Gut microbiota, nutrients, and depression

This review followed a systematic approach aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (). ²⁶

Adequate protein intake is essential for human growth, development, and health maintenance (), and it is also associated with the prevalence of depression (–). However, current research on the relationship between protein sources and depression risk remains limited. Existing studies have only confirmed two key findings: first, milk and plant-derived proteins can reduce the incidence of depression (); second, red meat and processed meat may increase the incidence of depression (). The mood-beneficial effect of milk/dairy and plant proteins stems from their "high biological value": they contain complete essential amino acids (e.g., tryptophan, tyrosine) that are critical for neurotransmitter synthesis—tryptophan is the precursor of 5-hydroxytryptamine (5-HT, a key mood-regulating neurotransmitter), and tyrosine is the precursor of dopamine (related to motivation and pleasure) (). In contrast, red meat/processed meat has lower tryptophan content and may induce gut microbiota dysbiosis [e.g., elevated Bacteroides ()], which exacerbates inflammation and depressive symptoms (). In addition, the impact of individual differences in eating habits on mood has rarely been studied. These research limitations further complicate the effort to clarify the relationship between protein intake and depression. Therefore, this section focuses on exploring the beneficial effects of protein intake. ^{12 27 30 29 30 31 23 30}

It is necessary to emphasize the synergistic role of both "quality" and "quantity" when examining protein's regulation of depression: 1. in terms of quality, the antidepressant effect of high-biological-value proteins (containing complete essential amino acids, such as dairy and fish proteins) is significantly superior to that of low-biological-value proteins (such as single-grain proteins). A cohort study of American adults () showed that individuals who consumed high-biological-value proteins (accounting for more than 50% of total protein intake) daily had a 28% lower risk of depression (OR = 0.72, 95% CI: 0.58–0.89), while low-biological-value proteins did not provide such a protective effect. This is directly related to the higher content of tryptophan and tyrosine in high-biological-value proteins, which support neurotransmitter synthesis (); 2. in terms of quantity, there is a "threshold effect": a study of Indian middle school students () indicated that when daily protein intake was ≥1.2 g/kg body weight, intestinal tryptophan supply was stable, 5-HT (5-hydroxytryptamine) synthesis was sufficient, and depression scores decreased significantly (mean difference = −1.8 points,< 0.01); intake below this threshold increased the risk of depression, while excessive intake (≥2.0 g/kg body weight) did not further enhance the antidepressant effect. Instead, the increased metabolic burden of protein led to a higher abundance of intestinal(), which may induce microbiota dysbiosis. Additionally, tryptophan supplementation (500 mg/day) can temporarily improve mood in patients with mild depression (reducing BDI-II scores by 2.5 points), but high doses (≥1,000 mg/day) may induce serotonin syndrome due to excessive activation of 5-HT (); tyrosine supplementation (1,000 mg/day) is effective for depressed patients with fatigue symptoms (increasing energy scores by 15%), which is related to tyrosine acting as a dopamine precursor to improve motivation (); in contrast, glutamine supplementation (2,000 mg/day) showed no antidepressant effect due to its low blood-brain barrier penetration rate (< 10%) (). These results suggest that single amino acids need to be applied precisely to specific depression subtypes (such as fatigue-type or low-5-HT-type depression) rather than being used as a broad-spectrum intervention. ^{27 31 28 23 31 32 33} P Bacteroides

Proteins are macromolecules composed of one or more long amino acid chains, and most neurotransmitters are amino acid derivatives. This material connection provides a key biological basis for proteins to influence depression:

In terms of food sources, tryptophan and tyrosine are widely distributed in different types of foods:

Based on the aforementioned material connections, studies have found that reduced protein intake in elderly mice leads to abnormal neurotransmitter levels and impairments in cognitive and behavioral functions (). This result further confirms the close link between protein intake, neural function, and mood regulation. ³⁷

(1) Tryptophan-serotonin pathway: regulating neurotransmitter synthesis

Notably, tryptophan entry into the CNS is competitively regulated by L-amino acid transporter 1 (LAT1), which is shared with branched-chain amino acids (BCAAs, e.g., leucine, isoleucine). When dietary BCAA intake is high, they occupy LAT1, reducing tryptophan uptake by the brain and subsequently decreasing 5-HT synthesis (,). Additionally, tryptophan hydroxylase exists in two isoforms: Tryptophan hydroxylase 1 (TPH1; predominant in gut enterochromaffin cells) and tryptophan hydroxylase 2 (TPH2; specific to CNS neurons). TPH2 activity in the brain is the rate-limiting step for 5-HT synthesis, and its expression is downregulated by chronic stress—an effect reversed by adequate tryptophan intake (,). Serotonin is a potential biological marker for depression; a decrease in serotonin levels in the body can induce anxiety and depressive symptoms (–). Notably, 90% of the body's serotonin is produced by intestinal enterochromaffin cells (ECs) (), but this intestinal serotonin cannot cross the blood-brain barrier (BBB). The BBB expresses L-amino acid transporter 1 (LAT1), which preferentially transports branched-chain amino acids (BCAAs) over serotonin—preventing intestinal serotonin from entering the CNS (). Instead, CNS serotonin is synthesizedfrom tryptophan that crosses the BBB via LAT1 (when BCAA competition is low) (,). This indicates that protein intake can regulate the synthesis of serotonin by controlling tryptophan supply, thereby participating in the process of mood regulation. ^{31 38 31 39 40 42 39 31 31 39} de novo

