According to the International Scientific Association for Probiotics and Prebiotics, a prebiotic is defined as “a non-digestible substance that is selectively utilized by host microorganisms conferring a health benefit” (1). In addition, the health beneficial effects from the prebiotic need to be partially caused by microbial changes. To conclude, the four major elements for the consensus definition of prebiotics include nondigestibility, fermentability and selectivity, a health-related beneficial effect, and microbiota-mediated mechanism (Figure 1). Since the “prebiotic” concept was first put forward by Gibson and Roberfroid (2), the physiological benefits of prebiotics have been widely explored, especially in nutrient absorption, glucose management, lipid metabolism, and immune modulation.

Depression is one of the most common mental and mood health conditions, with an estimated 3.8% of the global population affected, generating negative consequences such as weight gain, inability to take care of oneself, impaired cognitions, and even suicidal ideations (3). In consistent with these findings, the lost productivity caused by depression and anxiety costs the global economy $1 trillion each year, and the economic burden of depression is projected to increase (4). In light of this, the World Health Organization released Mental Health Action Plan 2013–2030 to emphasize the importance of providing appropriate interventions for patients with mental disorders including depression.

The pathophysiology of depression remains unclear due to its etiological heterogeneity. In recent years, accumulating evidence have shown that depression is linked to dysbiosis by the gut-microbiota-brain axis (GBA) (5, 6), which is a bidirectional network that connects the gastrointestinal (GI) system and the central nervous system through the interplay of multiple neuroimmune and neuroendocrine pathways (5). Despite a lack of deep understanding in the causal relationship between microbial changes and the development of diseases, the last decade witnessed a growing interest in utilizing microbiome manipulation to alleviate depressive disorders. Of several approaches that have garnered considerable interest, prebiotics attracted substantial attention for their broad applications in food and beverages, potential functionalities in improving texture (7), being free of addictive properties and generating less adverse effects (8).

There have been several review articles that discussed the role of prebiotics in depression (9–12). However, some of these publications lack mechanistic discussions on how prebiotics may alleviate depression, or mainly focused on dietary fibers and mental health instead of prebiotics and depression. Additionally, all these publications focused on carbohydrate-type prebiotics, whereas non-carbohydrate food ingredients that are also qualified for a prebiotic claim, such as fermentable phytochemicals (13), were left out from the studies. Chudzik et al. (11) synthesized the empirical evidence of pre-, pro-, and post-biotics for depressive symptoms, which provided the latest review on this topic. Nevertheless, with multiple animal studies and human studies published in the year 2022, it would be valuable to revisit the literature and update our knowledge.

Considering these, the objective of the current work is to summarize the animal and human studies that investigated the impact of prebiotics intake on depressive disorders. Since microbiota-mediated mechanism is a requisite for defining a substance to be prebiotic, this project highlights how the gut-brain-axis (GBA) moderates the effects of prebiotics in depression.

The human gut harbors 10–100 trillion microorganisms, forming a dynamic and complex ecosystem (14). Within a “reference man” that weighs 70 kg, the total number of bacteria is approximately 3.8 × 10¹³, and the ratio between human cells and resident microbes is approximately one-to-one (15). The gut microbiota is taxonomically classified by phyla, order, family, genus and species. Their genome consists of approximately over 3 million genes, encoding a large repertoire of biochemicals as a way of affecting the hosts’ health and susceptibility to diseases (16). The gut microbiota can be altered by various environmental cues such as medication, health status, physical activity, as well as diets (16). Prebiotics hold substantial appeal due to their capability of selective fermentation, meaning that these compounds will exclusively stimulate the growth of beneficial bacteria, not pathogenic bacteria. Naturally occurring prebiotics and their respective food sources were listed in Table 1.

