Gut bacteria: protective mediators, pathogenic contributors and novel therapeutic targets in Candida albicans infections
- Open Access
- 01.12.2025
- Review
Erschienen in:
Abstract
Introduction
The term “gut microorganisms” encompasses a diverse range of organisms that inhabit the human gut, including bacteria, archaea, fungi, and viruses. Collectively, these organisms constitute the human gut microbiota, and their presence has been linked to numerous crucial physiological processes, including immunity, metabolism, digestion, and nutrient absorption [1]. The gut microbial community is so vast that it has been designated the “second genome” of humans [2]. Among these microorganisms, bacteria are the most abundant and significant, representing more than 90% of the human microbiome. A majority of these bacteria belong to four phyla: thick-walled bacteria, Bacteroidetes, Actinobacteria and Ascomycetes [3]. Owing to the relatively limited diversity of human gut fungal communities in comparison with their bacterial counterparts, there is compelling evidence that gut fungi exert a substantial influence on human health [4, 5]. Characterization of the intestinal fungal community (comprising fungi and their genomes) in healthy populations revealed the existence of 66 genera and 184 species of intestinal fungi, with Candida identified as the dominant genus [6]. Intestinal fungi can collaborate with the host immune system to sustain intestinal well-being by regulating the equilibrium of the intestinal microbiota [7, 8]. Nevertheless, when the intestinal microbiota is disordered or the immune system is impaired, intestinal fungi may proliferate excessively, resulting in the development of intestinal disorders. Furthermore, intestinal fungi may gain access to the bloodstream from the gastrointestinal tract, resulting in potentially life-threatening infections [9‐11], such as invasive candidiasis [12], which can be caused by several species of Candida, with Candida albicans as the pathogen in a majority of cases [13].
Candida albicans is a fungus that can exist in a symbiotic relationship with the human body in a healthy state, but can also cause pathological infections. It is an opportunistic fungus that is commonly found in the oral cavity, digestive tract, and reproductive tract, among other locations [14]. However, under certain circumstances, such as immune system impairment, intestinal mucosal barrier damage, and antibiotic-induced disruption of the gut microbiome, it can become pathogenic (Fig. 1). Candida albicans is a dimorphic fungus that has the capacity to grow in either yeast or hyphal form [15, 16]. The morphological plasticity of Candida albicans plays a vital role in determining its virulence [16]. Moreover, the hyphal form is a key factor in the pathogenesis of Candida albicans infection. This finding is further supported by evidence that one of the antifungal mechanisms of azoles is to force the fungus to transition from the hyphal form to the yeast form, which prevents the spread of infection [17]. However, owing to technical constraints, it was not feasible to directly observe the morphological transformation process occurring in Candida albicans during infection. A team employed a transparent zebrafish infection model to gain a more comprehensive understanding of the manner in which Candida albicans utilizes morphological transitions for the purposes of transmission and invasion. The findings of this study support the hypothesis that the yeast form plays a specific role in the transmission process and indicate that the hyphal form is a key factor in the invasion of tissue and the development of disease [18]. Notably, Witchley, Penumetcha and colleagues demonstrated that it is not the hyphal form of Candida albicans itself that causes infection but rather the expression of hypha-specific virulence factors that mediate infection [14]. In 2016, David L. Moyes identified the first cytolytic peptide toxin in Candida albicans and named it ‘candidalysin’ [19]. The secreted candidalysin triggers a series of signaling pathways, including the activation of calcium channels and the release of intracellular signaling molecules, by binding to specific receptors on the host cell membrane. These signals lead to disruption of the cell membrane and alteration of intracellular structures, ultimately resulting in cell death or injury. Furthermore, candidalysin has been demonstrated to initiate an inflammatory response in host immune cells, thereby exacerbating cellular damage.
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Fig. 1
Changes in the gut microbiome under stress. This figure shows the changes that occur in the gut microbiome under prolonged treatment with antibiotics or immunosuppressants or in individuals with a compromised immune system, including a decrease in the abundance of some probiotic bacteria, an increase in the abundance of some opportunistic pathogens/pathogenic bacteria, and the proliferation and morphological transformation of fungi, specifically Candida albicans (created at https://BioRender.com)
This review focuses on the mechanisms by which the intestinal microbiota affects the invasiveness of Candida albicans. In addition, it describes the role of the immune system in intestinal microecology, with an emphasis on the impact of antibiotics on the intestinal microbiota. In conjunction with current microecological therapies, we also summarize information on the efficacy of probiotics, prebiotics, dietary interventions and FMT in the treatment of Candida albicans infections. These findings may provide new approaches for the prevention of Candida albicans infections of intestinal origin and provide theoretical foundations and practical guidance for the development of more effective microecological therapeutic strategies in the future.