(2) Gut microbiota-mediated protein metabolism: bidirectional regulation of depression-related substances

The gut is the core site for protein absorption and transformation, and gut microbiota, as a key component of nutrient absorption, participates in the absorption, metabolism, and transformation of dietary proteins in the gastrointestinal tract. It mediates the effects of proteins on depression through two pathways:

ECs in the gut are major epithelial chemical sensors and can produce more than 90% of the serotonin in the human body (). SCFAs exert their mood-regulating effects primarily through activating G protein-coupled receptors (GPRs) and inhibiting histone deacetylases (HDACs). G protein-coupled receptors 41 (GPR41) and G protein-coupled receptors 43 (GPR43; expressed on intestinal epithelial cells and immune cells) are activated by acetic acid and propionic acid, triggering downstream signaling that upregulates the expression of tight junction proteins [e.g., occludin, zonula occludens-1 (ZO-1)] to enhance intestinal barrier integrity (,). Butyric acid, in particular, acts as a potent histone deacetylase (HDAC) inhibitor in colonocytes and CNS neurons: it increases histone acetylation at the promoter of the BDNF (brain-derived neurotrophic factor) gene, promoting BDNF transcription—BDNF is critical for neuronal survival and synaptic plasticity, and its downregulation is linked to depression (,). ^{39 43 44 23 43}

Notably, both these protein-fermenting microbiota and their metabolites (e.g., SCFAs) are closely associated with the development of depression (,). For example, the abundance ofincreases in the gut of depressed patients, while the abundances of, anddecrease (). The association between these microorganisms and depression is determined by their metabolic functions: ^{45 46 23} Bacteroides Bifidobacterium, Lactobacillus Ruminococcus

After dietary protein intake, specific gut microbiota (e.g.,, and) can ferment the protein to produce short-chain fatty acids, mainly including acetic acid, propionic acid, and butyric acid (,). Bifidobacterium, Lactobacillus, Bacteroides, Roseburia, Coprococcus Ruminococcus ^{43 47}

Notably, both these protein-fermenting microbiota and their metabolites (SCFAs) are closely associated with the development of depression (,). For example, the abundance of Bacteroides increases in the gut of depressed patients, while the abundances of, anddecrease (). ^{45 46 23} Bifidobacterium, Lactobacillus Ruminococcus

In summary, there is a close association between protein absorption, gut microbiota, and depression, which is primarily achieved through the following two mechanisms:

The functions of gut microbiota directly involved in the development of depression (see). Figure 1

However, the current evidence has critical limitations that require balanced interpretation, including conflicting findings, overreliance on observational data, and unclear causality.

Lipids are essential macronutrients, and their dietary sources relevant to depression intervention primarily include:

Lipids and their metabolic intermediates are core components of brain structure and function, accounting for approximately 50% of the brain's dry weight (). The fatty acid composition of the brain is unique, being rich in long-chain polyunsaturated fatty acids (LC-PUFAs), especially arachidonic acid (AA), EPA, and DHA (). Dietary fatty acid intake can affect the fatty acid composition of different brain regions, thereby influencing mood and behavior (–). ^{54 55 56 58}

Numerous studies have confirmed that omega-3 PUFA deficiency (especially EPA and DHA) may induce depression (–). Deficiency is typically defined as serum EPA + DHA accounting for < 3% of total fatty acids (TFA)—a threshold validated in clinical studies linking low omega-3 status to higher depressive symptom severity (,). As a lipid component abundant in the brain (), Omega-3 polyunsaturated fatty acids are closely related to depression intervention: ^{59 61 62 63 64}

patients with depression have lower levels of Omega-3 polyunsaturated fatty acids (); a meta-analysis covering 26 studies showed that supplementation with EPA (≥1,000 mg/day) + DHA (≥200 mg/day) can improve depressive symptoms (). For food sources: consuming 100–150 g of deep-sea fish (e.g., salmon, mackerel; containing ~2,000 mg EPA + 500 mg DHA per 100 g) daily meets the mood-beneficial intake (,). Clinical evidence: ^{62 65 5 66}

DHA's high concentration in the frontal cortex is critical for maintaining the structure and function of neuronal membranes (e.g., lipid rafts) and neurotransmitter receptors (e.g., 5-HT2A). A reduction in frontal cortex DHA (not complete absence) impairs 5-HT signal transmission and neuroplasticity—key factors contributing to depressive symptoms, though not the sole cause of depression (,). Supplementation with 200–500 mg/day of DHA (as adjuvant therapy) can improve mild to moderate depression (); DHA: ^{67 68 66}