Inulin and inulin-type fructans, such as fructooligosaccharides (FOS), consist repetitive β–(2,1) fructosyl-fructose glycosidic linkages that are undigestible by the human intestinal brush boarder enzymes but readily fermentable by the gut microbiota (17). Although the chain length of inulin, FOS, and short-chain FOS differ, these compounds exhibit similar biological effects due to the same type of glycosidic linkage. The most consistently reported microbial alteration with the consumption of inulin and FOS is the increase of Bifidobacterium (32, 33), and other concordant data indicate that inulin supplementation may stimulate the growth of Lactobacillus, Faecalibacterium, and Anaerostipes (33). Galactooligosaccharides (GOS), xylooligosaccharides (XOS), arabinoxylan (AX) and Isomaltooligosaccharides (IMO) are considered prebiotics with their bifidogenic effects (22, 34–36). All of the above-mentioned oligosaccharides are naturally contained in food, but they can also be prepared by using enzymatic or chemical methods (17, 22, 37). While other soluble fibers such as β-glucan and konjac glucomannan oligosaccharides have displayed certain prebiotic features, there is insufficient evidence that linked their physiological benefits to microbial changes. Resistant starch (RS) refers to a group of non-soluble carbohydrates that are resistant to upper GI digestion. RS is divided into four categories: RS1 is physically protected from digestive enzymes; RS2 is native granular starch consisting of a high amount of amylose; RS3 is retrograde starch; and RS4 is chemically modified starch. Notably, although RS are generally insoluble, certain RS molecules can be fermented by the gut microbiota, particularly by Ruminococcus bromii and Parabacteroides distasonis (38).

In addition to carbohydrates, certain phytochemicals are considered as prebiotics (13), since they are able to confer health benefits by selectively promoting the healthy gut microbiota. Resveratrol, quercetin, and chlorogenic acid, exemplified the most-studied phytochemicals that have shown health-promoting effects by increasing the abundance or proportional representation of Bifidobacterium strains and, therefore, are recognized as prebiotics (39). Besides, quercetin may reduce the opportunistic or pathogenic bacteria including Listeria monocytogenes, taphylococcus aureus, and Vibrio parahaemolyticus, which are clinically significant bacteria that may cause infection or diseases (29). Epigallocatechin gallate (EGCG), another well-studied phytonutrient, was found to enrich Bifidobacterium (40) and the SCFA-producing microbiota, such as Akkermansia, and exerted potent anti-inflammatory and anti-oxidative effects through enhancing the gut SCFA concentrations (41).

Intestine is the major site where lipid digestion and absorption occur. Lipid absorption is a complex process, which is almost fully completed in the small intestine. The lipids appearing in the colon and fecal materials are partly from dietary lipids that escape digestion in the upper GI system. As estimated, 95% consumed lipids are absorbed in the jejunum and ileum, leaving only approximately 5% dietary lipids entering the large intestine for further bacterial fermentation. Even with such a small quantity, the certain undigested lipids are able to induce changes in the gut microbiota. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential fatty acids because the limited quantity of de novo n-3 PUFAs synthesis is insufficient to satisfy the needs of humans. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are long-chain n-3 PUFAs that are abundant in marine organisms or deep-sea fish, such as salmon, mackerel, and sardines (31). The influence of n-3 PUFAs on the gut microbiota was not widely studied. However, in the limited studies on adults, the authors showed a consistent effects of n-3 PUFAs in modulating the gut microbiota, with a decrease in Faecalibacterium and increase in Lachnospiraceae (42), Bacteroidetes, Roseburia, Coprococcus, and Blautia, which were associated with an enhanced production of SCFAs (43). Both DHA and EPA may attenuate multiple diseases by directly or indirectly affecting the gut microbiota (31). Conjugated linoleic acids (CLA) are isomers of linolenic acid and are heavily enriched in foods such as meat and dairy products (44). Multiple animal studies reported that CLA could modulate the gut microbiota, especially in promoting Prevotella, Akkermansia muciniphila (45), Lachnoclostridium, Roseburia, Dubosiella, Oscillibacter, and Anaerostipes (46), as well as harboring a higher proportion of Bacteroidetes phylum in general (47). However, the efficacy of CLA on the gut microbiota has not been investigated in any clinical trials. The taxonomy of the promoted bacteria varied based on different animal models and different CLA isomers, causing a huge homogeneity in evidence. Therefore, more studies, especially in humans, are warranted to explore the efficacy of CLA in modulating the gut microbiota. Interestingly, certain gut microbiota, such as Lactobacillus, Butyrivibrio, and Megasphaera can feed on undigested linoleic acids and produce CLA (48, 49), which demonstrates a bidirectional relationship between CLA and the gut microbiota.