Interaction between gut bacteria and Candida albicans
Bacteroides and clostridium
Among the gut bacteria, Bacteroides and Clostridium are genera of short-chain fatty acid-producing bacteria that play key roles in maintaining intestinal mucosal barrier integrity and immune function. Their role in regulating intestinal barrier function and providing immune protection is mainly based on the short-chain fatty acids (SCFAs) they produce, such as acetic acid, propionic acid, and butyric acid. SCFAs are mainly metabolites produced during the bacterial fermentation of dietary fiber in the intestinal tract, and are also the most important components for maintaining the integrity of the intestinal barrier [20]. The Mediterranean diet, which involves consuming large amounts of fiber-rich plant foods, olive oil, and seafood, while reducing intake of red meat and sweets, can promote the production of propionate and butyrate by gut bacteria to maintain the integrity of the intestinal barrier [21]. SCFAs also regulate intestinal barrier function and maintain intestinal homeostasis by promoting the production of antimicrobial peptides, mucus and other beneficial substances by intestinal epithelial cells [22]. SCFAs regulate the function of immune cells to participate in the immune system [23]. They regulate mucosal and systemic immunity by inducing different cellular signals that target different signal receptors on immune cells [24].
Assuming that certain methods are used to disrupt the Bacteroides and Clostridium communities, this may result in a reduction in intestinal SCFAs production, leading to colonization and infection by pathogenic bacteria. Jack Guinan et al [25]. employed antibiotic treatment to disrupt the intestinal community, which resulted in a decrease in SCFAs levels in the intestines of mice, along with an increase in colonization by Candida albicans. To clarify whether the increase in Candida albicans colonization was related to the decrease in SCFAs levels in vivo, the in vivo intestinal SCFAs concentrations were further used in experiments with Candida albicans in vitro, and the results demonstrated that SCFAs inhibited Candida albicans growth and budding tube, hypha and biofilm formation in vitro. That is, the antibiotic-induced decrease in SCFAs levels in the cecum enhanced Candida albicans growth and colonization of the gastrointestinal tract.
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Bacteroides
Bacteroides is a member of a group of opportunistic pathogens that, when normally distributed in the intestine, has the potential to exert beneficial effects, such as by antagonizing the virulence and growth of Candida albicans [26]. However, the exact mechanism remains unclear. HIF-1α is a key transcription factor that regulates mammalian innate immune defense, whereas LL37-CRAMP is an antimicrobial peptide that plays an important role in maintaining mammalian immune defense. Di Fan et al [27]. reported that Bacteroides thetaiotaomicron significantly increased the expression of HIF-1α and LL37-CRAMP, key determinants of Candida albicans colonization resistance, in the mouse colon. Thus, the modulation of gastrointestinal colonization by Candida albicans through the activation of intestinal mucosal immune effectors may provide a novel therapeutic approach for the prevention of invasive fungal diseases in humans.
Clostridium difficile
C. difficile is a gram-positive anaerobic bacterium, and the symptoms of C. difficile infection are markedly heterogeneous, ranging from mild diarrhea and severe colitis to death. FMT is currently the only effective and approved treatment for C. difficile infection. Nevertheless, Candida albicans markedly diminishes the efficacy of FMT, which can be restored through antifungal therapy [28]. In contrast, mice that had been precolonized with Candida albicans presented elevated levels of IL-17 A after C. difficile infection, thereby enhancing the protective immune response. This may be related to alterations in the intestinal microecosystem caused by Candida albicans colonization [29]. This is the first study to investigate the interaction between Candida albicans and C. difficile [30]: C. difficile can produce a secretion, p-Cresol, which inhibits the yeast‒hyphal morphology transition of Candida albicans on the one hand and biofilm formation by Candida albicans on the other hand. However, the experiment was conducted in vitro and did not consider the influence of the entire microecological environment. Consequently, further in vivo experiments are needed to improve the credibility of the findings.
Lactobacillus family
The Lactobacillus family of intestinal bacteria primarily comprises the genera Lactobacillus and Bifidobacterium. These genera play an important role in the maintenance of intestinal health and human health; maintaining a balanced gut microbiome, consuming foods rich in lactobacilli or supplementation with lactobacillus preparations can improve intestinal function and enhance immunity.