Constitutes less than 1% of total fatty acids in the brain, but when supplemented at 1,000–2,000 mg/day (combined with 200–500 mg/day DHA), it can inhibit the reduction of neurogenesis and decrease the secretion of inflammatory factors () [these cytokines can induce apoptosis and neuroinflammation, and are positively correlated with depressive symptoms ()]; EPA: ^{69 70}

as a precursor of Omega-3 fatty acids, it can be converted into DHA and EPA [the human body cannot synthesize it on its own and must obtain it through foods such as deep-sea fish ()]. A longitudinal study showed that increased ALA intake can alleviate depressive symptoms (), but its antidepressant effect remains controversial (). ALA: ^{52 71 62}

serum levels of EPA and DHA are negatively correlated with moderate to severe depression (,), further confirming the importance of dietary Omega-3 supplementation. Serum metabolic association: ^{63 72}

(1) Regulating neurotransmitter transmission

(2) Modulating immune and inflammatory responses

Depression is often accompanied by an excessive inflammatory response of the immune system, characterized by increased levels of pro-inflammatory cytokines and linoleic acid metabolites (–). EPA and DHA are natural anti-inflammatory substances (), and their anti-inflammatory mechanisms include: ^{80 82 83}

Therefore, Omega-3 fatty acids may achieve antidepressant effects primarily by regulating the functions of immune cells and pro-inflammatory cells.

The intestine is the main site of lipid metabolism. Gut microbiota can affect mood indirectly by transforming and synthesizing lipids, decomposing dietary lipids to produce regulatory metabolites (–). The specific pathways are as follows: ^{88 90}

(1) Association between gut microbiota and lipid metabolites

Some gut microbiota (such as, and) are associated with lipid metabolites in the blood (,–). Depression can disrupt the structure of gut microbiota (), and microbial metabolites [triglycerides, low-density lipoproteins, high-density lipoproteins, phosphatidylcholine, etc. (,–)] can affect human lipid metabolism (–), thereby influencing mood and cognitive function (–). Bacteroides, Clostridium, Lactobacillus, Bifidobacterium Ruminococcaceae ^{89 91 94 45 89 91 94 94 96 97 99}

(2) How do lipids influence SCFAs production?

SCFAs (acetate, propionate, butyrate, etc.) are the end products of dietary fiber fermentation by gut microbiota, mainly synthesized by genera such as, and(–). Lipids (especially omega-3 PUFAs) do not directly participate in carbohydrate fermentation but indirectly promote SCFA production by: Akkermansia, Bifidobacterium Faecalibacterium ^{100 102}

Their functions include: maintaining intestinal barrier function (), participating in serotonin synthesis (), and regulating lipid metabolism (,). ^{44 19 104 105}

patients with depression have lower levels of acetate and propionate, and higher levels of isocaproic acid in their feces (); Valeric acid, produced mainly by Oscillibacter, has a structure similar to GABA and can bind to its receptors (). The content ofis higher in the feces of depressed patients (), which may play an important role in severe depressive disorders. Association with depression: ^{24 106 107} Oscillibacter

(3) There exists a distinct "dose-effect window" for the antidepressant effects of Omega-3, which should be stratified based on the severity of depression:

(4) Summary and prospects

Existing studies indicate that lipid metabolism is closely related to mood. It is hypothesized that lipids may affect depression through three main pathways:

However, there is still insufficient evidence to explain the specific associations between lipid metabolism, gut microbiota, and mood, which remains a hot topic in current research.

The cited evidence has gaps, including overreliance on observational data and heterogeneous intervention studies:

Dietary fiber is a class of carbohydrates found in plant-based foods such as whole grains, vegetables, fruits, and legumes (). Based on the physiological properties of monomer unit (MU) polymerization, it can be categorized into three main types: ¹¹³

The human body cannot secrete the polysaccharide hydrolases required to decompose dietary fiber independently. However, gut microbiota can produce a variety of polysaccharide hydrolases to degrade dietary fiber and utilize it as an energy source (). Different types of dietary fiber exhibit specific regulatory effects on the composition of gut microbiota: ¹¹⁶

(1) Regulation of gut microbiota by NSPs

Inulin, a representative NSP, can significantly increase the abundance of beneficial bacteria in the gut. Studies have shown that inulin supplementation increases the abundance ofby 8.38%, Lactobacillus by 0.26%−1.26%, andby 0.2% (), supporting the balance of the intestinal microecosystem. Bifidobacterium Faecalibacterium ¹¹⁷

(2) Regulation of gut microbiota by RS

When the diet is rich in resistant starch, the abundance of specific gut bacteria changes: the counts of, andincrease significantly (). The proliferation of these bacteria helps enhance intestinal metabolic function, laying the foundation for subsequent metabolite production. Faecalibacterium, Roseobacter Ruminococcus ¹¹⁴

(3) Regulation of gut microbiota by RIOS

Different types of oligosaccharides exert targeted regulation on gut microbiota:

Notably, previous studies have confirmed that the aforementioned gut bacteria regulated by dietary fiber (e.g.,) are closely associated with depression (), providing a critical link for dietary fiber to intervene in depression via gut microbiota. Bifidobacterium, Lactobacillus, Faecalibacterium ⁴⁵

(1) Mood regulation mediated by SCFAs produced via gut microbiota fermentation

Dietary fiber cannot be digested and absorbed by the human body but can be partially or fully fermented by gut microbiota (). This fermentation process generates various byproducts, among which SCFAs are the core pathway connecting gut microbiota and host metabolic interactions (consistent with the previously mentioned mechanism by which proteins and lipids improve mood through the microbiota-SCFAs axis). The specific functional logic is as follows: ¹²²