Dysbiosis describes an imbalanced microbial profile characterized by loss of beneficial microbial abundance or signal and an augmentation of opportunistic and pathogenic microflora. Although the study of gut microbiota and mental health is a relatively new area that has caught researchers’ attention in the past few years, converging clinical data already showed that patients diagnosed with depression may experience gut microbiome dysbiosis (50). The correlation between dysbiosis and depression has been portrayed in several observational studies. An overrepresentation of Bacteroidales, and an underrepresentation of Lachnospiraceae families, within the phylum Firmicutes, were observed in depressive patients (51). Patients with major depressive disorder (MDD) showed increased fecal bacterial α-diversity and enhanced Bacteroidetes, Proteobacteria, and Actinobacteria, but decreased Firmicutes. In particular, these patients had increased levels of Enterobacteriaceae and Alistipes, whereas their levels of Faecalibacterium were reduced and were negatively correlated with depressive symptoms (52). These results were, to a certain degree, consistent with the study by Naseribafrouei et al. (51) showing enrichment of the Alistipes in the subjects with depressive symptoms, indicating that depression patients may have a higher risk of undergoing dysbiosis.

Vice versa, the incidence of depression and other mental conditions were significantly higher in the patients with inflammatory bowel disease (IBD) than the subjects who had a healthy GI system (53, 54). A study by Chung et al. (55) explored the association between dysbiosis and depression by retrospectively utilizing a cohort where adult patients who were diagnosed with dysbiosis (N = 552) and their healthy counterparts (N = 52) were followed up for 5 years. The researchers found that the incidence of depression within 5 years of the index data was significantly higher in the patients who were diagnosed with dysbiosis, compared with the healthy controls (HR = 2.85) (55). Interestingly, the association was more potent in males than in females. Age was another important variable that modulated the degree of association, with a stronger association observed in the age group more than 60 years old (55). However, this retrospective study, along with the other observational studies, did not show causal relationships between the gut microbial changes and the onset or development of depression; instead, they focused solely on associations.

Since dysbiosis was closely linked to depression, and prebiotics are functional to alter the gut microbiota and mitigate dysbiosis, several well-designed clinical trials evaluated the effects of different prebiotics in alleviating depression. Clinical trials are the gold standard for evaluating the effectiveness of the compounds in certain conditions or diseases, as they represent the most rigorous method of examining causal relationships between interventions and outcomes.

The gut microbiota, referred to as the “second brain” in humans due to its regulatory impact on the central nervous system through neuronal, chemical, and immune pathways, has been shown to establish a bidirectional communication channel between the gut and the brain (86). The gut-brain-axis (GBA) was discovered when gastrointestinal endocrine system changes were linked to alterations in neurons and brain cells. This concept was supported by studies that showed the contribution of gut microbiota to the development of cognitive diseases. Over 20 years ago, the observation of significant improvement in patients with hepatic encephalopathy after receiving oral antibiotics provided the most convincing evidence of a connection between gastrointestinal microbes and the brain in humans (87). Recently, emerging data suggested that the microbiota plays a role in influencing anxiety, depression, and other mood disorders. Patients with depression have different gut microbial profiles compared to healthy controls, while patients with gut inflammation experience mood and cognitive disturbances. In vivo studies show that gastrointestinal inflammation can induce anxiety-like behavior and alter the central nervous system (88). Germ-free animals have been used to determine causality, reporting that the absence of gut microbiota promotes anxiety and neuroendocrine response to stress (89). Prospective studies indicate the impact of dysbiosis on mental health disorders. Fecal microbiota transplantation studies have also shown that depressive symptoms can be transmitted to recipients, with those receiving fecal microbiota from depressed patients exhibiting more severe symptoms compared to those who received fecal microbiota from healthy subjects (90). These findings indicate a causal role of gut microbiota in the development of depressive symptoms.

The current work summarized the role of promising prebiotics on modulating the development and severity of depression. By summarizing the existing clinical trials on prebiotics and depression, we concluded that GOS and n-3 PUFAs are effective in mitigating depressive symptoms. It is postulated that EGCG exhibits potential antidepressant properties, however, a higher dosage of EGCG may be required to elicit a significant effect. The plausible mechanisms that account for the impact of prebiotics are the synthesis of neurotransmitters, production of short-chain fatty acids (SCFAs), and regulation of inflammation (Figure 3). The impact of alternative prebiotics on depression has yet to be fully elucidated owing to several factors, including a dearth of clinical trials, disparate methodologies, variations in ingredient sources, and divergent extraction techniques.

