via food images and smart phone applications that capture the food intake.
Biomarkers: Identification and measurement of biomarkers exclusively associated with intake of a specific fermented food can be of tremendous importance as it can accurately measure fermented food consumption in a clinical atmosphere.It is a much more accurate measure compared to dietary questionnaire counterparts that are used to register food intake.Biomarkers can be of critical clinical relevance, especially when diverse fermented foods are being consumed.However, since fermented foods and other food products might share the same core substrate profile, they might result in overlapping biomarker profiles.This requires the need for identifying biomarkers that can be accurately associated with the consumption of the fermented food.Advancements such as plant metabarcoding offers a unique solution, wherein genomic sequences from human digest and faecal samples act as unique fingerprints in identifying food consumed especially when

Table 7
Observational clinical studies detailing on the correlational relationship between fermented food consumption and modulation of microbiota-gut-brain axis.The table provides information on the type of dietary assessment adopted, size of the cohort and major neurological outcomes, as well as outcomes pertaining to the intestinal milieu hinting at potential communicatory pathways.multiple food are part of the regimen (Petrone et al., 2023).A recent systematic analysis has revealed certain biomarkers that show a high degree of fidelity towards fermented foods such as wine, beer, sourdough bread, cheese and tea (Li et al., 2021a).Biomarkers can then be used as a proxy to titrate the frequency of consumption of a given intervention in participants thus becoming a part of the next generation of tools employed for precise dietary assessment.The study by Li et al. also revealed biomarkers for fermented vegetables, fish, fruit and meas consumption were less explored, and as a result a dearth of information on microbial metabolites as well as other host derived metabolites related to these substrate categories (Li et al., 2021a).Follow up studies have furthered the use of biomarkers to titre for food consumption of a given substrate category and also their potential correlation to cardiometabolic health (Li et al., 2023).This information could be curated/extrapolated to mental health and can be used to formulate an optimised fermented food dosage regimen by which the foods are able to confer mental health benefit to the individual.
Employing appropriate methods to capture microbiome: Most of the studies investigating the causal impact of the microbiome on host health utilise 16 S rRNA gene sequencing to capture the residents in the gut environment.Although metabarcoding approaches are cost effective and comprise of well-established pipelines that are less computationally intensive, they drastically reduce the degree of granularity required in understanding the key microbial members and functional underpinnings of the microbiome along with their influence on host health (Shankar, 2017).In fact, immunological responses towards microbes are highly tailored at a strain level, as also seen with metabolism of xenobiotics (Anderson and Bisanz, 2023), thereby justifying the need for greater degree of resolution offered by shotgun metagenomics techniques.Metatranscriptomic and metaproteomic techniques are increasingly being used to identify the genes expressed by the microbial community and proteins produced as a consequence of a given microbiota-targeted intervention.Though these techniques are computationally expensive and difficult to integrate into traditional microbiome analytic pipelines, they are increasingly being recognised as the way forward in understanding the functional potential of the gut microbiome.

Conclusion: fermented thoughts -the way forward
Fermented foods can have a considerable impact on health by virtue of the variety of different microbial strains, metabolites and other bioactives that can be present therein.These components can be optimised to offer maximal neural and mental health benefits to the individual.This in-depth review has highlighted the individual components of the microbiota-gut-brain axis that, on the basis of clinical and pre-clinical studies, can be modulated by fermented foods and/or components thereof.While noting the increasing body of research that has been generated in recent years, it also reveals the critical need for additional human studies with unfermented controls to truly identify beneficial impacts that act on the microbiota-gut-brain axis.Understanding the factors that mould the fermented food microbiome and microbial metabolites will help to reveal the impact these factors can have on the biological benefit conferred by the fermented food.Finally, although there are many obstacles and considerations that need to be accounted for, fermented foods form a vital part of the next generation of microbiota-based therapeutics targeting mental health.It is hoped that, in the words of Goethe "time will only, strengthens the fine fermentation".R. Balasubramanian et al.

Funding
the release of IL-10, TNF-α 2. Release of microbial metabolites that can bind to HCA3R receptor 3. Lower levels of IL-6, TNF-α and IFN-γ upon challenge with pathogen 4. Stimulation of IgA release by probiotic components present in milk kefir circulating levels of IL-6, IL-10 and IL-12b and immune cells such as CD4 + , CD8 + , T and B cells 2. Reduction in circulating cytokines such as IL-4, IL-10, IL-12 and MCP- of GLP-1 via activation of GPR-120 2. Release of GLP-1 by phosphorylation of Erk1/2 (p42/44 MAP kinase) 3. Activation of GLP-1 release via increased expression of CCK and c-FOS along with DDP-1 V 4. Reduction in serum leptin, insulin and ghrelin 5. Higher levels of somatostatin, vasoactive polypeptide and motilin with consumption of fermented food Human studies diversity metrics of the gut microbiota in self-reported consumers of fermented food R. Balasubramanian et al.
APC Microbiome Ireland is a research centre funded by Science Foundation Ireland (SFI/12/RC/2273_P2). Paul D. Cotter is also funded by the European Union's Horizon 2020 research and innovation programme, under the MASTER project [grant number 818368], by Science Foundation Ireland (SFI) under [grant number SFI/12/RC/2273_P2]

Table 2
Nuances of Nomenclature: This table serves as a guide to aid the understanding and usage of appropriate terminology.