(2) Improvement of depression by regulating inflammatory levels

Inflammation is closely associated with mood, as evidenced by the following: patients with acute symptomatic psychosis often exhibit acute inflammatory states; psychological stress—a major risk factor for depression—can induce inflammatory responses and increase inflammatory markers in healthy volunteers (–); cytokines are involved in the development of depressive symptoms, and environmental factors may also trigger both depression and immune disorders (–). Additionally, the levels of anti-inflammatory cytokines are often elevated in patients with major depressive disorder (,), further highlighting the key role of inflammation in depression. ^{127 129 127 129 130 131}

Dietary fiber-derived SCFAs suppress intestinal inflammation by inhibiting the activation of the NLRP3 (NLR family pyrin domain containing 3) inflammasome—a multiprotein complex that mediates caspase-1-dependent maturation of IL-1β. GPR43 activation by SCFAs reduces intracellular ATP depletion and reactive oxygen species (ROS) production, which are critical for NLRP3 assembly (,). Furthermore, fiber fermentation increases gutabundance; this bacterium produces anti-inflammatory metabolites (e.g., butyrate androsmarinic acid) that downregulate the expression of TLR4 and CD14 (Cluster of Differentiation 14) on intestinal macrophages, limiting LPS (Lipopolysaccharides)-induced inflammatory responses (,). ^{132 133 132 134} Faecalibacterium prausnitzii

Dietary fiber can indirectly intervene in depression by regulating inflammatory levels, supported by the following research evidence:

Thus, dietary fiber can break the "inflammation-depression" vicious cycle by reducing systemic inflammatory levels, thereby improving depressive symptoms (). Figure 2

Section 5.3 has partially discussed the regulatory role of dietary fiber in gut inflammation; however, the differential effects of various dietary fiber types on gut inflammation warrant further elaboration. Based on the existing evidence and the central framework of this review, the specific distinctions and underlying mechanisms are further detailed as follows (): Table 1

(1) NSPs: targeted inhibition of pro-inflammatory pathways

As one of the most extensively studied categories of dietary fiber (see Section 5.1), NSPs, such as inulin and β-glucan, demonstrate significant anti-inflammatory properties through modulation of gut microbiota and enhancement of SCFAs production.

(2) RS: Regulation of inflammation via microbiota-metabolite axis

RS, such as RS3 derived from cooled potatoes, differs from NSPs in terms of fermentation rate and anti-inflammatory targets, demonstrating particularly pronounced effects on colonic mucosal inflammation.

(3) RIOS: modulation of local inflammatory microenvironment

RIOS, such as FOS (Fructo - OligoSaccharide), are characterized by shorter monomer chains (degree of polymerization 3–9) and rapid fermentation, making them particularly effective in alleviating mild-to-moderate gut inflammation.

The SCFA-mediated pathway has notable limitations, including overreliance on animal models and unproven causality.

Water-soluble vitamins mainly include B-group vitamins (B1, B2, B3, B5, B6, B7, B9, and B12) and vitamin C. Among them, B-group vitamins can be synthesized by the gut microbiota (), while vitamin C can be synthesized by the gut microbiota in addition to dietary supplementation (). ^{144 145}

(1) Effects of B-group vitamins on the gut microbiota

B-group vitamins maintain the balance of the intestinal microecosystem by regulating the abundance of specific microbiota, supported by the following research evidence:

(2) Effects of vitamin C on the gut microbiota

Vitamin C (ascorbic acid) has attracted considerable attention due to its well-documented antioxidant and anti-inflammatory properties (,). However, research on the relationship between vitamin C and the gut microbiota remains limited, with only two clinical trials exploring the effects of vitamin C supplementation on the gut microbiota: ^{150 151}

Fat-soluble vitamins mainly include vitamin A, vitamin D, vitamin E, and vitamin K (). Among them, vitamin A, vitamin D, and vitamin E are primarily obtained through dietary supplementation and absorbed via metabolism in the small intestine (–); in addition to dietary intake, vitamin K can also be synthesized by the gut microbiota (,). ^{137 154 156 157 158}

(1) Effects of vitamin A on the gut microbiota

Vitamin A improves vision, regulates growth and development, and modulates immune function. It is mainly derived from retinol in meat and fish, and carotenoids in fruits and vegetables (). Since 70%−90% of vitamin A is absorbed in the gut (), it has a potential association with the gut microbiota, as evidenced by: ^{159 160}

(2) Effects of vitamin D on the gut microbiota

Vitamin D deficiency is associated with intestinal diseases such as ulcerative colitis, Crohn's disease (CD), and other inflammatory bowel diseases (,). Based on studies of these intestinal diseases, vitamin D has been confirmed to regulate the growth of the gut microbiota, with specific findings as follows: ^{168 169}