While alterations in the microbial composition have been commonly documented in individuals with depression, there exists considerable variability in the specific microbiota that exhibit augmentation or reduction. The taxonomy that predominantly contributes to the onset and progression of depression is a subject of current investigation by several research teams; however, the answer to this question remains elusive. Multiple factors, such as age, gender, medication or antibiotic usage, geographical location, health status, physical activity, dietary patterns, and sleep duration, among others, may impact the diversity and profile of gut microbiota. Thus, it is crucial to record and report detailed subject characteristics to account for potential discrepancies between studies.

Considering that a beneficial microbial profile may function to prevent or alleviate depression and other mood disorders, it raises the possibility that probiotics may be functional for anti-depression as well. Prebiotics and probiotics differ in their mode of action, mechanisms, evidence, dosage, efficacy, side effects, study design, and future research directions. Prebiotics indirectly promote the growth of beneficial gut bacteria by providing nourishment, while probiotics introduce beneficial bacteria directly into the gut (125). Prebiotics affect depression through mechanisms such as neurotransmitter synthesis, short-chain fatty acid production, and inflammation regulation. Evidence for prebiotics is limited but promising, while probiotics have shown positive effects in numerous studies. Dosages vary for both, with prebiotics typically ranging from 2 to 10 g and probiotics ranging from 1 to 50 billion CFUs per day (10, 126, 127). Further research is needed to establish effectiveness, optimal dosages, and strains for both prebiotics and probiotics in depression treatment. The differences between the trials using prebiotics and postbiotics in depression are described in Table 4. A comprehensive evaluation of 10 clinical trials comprising a cumulative patient population of 1,349 subjects showed that no statistically significant difference in mood was observed between the intervention group with probiotics supplementation and the placebo group, although a subgroup analysis of studies conducted on depressed individuals exhibiting mild to moderate depressive symptoms revealed a noteworthy enhancement in the moods (127). The effects of probiotics on mitigating perinatal depression have also been controversial, and even the supplement of same probiotic strain showed different effects (6). The comparability of current clinical trials is hindered by inter-study discrepancies in probiotic dosing, bacterial strains, and strain combinations. Additionally, the generalizability of findings to depressed individuals is impeded by the fact that the majority of existing randomized controlled trials were performed on healthy populations. Nevertheless, it leads to the hypothesis that modulating the abundance of one group of gut microbiota may be insufficient to show anti-depressive effects. Thus, manipulating the gut microbiota as an integrated system by using different ingredients, such as prebiotics and fibers, may serve as a more effective approach to prevent or alleviate the development of depression.

Combined prebiotic and probiotic therapy and the use of prebiotics in combination with traditional antidepressants have garnered attention as potential treatment approaches for depression (128). This synergistic approach has the potential to improve gut microbiota composition and function, which may positively impact mental health. However, a recent RCT showed that in adults experiencing moderate psychological distress and low prebiotic intake, adopting a high-prebiotic dietary intervention shows potential in enhancing mood, reducing anxiety, alleviating stress, and improving sleep. However, the combination of a high-prebiotic diet and probiotic supplement, known as a synbiotic approach, does not seem to yield beneficial effects on mental health outcomes (129). More research is needed to explore the specific combinations, dosages, and strains that would yield optimal outcomes. Additionally, the efficacy and safety of combined therapy should be thoroughly evaluated through well-designed clinical trials.

