Current landscape of fecal microbiota transplantation in treating depression

Coprophagy, the ingestion of feces from the same or different species, allows rodents to preserve essential gut microbiota diversity and function through this scavenging behavior (25, 26). Sha et al. discovered that blocking coprophagy in healthy mice led to increased levels of depression and pro-inflammatory cytokines (27). Furthermore, when the fecal microbiota of mice with CUMS mice and lipopolysaccharide (LPS) mice were transplanted into healthy recipient mice, the coprophagy-blocked group exhibited more severe depressive symptoms and higher levels of pro-inflammatory cytokines, in the serum, prefrontal cortex (PFC), and hippocampus, compared with the coprophagy-unblocked group. Thus, autophagy inhibition appeared to amplify inflammatory responses and precipitate depressive behaviors in both normal mice and those receiving FMT from disease model donors.

Rheumatoid arthritis (RA) and depression are prevalent diseases that harm patient quality of life and impose a significant economic burden on society (28, 29). Depression is a frequent comorbidity in patients with RA, which not only reduces treatment effectiveness but also increases the risk of disability and death (30). Moreover, there appears to be a bidirectional link between depression and RA (31). Pu et al. examined the impact of FMT from RA patients on depression-like behaviors using the mouse model of collagen-induced arthritis (32). Before FMT, mice underwent ABX treatment to deplete their endogenous gut microbiota. FMT from patients with RA into the ABX-treated mice resulted in depression-like behavior, changed gut microbiota composition, elevated levels of IL-6 and TNF-α, and downregulated levels of synaptic proteins in the PFC. In addition, significant correlations were observed between the relative abundance of microbiota and plasma cytokines, expression of synaptic proteins in the PFC, or depression-like behavior. In the RA FMT group, the ratio of Peyer’s patches and splenic CD4⁺ T cells to Th1/Th2 increased, while the ratio of Treg cells decreased. These findings suggest that FMT from RA patients induced depressive-like behaviors in ABX-treated mice through T cell differentiation, providing evidence for the involvement of the gut-microbiome-brain axis in depression.

The emergence of depressive symptoms is often a multifactorial process where various elements such as chronic alcohol misuse, the negative side effects of certain medications, and the habitual abuse of substances can play a significant role (33, 2). These factors, individually or in combination, can lead to alterations in an individual’s emotional and psychological equilibrium, thereby potentially triggering the onset or intensifying the severity of depressive symptoms (34). Prolonged exposure to these conditions can disrupt the neurochemical balance within the brain, affecting mood-regulating neurotransmitters and leading to sustained mood disturbances (35). The complex interplay between pharmacological stimuli, psychological stressors, neurobiological alterations, and systemic changes highlights the intricate nature of depression, in which drugs such as alcohol, 5-Fluorouracil (5-FU), and methamphetamine (METH) have been identified to be tightly associated with depression.

Alcohol, commonly known as ethanol, is recognized as one of the most frequently abused substances globally (36). Recent studies indicate a positive correlation between the amount of alcohol consumption and the likelihood of developing depression (37) (38). The recognized significance of the gut microbiome has spurred research into its role in mediating neurotoxic effects associated with ethanol exposure. There was a marked distinction in the gut microbiota composition between alcoholics and healthy individuals, characterized by a significant increase in the abundance of E. faecalis in alcoholics (39). Zhao et al. transplanted fecal microflora from alcoholic patients into mice with gut microflora severely suppressed by ABX, demonstrating that recipients decreased BDNF, alpha 1 subunit of α1GABA_AR in mPFC, and decreased mGluR1, PKC ϵ in NAc (40). Therefore, FMT from alcoholic patients could reduce the level of mGluR1/PKC ϵ, and induce anxiety and depressive behavior in mice. On the contrary, the FMT from mice to chronic ethanol exposure (CEE) in healthy recipient mice led to the emergence of depressive behavioral characteristics, neuroinflammatory responses, and activation of the NLRP3 inflammasome (41). Furthermore, the hippocampal downregulation of NLRP3 expression exhibited a mitigating effect on the depression-like behavioral manifestations and neuronal damage induced by CEE. Consequently, FMT produced positive treatment of CEE-induced hippocampal NLRP3-mediated neuroinflammation and depressive-like behaviors.