Vitamin D exerts its effects by binding to the vitamin D receptor (VDR), a nuclear transcription factor. In intestinal epithelial cells, VDR forms a heterodimer with the retinoic acid X receptor (RXR) and binds to vitamin D response elements (VDREs) in the promoter regions of genes encoding antimicrobial peptides (AMPs), such as defensins and cathelicidins (,). AMPs selectively inhibit the growth of pro-inflammatory bacteria (e.g.,) while promoting the proliferation of beneficial taxa (e.g.,(,). Additionally, VDR activation upregulates tight junction proteins (ZO-1, occludin) and downregulates pro-inflammatory cytokines (IL-6, TNF-α) by inhibiting NF-κB, thereby linking gut microbiota balance to reduced systemic inflammation and depression (,). ^{103 170 170 171 103 172} Enterobacteriaceae Roseburia, Akkermansia)

Schäffler et al. () conducted oral vitamin D intervention in CD patients and found that 1 week after vitamin D1 supplementation, the abundances of Alistipes, Barnesiella, unclassified Porphyromonadaceae, Roseburia, Anaerotruncus, Subdoligranulum, and unclassified Ruminococcaceae in the patients' guts increased significantly (); Study on CD patients: ^{103 103}

Ooi et al. () found that vitamin D regulated the composition of the gut microbiota (including Bacteroidetes, Proteobacteria, Firmicutes, Deferribacteres, Lactobacillaceae, and Lachnospiraceae) in a mouse colitis model induced by dextran sulfate sodium (); Study on mouse colitis model: ^{171 171}

two large-scale cohort studies on the effects of vitamin D supplementation on the infant gut microbiota showed that maternal diet and plasma vitamin D levels were negatively correlated with Bifidobacterium and Clostridioides difficile in infants (); moreover, maternal vitamin D supplementation may reduce the growth of Clostridioides difficile in infants (). Mother-infant cohort studies: ^{173 172}

Although the above studies have specific designs, they all confirm that vitamin D has the ability to regulate the gut microbiota (). ¹⁷⁰

(3) Effects of vitamin E on the gut microbiota

The natural sources of vitamin E are mainly the oily components of nuts and oilseeds, which exhibit antioxidant, anti-inflammatory, anti-aging, and anti-cancer properties (,). Vitamin E also interacts with the gut microbiota, supported by the following evidence: ^{174 175}

a study exploring the relationship between dietary intake and maternal gut microbiota showed that higher vitamin E intake was associated with lower levels of(especially Sutterella) ().have pro-inflammatory properties, andis highly abundant in the guts of autistic patients (); Study on maternal gut microbiota: Proteobacteria Proteobacteria Sutterella ^{176 177}

Tang et al. () conducted a randomized trial of iron and vitamin E supplementation in Fe-deficient infants in the United States. They found that higher serum vitamin E concentrations in infants were associated with higher relative abundance of(a butyrate-producing bacterium) (); Fe (Iron) and vitamin E supplementation trial in infants: ^{178 178} Roseburia

Pham et al. found that vitamin E increased the relative abundances of, and, while also increasing the levels of acetate, butyrate, and propionate (); supplementation with tocotrienols (one of the main natural forms of vitamin E) increased the level ofin the guts of mice (). In vitro Akkermansia, Bifidobacterium Faecalibacterium Verrucomicrobia and animal experiments: ^{146 179}

Currently, research on the effects of vitamin E on the gut microbiota remains limited, lacking systematic study validation.

(4) Effects of vitamin K on the gut microbiota

Vitamin K is mainly obtained from green leafy vegetables and vegetable oils in the diet. It can also be acquired from menadione in fermented foods or through biosynthesis by the gut microbiota (). Its main function is anticoagulation (), and it also regulates osteocalcin synthesis (), inhibits inflammation (), and suppresses the growth of certain cancer cells (,). Research on vitamin K and the gut microbiota is scarce, with existing evidence as follows: ^{158 180 181 182 183 184}

Wagatsuma et al. () explored the relationship between the gut microbiota and vitamin K deficiency in CD patients and found that vitamin K deficiency significantly reduced the diversity of the gut microbiota, includingand; Study on CD patients: ¹⁸⁵ Ruminococcaceae Lachnospiraceae

Seura et al. () investigated the relationship between habitual dietary intake and the gut microbiota in the Japanese population. They found that young Japanese women with high vitamin K intake had higher relative abundances ofandin their guts (); Study on diet and microbiota in Japanese population: ^{186 186} Bifidobacterium Lactobacillales

A study exploring the effects of a diet high in whole or refined grains on(fecal/serum) menadione concentrations and gut microbiota composition in men and postmenopausal women showed that menadione increased the abundances ofand(); Study on fermented foods and menadione: in vivo Bacteroides Prevotella ¹⁸⁷

In vitamin K-deficient female C57BL/6 mice, the abundances ofandin the gut were reduced (), consistent with the findings of Wagatsuma et al. However, gender differences may exist in the effects of vitamin K deficiency on the gut microbiota (), leading to insufficient evidence to explain the relationship between vitamin K and the gut microbiota. Animal experiments: Lachnospiraceae Ruminococcaceae ^{188 189}

Furthermore, recent studies have found that the gut microbiota affects patients' responses to anticoagulants and the vitamin K antagonist warfarin (,). Therefore, there is an urgent need to strengthen basic research on the relationship between vitamin K and the gut microbiota. ^{190 191}

Based on the above research on the relationship between vitamins and the gut microbiota, it can be concluded that both water-soluble vitamins (B-group vitamins, vitamin C) and fat-soluble vitamins (vitamin A, D, E, and K) can alter the composition of the gut microbiota. They can also promote the growth of probiotics such as, and()—these microbiota have been confirmed to be negatively associated with depression (). The specific mechanisms by which vitamins regulate depression can be summarized into two points: Bifidobacterium, Faecalibacterium, Akkermansia, Clostridia Lactobacillus ^{192 45}

(1) Improving depression by promoting probiotic growth and SCFA metabolism

Thus, dietary vitamin supplementation can regulate and prevent depressive mood by promoting probiotic growth and optimizing SCFA metabolism.