Regarding prebiotics in combination with traditional antidepressants, the rationale behind this approach lies in the potential of prebiotics to modulate gut microbiota and influence the efficacy of antidepressant medications. By improving gut health and promoting the production of beneficial metabolites, prebiotics could potentially enhance the therapeutic effects of traditional antidepressants. However, the interactions between prebiotics and specific antidepressant medications need to be further investigated to understand potential synergies or adverse effects. Additionally, individual variability and personalized treatment strategies should be considered. Both combined prebiotic/probiotic therapy and the combination of prebiotics with traditional antidepressants offer intriguing possibilities for improving treatment outcomes in depression. Nevertheless, more robust clinical trials and mechanistic studies are required to determine the optimal protocols, dosages, and mechanisms underlying these approaches. The field of psychobiotics, which explores the interaction between the gut microbiota and mental health, holds promise for advancing our understanding and refining these combination therapies for depression. Currently, there are commercially available prebiotic antidepressant preparations that aim to harness the potential benefits of prebiotics in managing depression. These products typically contain specific types of prebiotics that are believed to support a healthy gut microbiota and potentially improve mental well-being. It is important to note that while these prebiotic antidepressant preparations are available, their efficacy and safety in treating depression have not been extensively studied or established. The scientific literature on the specific formulations and their effects on mental health outcomes is limited. Individuals considering the use of commercially available prebiotic antidepressant preparations should exercise caution and consult with healthcare professionals before incorporating them into their treatment plan. It is advisable to seek evidence-based treatments and interventions that have undergone rigorous scientific evaluation and have a proven track record in managing depression.

Although the production of SCFAs is considered one of the primary mechanisms through which prebiotics alleviate depression and modulate mood, quantifying the dose of SCFAs delivered to the colon presents a significant challenge. Whole food or natural dietary sources cannot provide supraphysiological quantities of SCFAs, thereby impeding investigations into the potential benefits of SCFAs on brain function. To explore the dependent effects of SCFAs, animal studies often rely on oral administration, which may lead to distinct physiological outcomes due to the absorption of SCFAs from the upper gastrointestinal tract. Intravenous administration of SCFAs bypasses the absorption and oxidation processes that occur in colonocytes and is thus non-physiological. Additionally, rectal administration is not suitable for chronic use (103). Consequently, future studies should be undertaken to establish the optimal dosage of SCFAs delivered to the gut through prebiotic supplementation. Moreover, research into identifying prebiotic sources that produce the most abundant SCFAs would be valuable in developing dietary strategies for preventing the onset of depression.

The existing literature on the relationship between prebiotics and depression exhibits several limitations, both in terms of methodological rigor and conceptualization of future research. These limitations highlight the need for further investigation to establish a clearer understanding of this topic. Methodologically, many studies suffer from small sample sizes, limiting the generalizability of their findings. Depression is a complex and multifaceted condition, and studying it requires large and diverse participant groups to capture its full spectrum. Moreover, the majority of studies rely on self-report measures for assessing depression symptoms, which can introduce biases and inaccuracies. The use of more objective and standardized diagnostic criteria, such as structured clinical interviews, would enhance the reliability of the results. Another limitation lies in the inconsistency of prebiotic interventions across studies. There is a lack of consensus on the optimal dose, duration, and type of prebiotics to administer. This heterogeneity hampers the ability to compare findings across studies and draw definitive conclusions. Future research should strive for standardized protocols to facilitate more meaningful comparisons and meta-analyses. Additionally, most studies focus solely on the effects of prebiotics on depressive symptoms, neglecting potential underlying mechanisms. Exploring the gut-brain axis and investigating the specific pathways through which prebiotics influence brain function would provide a more comprehensive understanding of their antidepressant effects. Last but not least, the generalizability of the findings might be impeded because the majority of existing studies were conducted on diseased population, so it would be challenging to leverage the current findings to indicate how healthy individuals may benefit from consuming the prebiotics. Overall, the existing literature on prebiotics and depression is limited by methodological shortcomings, including small sample sizes and inconsistencies in intervention protocols. Moving forward, it is essential to address these limitations by employing larger, more diverse samples, utilizing longitudinal designs, establishing standardized intervention protocols, and investigating underlying mechanisms. By addressing these gaps, future research can advance our knowledge of the potential role of prebiotics in the treatment and prevention of depression.

In conclusion, the results of our study indicate that a daily intake of 5 g of GOS and 1 g or less of EPA can be effective in alleviating depressive symptoms. Although EGCG shows promise as an antidepressant, a higher dosage of 3 g per day might be required to achieve notable effects. The potential mechanisms that explain the influence of prebiotics on depression include the synthesis of neurotransmitters, the production of short-chain fatty acids, and the regulation of inflammation.

YY and BZ performed literature search and data collection. YY, BZ, SZ, LS, FL, and XL conducted the study design and wrote the manuscript. FL and XL provided scientific proofreading and supervised the study. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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