5-FU is a fluorinated pyrimidine analog that acts as an antimetabolite by replacing the hydrogen atom at the C-5 position of uracil with fluorine (42). This substitution facilitates the incorporation of 5-FU instead of thymine into DNA, resulting in aberrant adenine-uracil/5-FU base pairing (43). Clinically, 5-FU has been extensively utilized in the treatment of several gastrointestinal cancers, such as colorectal cancer, which is one of the most common malignancies worldwide (44, 45). Despite its broad therapeutic applications and being considered relatively safe within the spectrum of chemotherapeutic drugs, 5-FU carries a risk of specific side effects and toxicity (46, 47). The imbalance of the intestinal microbiota was commonly acknowledged to be linked with gastrointestinal lesions induced by 5-FU (48). Zhang et al. established a rat model to evaluate depression-like behaviors in 5-Fu-treated rats (48). The results demonstrated that 5-FU-induced depression-like behavior reduced the diversity of bacterial communities, altered the composition of bacterial communities, and caused changes in PFC metabolism. Furthermore, FMT from healthy donors into 5-Fu-treated rats reversed the 5-Fu-induced depression-like behaviors, restored PFC metabolism to normal levels, and alleviated amino acid imbalances in both the peripheral and central nervous systems. Therefore, 5-Fu caused depression-like behaviors through dysregulation of the microbiome-gut-brain axis, which FMT methods could reverse.

METH, commonly referred to as crystal meth, is a synthetic stimulant drug that belongs to the amphetamine class of compounds that have an exciting effect on the central nervous system, resulting in increased heart rate, increased blood pressure, increased alertness and energy, and appetite suppression (49, 50). The prolonged use of METH and its sudden withdrawal lead to substance withdrawal syndrome, encompassing symptoms such as anxiety, depression, and other manifestations. Concurrently, METH-dependent individuals experience substantial alterations in the composition of their gut microbiota, characterized by heightened alpha diversity and the relative abundance of distinct microorganisms (51). Notably, the relative abundance of Rikenellaceae could serve as a potential diagnostic biomarker to diagnose METH withdrawal syndrome. FMT was performed on recipient mice using fecal samples from METH addicts and METH-treated mice resulting in the induction of anxiety and depression-like behaviors in recipient mice, which could be reversed by metformin, through the regulation of microbiota-derived metabolites such as creatinine.

Administering ABX markedly diminishes the fecal bacterial population and exerts a depressive impact on the microbiota composition (52). Li et al. demonstrated that after depleting the gut microbiota of mice using an ABX cocktail, FMT from CUMS-exposed mice induced anxiety-like and depressive behaviors in recipient mice, associated with changes in their gut microbiota, notably decreased lactobacillus and increased Akkermansia (53). Further research transplanted feces from chronic social defeat stress mice and control mice into ABX-treated recipient mice and discovered that the anhedonia-like phenotype observed in ABX-treated mice after FMT might be associated with two specific microorganisms, Lactobacillus intestinalis and Lactobacillus reuteri (54). And, subdiaphragmatic vagotomy significantly reversed these behavioral and biochemical abnormalities, revealing the role of the gut-brain-microbiome axis in the pathogenesis of depression via the subdiaphragmatic vagus nerve.

The specific ABX regimen precipitates depressive behaviors by altering the gut microbiota. Moreover, ABX-induced depressed mice exhibited notable differences in the abundance of gut microbiota, neurobiological factors, and functional gene abundance (55). ABX mixtures caused depression-like behavior in mice. FMT from antibiotic-induced depressed mice to normal mice resulted in the development of depression-like behavior, along with significantly reduced levels of norepinephrine, 5-HT, and BDNF in the hippocampus and PFC tissues (55). Those with ABX-induced depressive behavior exhibited reduced gut microbial diversity, activated taurine pathway, and increased abundance of functional gene lipA. Remarkably, ABX-induced depletion of donor microbiota has significant implications for the development of behavioral, biochemical, and other depressive phenotypes induced by FMT in recipient mice.