(2) Counteracting mood-related damage by enhancing anti-inflammatory capacity

Negative emotions can increaseinflammatory levels (,), and vitamins can offset the damage to the host caused by negative emotions by enhancing the body's anti-inflammatory capacity (,,), thereby indirectly improving depressive states (). in vivo ^{21 22 179 199 200} Figure 3

The claim of a "synergistic relationship" between B-group vitamins and the gut microbiota is overstated, as the supporting evidence has critical quality limitations.

Mineral elements are essential for sustaining human life activities and normal physiological functions, and the gastrointestinal tract serves as the primary site for their absorption and metabolism. However, comprehensive studies on the relationship between the gut microbiota and mineral elements remain limited, with most research focusing on essential elements (,–). This section therefore discusses the associations between five key essential elements (Ca, Mg, Fe, Zn, and Se) and the gut microbiota. ^{205 212 214}

(1) Ca and the gut microbiota

Ca is an essential element for the human body. As an enzyme activator, it participates in biological pathways such as bioelectrical impulse conduction, blood coagulation, muscle contraction, inflammation, and hormone secretion (,). Dairy products are the primary dietary sources of Ca, with milk, yogurt, and cheese being the most common. After ingestion, Ca is mainly absorbed in the small and large intestines (). Research on the Ca-gut microbiota relationship has primarily focused on animal studies related to osteoporosis: ^{215 216 217}

While the specific mechanism underlying the interaction between Ca and the gut microbiota has not been fully elucidated, a potential pathway has been proposed:andin the gut produce short-chain fatty acids (SCFAs, primarily butyrate), which lower colonic pH, increase ionic Ca concentration, and promote Ca absorption via passive diffusion through the paracellular pathway (,). This provides a direction for further investigating the Ca absorption-microbiota interaction. Bifidobacterium Lactobacillus ^{221 222}

(2) Mg and the gut microbiota

Mg is the fourth most abundant cation in the human body (). As a cofactor for over 300 enzymatic reactions, Mgis involved in critical metabolic pathways, including nutrient catabolism, oxidative phosphorylation, DNA and protein synthesis, neuromuscular excitability, and parathyroid hormone secretion (). The main dietary sources of Mg include nuts, vegetables, and dairy products (). The intestinal absorption rate of Mgranges from 30 to 50%, with absorption occurring primarily in the small intestine and to a small extent in the colon (). Understanding of the interaction between Mg and gut microbiota diversity remains limited, with key findings as follows: ^{223 224 225 226} 2+ 2+

Conversely, a high-Mg diet increased the abundances of, and(). Since Proteobacteria is a key marker of microbiota dysbiosis (), excessive dietary Mg supplementation may disrupt intestinal microbial balance. Proteobacteria, Parabacteroides, Butyricimonas Victivallis ^{230 231}

These findings suggest a dose-dependent relationship between dietary Mg intake and the gut microbiota, but additional clinical studies are needed to clarify its physiological regulatory pathways.

(3) Fe and the gut microbiota

As a key component of hemoglobin, Fe not only facilitates oxygen transport in the body but also participates in biological pathways such as DNA metabolism and mitochondrial function (). It also serves as an active-site metal for enzymes like catalase, peroxidase, and cytochrome (). Dietary Fe exists in heme and non-heme forms, with primary sources including cereals, vegetables, legumes, and fruits. In the small intestine, Febinds to transferrin to form ferritin, which enables Fe absorption (). Key insights into the Fe-gut microbiota relationship include: ^{232 233 234} 2+

Notably, several studies showed that dietary Fe supplementation reduces the abundances ofandin the infant gut (–). Additionally, Fe supplementation was associated with increased calprotectin levels in infants, indicating heightened intestinal inflammation (). These results suggest that the impact of Fe supplementation on gut microbiota diversity may vary with host age. Currently, studies on host-related factors influencing the Fe-gut microbiota relationship are scarce, and the exact mechanism by which Fe levels alter gut microbiota structure and activity remains unclear, requiring more experimental evidence. Bifidobacteria Lactobacillus ^{242 244 244}

(4) Zn and the gut microbiota

Zn is the second most abundant metallic element in the human body (after Fe). It is involved in biological functions such as biomacromolecule synthesis, neurotransmission, hormone release, and regulation of the oxidative cascade and immune system (,). It also acts as a cofactor in enzymatic catalytic processes (). Dietary Zn is widely available in poultry, seafood, legumes, nuts, whole grains, and small amounts in dairy products (). Zn absorption occurs throughout the small intestine, primarily in the duodenum and jejunum (). ^{245 246 247 248 249}

Zn exerts its mucosal protective effects by binding to zinc finger transcription factors (e.g., ZNF365) and activating the expression of mucin 2 (MUC2)—the major component of intestinal mucus (,). Additionally, Zn inhibits the TLR4/MyD88/NF-κB pathway in intestinal macrophages: it binds to the TLR4 extracellular domain, preventing LPS binding, and suppresses IκBα phosphorylation, thereby reducing the transcription of pro-inflammatory cytokines (IL-1β, IL-6) (,). In gut microbiota, Zn is a cofactor for bacterial metalloenzymes (e.g., alkaline phosphatases in), which dephosphorylate LPS and reduce its endotoxin activity (,). Zn is essential for the gut microbiota, which absorbs approximately 20% of dietary Zn. However, clinical evidence for the Zn-gut microbiota relationship is limited, with most data from animal studies: ^{250 251 252 253 254 255} Lactobacillus

However, dose-response studies are currently lacking. Further evidence is required to fully elucidate the relationship between zinc intake and the composition of the gut microbiota.

(5) Se (Selenium) and the Gut Microbiota

Se is an essential micronutrient with antioxidant, anti-inflammatory, and antiviral properties (). Se deficiency can cause thyroid, cardiac, and skeletal muscle diseases (,), and low plasma Se levels are associated with impaired cognitive function and neurological disorders (). Dietary Se is obtained in both organic and inorganic forms, with Brazil nuts, cereals, meat, fish, seafood, and dairy products being the best sources (). Se absorption primarily occurs in the small intestine ()—the colon has lower Se absorption due to its low oxygen content (). ^{257 258 259 260 261 262 263}

Se exerts its biological effects as a component of selenoproteins, such as glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). In the gut,andconvert inorganic Se to organic Se, which is more bioavailable to the host (,). GPx1, expressed in intestinal epithelial cells, scavenges ROS and prevents lipid peroxidation of the gut barrier. TrxR1 regulates Treg cell differentiation by reducing oxidative stress, promoting IL-10 secretion and suppressing T helper cell 17 (Th17)-mediated inflammation (,). Additionally, Se supplementation increasesabundance, which enhances gut barrier function by upregulating MUC2 and tight junction proteins—this reduces LPS translocation and systemic inflammation linked to depression (,). Lactobacillus Bifidobacterium Akkermansia muciniphila ^{264 265 264 266 264 267}

Key insights into the Se-gut microbiota relationship include:

These studies confirm a close relationship between dietary Se and the gut microbiota, suggesting Se may have potential for microbiota-mediated disease treatment. Thus, understanding the Se-gut microbiota interaction is of great significance.

It is estimated that over 2 billion people worldwide are deficient in key mineral elements (). Mineral elements have been linked to cognitive function (), intestinal disorders (), and mental disorders (). However, their role in the etiology and progression of depression remains unclear. Based on the aforementioned mineral element-gut microbiota relationships and the role of the gut-brain axis in depression (,), this section analyzes the association between mineral elements and depressive symptoms from the perspective of how dietary mineral intake modulates the gut microbiota. ^{272 273 274 275 276 277}

(1) Evidence for mineral elements in depression intervention

Micronutrient supplementation has been investigated as an adjunctive treatment for depression, with Fe, Zn, Mg, and Se being the most studied:

(2) Potential mechanisms: mineral elements → Gut microbiota → depression

These micronutrients may influence depression through similar biological pathways, with the gut microbiota serving as a key mediator. As highlighted in the preceding sections, mineral elements (Ca, Mg, Fe, Zn, and Se) promote the growth of beneficial gut bacteria, including, and Akkermansia (,,,); these beneficial microbiota improve depression-like symptoms through two core pathways: Bifidobacterium, Lactobacillus ^{227 242 254 264}

Further prospective studies are required to:

Fe: A "U-shaped dose-response relationship" exists between iron and depression:

Zn: the antidepressant effect of zinc depends on a "precise dose":

Se: the antidepressant dose window of selenium is 50–100 μg/day

The association between minerals and depression has critical limitations, including weak intervention evidence and unclear mediation by microbiota.

In modern society, individuals face growing levels of stress and often turn to junk foods such as cola, cakes, and potato chips under the perception that these foods can induce temporary feelings of pleasure. While many believe such foods—despite the risk of weight gain—contribute to happiness, this is a misconception. The short-term pleasure derived from an unhealthy diet is quickly followed by a return to low mood or even exacerbated depression over the long term.

Diet plays a critical role in the onset and intervention of psychiatric disorders. Adopting an anti-inflammatory diet—including increased intake of deep-sea fish, adequate consumption of fatty acids (e.g., folic acid) and magnesium, and avoidance of processed foods—has been linked to a reduced risk of psychiatric disorders (). Thus, selecting an appropriate dietary structure is crucial for the prevention and early intervention of depression. The following sections discuss the relationships between three specific dietary patterns (Mediterranean diet, DASH (Dietary Approaches to Stop Hypertension) diet, and Okinawa diet) and depression. ²⁸⁶

Mind-body medicine (MBM, e.g., mindfulness, yoga, Cognitive Behavioral Therapy (CBT) enhances dietary interventions by reducing stress, improving nutrient absorption, and modulating gut microbiota—offsetting the depressive effects of poor diet (e.g., high sugar, low fiber).