Sigma receptors are classified into two subtypes, including Sigma-1 and Sigma-2 (72). The Sigma-1 receptor (Sig-1R), a 28 kD molecular chaperone protein, is pivotal in regulating various cellular processes including intracellular calcium homeostasis, apoptosis, and cell membrane permeability (73). Its role in influencing neuronal survival and function has attracted considerable attention as a potential therapeutic target for central nervous system diseases (74). Li et al. discovered that Sig-1R KO mice exhibited depression-like behavior and gut microbiota disorder, while the depressive behavior was improved after the removal of gut microbiota through ABX treatment (75). After FMT of the Sig-1R KO group into recipient mice, the mice exhibited depression-like behavior, along with a significant decrease in the diversity and abundance of the gut microbiota, specifically Alistipes, Alloprevotella, and Lleibacterium. In addition, the cAMP/CREB/BDNF signaling pathway was inhibited, while the expression of CTNF, TGF-α and NGF was decreased. The results revealed that the gut microbiota from Sig-1R KO mice induced depression-like behavior by modulating the cAMP/CREB/BDNF signaling pathway, and furnished supportive evidence for subsequent investigations into the brain-gut axis.

The inflammasome regulates immune and inflammatory responses in the gut axis of the brain, influencing the synthesis and release of neurotransmitters, which in turn affects neural activity and emotional states in the brain (76–78). The NLRP3 inflammasome is a complex comprising Nucleotide-binding and oligomerization domain, Leucine-rich repeat, and Pyrin, and is involved in multiple diseases (79–81). NLRP3 could be located intracellularly in neurons, astrocytes, and microglia (82). Upon activation, it initiates an intracellular signaling cascade aimed at reinstating homeostasis (83). Given the critical role of NLRP3 in gut-immune-brain communication, deciphering the role and dysfunction of NLRP3 is crucial for depression (83). Zhang et al. transplanted the fecal microbiota of NLRP3 KO mice into chronic unpredictable stress (CUS) mice (84). Depression-like behaviors of the mice were significantly improved after FMT, accompanied by alleviated astrocyte dysfunction. In addition, FMT suppressed the elevation of circHIPK2 levels in CUS mice. The gut microbiota of NLRP3 KO mice regulated astrocyte dysfunction via circHIPK2, attenuating depressive-like behaviors and providing a novel strategy for the treatment of depression.

In ABX-treated rats that received FMT of CUMS, Huang et al. discovered that inflammasomes and inflammatory cytokines IL-1β and IL-18 were increased, and tight junction proteins Occludin and ZO-1 were decreased (85). Furthermore, in recipient rats, the relative abundance of actinobacteria, proteobacteria, patescibacteria, Lactobacillaceae, and erysipelotrichichaceae was highly upregulated while that of lachnospiraceae was significantly downregulated. The microbiota composition was partially overlapped with that of donor rats. Collectively, modulating the gut microbiota composition mitigated inflammation and depressive symptoms by reshaping the microbiota and inhibiting NLRP3 inflammasome activation.

Plant polysaccharide (OP) is a kind of OP extracted from plants, especially from Chinese herbs. Common plant OP includes ginkgo biloba OP, okra OP, yellow extract OP, ginseng OP, bupleurum OP, and so on (87). The OP has various biological functions, such as improving immune function, anti-oxidation, anti-virus, and regulating intestinal microecology (88). In recent years, studies have shown that OP from different sources plays an important role in the regulation of gut microbiota, which can significantly affect the occurrence of depression-like behaviors by regulating gut microbiota and related pathways.