(1) Stress reduction and gut barrier protection

(2) Improving nutrient absorption

Research articles examining the impact of psychosomatic medicine on nutrient absorption have not yet been compiled. However, a related concept—mindful eating—has been identified, which integrates mental and physical health through dietary practices. Mindful eating is grounded in the interplay between neurogastrointestinal physiology and stress regulation. By activating the parasympathetic nervous system and assisting patients in recognizing the relationship between stress and dietary habits—such as through the Mindful Eating Questionnaire (MEQ) and handwritten dietary journals—it helps reduce stress responses and enhance digestive function, thereby promoting more favorable conditions for nutrient absorption. Furthermore, as a non-standardized intervention, it allows for personalized implementation tailored to individual patient needs. Mindful eating thus represents a scientifically grounded and effective approach to optimizing digestion and improving overall health (). ³³⁶

The "Nutrient-Gut Microbiota Inhibition" comprehensive evidence table systematically summarizes the evidence regarding the associations between five core nutrient categories—protein, Omega-3 polyunsaturated fatty acids, dietary fiber, vitamins, and minerals—and the "Gut Microbiota Inhibition" axis, as detailed in Sections 3–7 of the manuscript (). The primary objective is to enable horizontal comparisons of the strength of evidence, key mechanistic findings, and inherent limitations across different nutrients. This synthesis addresses the need for a concise summary of dispersed data and clarifies which nutrients demonstrate robust clinical and mechanistic support for their role in depression intervention via gut microbiota modulation, and which require further investigation. It also lays the groundwork for the subsequent discussion on clinical implications and research gaps presented in Section 9. Key findings frominclude the following: dietary fiber (NSPs/RS) and Omega-3 (EPA/DHA) exhibit strong or high evidence levels, supported by consistent, low-bias human RCT. Both nutrients exert antidepressant effects through gut microbiota regulation, either by enhancing SCFA production or reducing inflammation, making them the most promising candidates for clinical translation (consistent with Sections 4.3, 5.3). Protein (milk- or plant-based) and minerals (Zn/Se) are categorized as having moderate evidence, indicating potential but necessitating further targeted RCT—for instance, the efficacy of protein depends on bioavailability and an intake threshold of 1.2 g/kg body weight/day (,), while zinc dosage should be maintained at 15–20 mg/day (,) to avoid microbiota disruption. Evidence for vitamin E/K and minerals such as iron, calcium, and magnesium remains weak or very low, with insufficient human data. For example, vitamin K research has been largely limited to patients with Crohn's disease (), and iron's effects vary by age group [infants vs. adults ()], underscoring the importance of population-specific investigations. The findings compiled in this table directly inform Section 9 ("Discussion") in three key areas: regarding clinical significance, it supports the prioritization of stratified interventions based on nutrients with strong evidence (e.g., dietary fiber and EPA/DHA), particularly for inflammatory depression subtypes (,); concerning research gaps, it identifies critical areas requiring further exploration, such as developing dose-response models for the "nutrient-microbiota inhibition" axis and investigating potential synergistic effects among nutrients; finally, in terms of limitations, it highlights the heterogeneity in evidence [e.g., variations in Omega-3 dosing across RCTs ()] and population-specific biases [e.g., vitamin D studies focusing on IBD patients ()]. Table 2 Table 2 ^{27 28 252 279 185 242 65 124 65 169}

(1) Strength ranking of core mechanistic evidence and prioritization for clinical translation

Based on a systematic analysis of each nutrient's regulatory pathway, the mechanisms with the strongest evidence for clinical translation are prioritized as follows:

In contrast, mechanisms supported by weak or preliminary evidence [e.g., the vitamin C/gut microbiota/depression axis (,), and the calcium/gut microbiota/depression axis (–)] require further validation. These mechanisms rely primarily on small-sample studies or animal models and lackmechanistic data from human subjects. ^{152 153 218 220} in vivo

(2) Cross-nutrient common mechanistic gaps and future research directions

Across all nutrient categories, three critical gaps in mechanistic understanding persist and must be addressed in future research:

(3) Prevalent potential confounding factors and recommendations for study design optimization

Several confounding factors consistently obscure the causal links between nutrients, the gut microbiota, and depression. Future studies should adopt targeted designs to mitigate these issues:

However, this review has several limitations. First, it does not clearly describe the relationships among dietary nutrient intake, bacterial availability, and depressive symptoms. Second, excessive mineral intake can also reduce gut microbiota abundance; yet, information on the relationship between mineral intake levels and the gut microbiota remains scarce, and insufficient research currently limits our ability to clarify this relationship. Additionally, research on the interactions between the gut microbiota and nutrients is still inadequate, and the specific mechanisms underlying these interactions remain unclear. Despite these limitations, this review highlights that dietary nutrients can modulate gut microbiota composition and alleviate depression-like symptoms. A growing body of evidence supports the need to explore links between dietary factors and mental disorders. Future research should bridge the gap between nutritional neuroscience and clinical evidence, optimize overall dietary patterns, and investigate the mechanisms by which nutrients interact with the gut microbiota and central nervous system—ultimately improving and preventing mental health through dietary interventions.