Treatment with Ginkgo biloba leaves (GPS) was shown to reverse the reduction in serotonin-positive and dopamine-positive cell density induced by unpredictable chronic mild stress mice, thereby improving depressive-like behavior (89). The antidepressant effects of GPS OP were likely mediated through its regulation of gut microbiota imbalances associated with depression and an increase in lactic acid bacteria abundance, particularly Lactobacillus reuteri. The isolated OP from okra (Abelmoschus esculentus (L) Moench) possesses the capability to hinder the activation of the inflammatory response in the colon, serum, hippocampus, and BV2 cells (90). Additionally, OP could regulate dysbiosis in gut microbiota, alterations in short-chain fatty acids, down-regulation of the TLR4/NF-κB pathway, and enhancement of MAPK signaling. Transplantation of OP-modulated microbiota into CUMS receptor mice alleviated depression and anxiety, reduced elevated cytokine levels (TNF-α, IL-1β, IL-6, etc.), and restored histopathological damage in the colon. OP exhibited antidepressant effects through its anti-inflammatory properties and modulation of the gut microbiota. The underlying mechanism of OP for antidepressant-like effects was closely associated with bidirectional communication within the microbiota-gut-brain axis through the regulation of inflammatory responses. Additionally, novel agar-oligosaccharides (NAOs) treatment significantly improved depressive symptoms in chronic restraint stress (CRS) mice, decreasing IL-18 levels in serum, increasing 5-HT levels in serum and brain, and elevating BDNF levels (91). Thus, NAOs exerted an antidepressant effect by raising levels of serotonin and BDNF in the brains of mice and by reorganizing the gut microbiota. FMT from polysaccharide peptide (PSP)-treated mice to CUMS subjects ameliorated depressive behaviors via hypothalamic-pituitary-adrenal (HPA) axis modulation (92). Post-FMT, increased 5-HT, norepinephrine, ZO-1, and occludin, and decreased hippocampal pro-inflammatory cytokines, corticosterone, LPS, and interferon-γ were observed. In summary, PSP administration exerted antidepressant effects through the MGB axis by modulating PI3K/AKT/TLR4/NF-κB and ERK/CREB/BDNF pathways.

XCHT, as an effective treatment for depression, is composed of seven herbal extracts bupleurum, Spinelli, Scutellaria, jujube, ginseng, ginger, and licorice (93). Early investigations suggest that XCHT exhibits potential antidepressant properties by modulating immune responses, inhibiting angiogenesis, and inducing apoptosis in tumor cells (94). To examine the impact of XCHT on tumors associated with depression, Shao et al. implemented a xenograft colorectal cancer mouse model exposed to CRS (95). Transplantations of XCHT-regulated microbiota into CRS-associated xenografted mice showed that XCHT treatment regulated the gut microbiota, inhibited activation of the TLR4/MyD88/NF-κB signaling pathway, and regulated inflammatory cytokine levels, resulting in significant anti-tumor effects in vivo. Moreover, XCHT partially ameliorated disruptions in the gut microbiota and depressive symptoms in cancer patients by reducing the abundance of bacteria in the families Parabacteroides, Blautia, and Ruminococcaceae bacterium. As a result, XCHT exerted antitumor activity by inhibiting the TLR4/MyD88/NF-κB signaling pathway through the regulation of the gut microbiota. Gut microbiota might be potentially a novel target for XCHT in the treatment of comorbid depression in anticancer therapies.

Fermented red ginseng (fRG) undergoes processing that alters its chemical composition, potentially augmenting the concentration of active compounds and yielding novel bioactive metabolites (96) (97). In contrast to conventional red ginseng (RG), fRG exhibits enhanced pharmacological properties, offering promising prospects for augmenting immune function, enhancing energy levels, ameliorating cognitive function, and fostering overall health and well-being. FRG has been shown to mitigate hippocampal neuronal damage in mice and modulate the function of the HPA axis, thereby exerting an antidepressant effect. Shin et al. created mouse models of anxiety/depression (AD) and colitis by subjecting them to chronic immobilization stress or FMT from individuals with ulcerative colitis and depression (98). Oral administration of fRG or RG attenuated hippocampal and hypothalamic expression, and serum corticosterone levels induced by unpredictable chronic mild stress. Similarly, oral ingestion of fRG, RG, ginsenoside Rd, or compound K mitigated stress-induced AD-like behaviors, circulating IL-6 and corticosterone, colonic IL-6 and TNF-α levels, and dysbiosis of the gut microbiota.

Additionally, ZZCD, consisting of Gardenia jasminoides J. Ellis and Glycine max (L.) Merr is also extensively utilized for addressing anxiety and depression (99). Tian et al. used corticosterone combined with chronic constraint stress to establish the model of anxiety and depression, and transplanted fecal intestinal flora of the ZZCD group into anxious and depressed mice (100). ZZCD exerted an influence on and participated in the neuroactive ligand/receptor interaction process, regulated the HPA axis, influenced the secretion of prolactin and estrogen, interfered with MAPK and TNF signaling pathways, and reduced inflammation levels, thus contributing to inhibiting anxiety and depression.