Lactobacillus
Multiple studies have shown that Lactobacillus species can inhibit the invasive effects of Candida albicans in the oral cavity, intestines, or vagina [31‐35]. Different species of Lactobacillus may have different mechanisms for inhibiting the growth of Candida albicans, and the specific possible mechanisms can be categorized as follows: ① Lactobacillus species produce lactic acid by metabolizing carbohydrates, forming an acidic intestinal microecological environment, which in turn inhibits the growth of Candida albicans hyphae [36]; ② Lactobacillus species inhibit the growth of Candida albicans by suppressing biofilm formation and regulating related gene expression in Candida albicans [31]; ③ lactic acid produced by Lactobacillus can penetrate into Candida albicans cells, interfering with cell metabolism and thus inhibiting the growth of Candida albicans [34]; ④ Lactobacillus can competitively bind to host surfaces with Candida albicans, preventing adhesive colonization by Candida albicans; ⑤ Lactobacillus species may protect epithelial cells from fungal damage by a mechanism that induces mycelial shedding of Candida albicans [35]; ⑥ Lactobacillus species can induce cell wall degradation directly with Candida albicans through enzymatic action, restoring the microbial balance of the gut and alleviating the symptoms of enteritis by reducing the levels of inflammatory factors, enhancing the anti-inflammatory cytokine response and promoting the elimination of fungi [37]. Catabolism of tryptophan by Lactobacillus brevis produces an aromatic hydrocarbon receptor ligand, indole aldehyde, which in turn increases AhR-dependent IL22 transcription and stimulates IL22 production by mucosal cells, thereby maintaining the symbiotic relationship between the gut microbiome and the host, and influencing the host’s immune response to Candida albicans, providing colonization resistance to Candida albicans [38]. Rather than opting for direct coculture to exclude competitive effects (competition for ecological niches, nutrition, etc.) and physical interactions (adhesion, phagocytosis, etc.) between the two microorganisms, the effects on Candida albicans biofilms have been investigated by using Lactobacillus supernatants and cell suspensions, respectively, in a study by Victor Haruo Matsubara et al [31]. However, although this approach can avoid interference caused by coculture, it may not be able to effectively simulate the ecological niche relationship between the two microorganisms in vivo. Many studies on the interactions between enteric bacteria and Candida albicans have similarly focused more on in vitro experiments, and the conclusions obtained need to be validated to further explore the interactions between the two microorganisms occurring in vivo in greater depth.
Bifidobacterium
Bifidobacterium bifidum is now a commonly used probiotic lactobacillus and a common intestinal commensal. Bifidobacterium has been demonstrated to inhibit the growth of Candida albicans [39]. Furthermore, fermentation acids (FAs), including acetate and lactate, in the supernatant of Bifidobacterium cultures have been identified as key inhibitory agents. The concentration of these compounds was positively correlated with the inhibition of Candida albicans growth, whereas the ambient pH was negatively correlated with the inhibition of Candida albicans growth. These findings suggest that both ambient pH and FAs have combined effects on the inhibition of Candida albicans growth. There is a paucity of research exploring the interaction between Bifidobacterium and Candida albicans. Despite its prevalence and safety as a probiotic ingredient, the mechanism underlying the interaction between these two entities remains poorly understood, impeding the precise treatment of associated conditions.
Enterococcus faecalis
Enterococcus faecalis and Candida albicans have antagonistic effects on each other’s pathogenicity, probably because they occupy the same ecological niche in the gut. Specifically, the antagonism of Candida albicans virulence by Enterococcus faecalis occurs via the inhibition of Candida albicans mycelial morphogenesis, a step that is essential for the pathogenicity of Candida albicans. Enterococcus faecalis can produce an anticandida protein (ACP) [40], which may prove to be a promising anticandida agent. This inhibitory effect was found to be partially dependent on the Fsr population-sensing system, a key regulator of Enterococcus faecalis virulence. Two of the Fsr-regulated proteases, GelE and SerE, were partially required for the inhibitory effect [41] Enterococcus faecalis also produces a bacteriocin, EntV, containing 68 amino acids. EntV was found to significantly inhibit Candida albicans mycelial morphogenesis and biofilm formation and attenuate its pathogenicity in a mouse model of oral mucosal infection [42], and its activity requires cleavage by the protease GelE and disulfide bond formation by the thioredoxin DsbA [43]. These authors subsequently analyzed the structure of EntV and reported that a 12 amino acid EntV-derived peptide could still maintain good antifungal activity [44]. Akshaya Lakshmi Krishnamoorthy et al [45]. described the interaction between Enterococcus faecalis and Candida albicans on the surface of the oral mucosa for the first time. These findings revealed that mixed-species biofilms formed by Enterococcus faecalis and Candida albicans increase the invasive capacity of mucosal tissues. The capacity of mucosal tissues is expanded, the number and distribution of both are increased in the biofilm, and Candida albicans-related mycelial transformation, biofilm formation, adhesion and invasion are upregulated. Conversely, Enterococcus faecalis-related biofilm formation and invasion was downregulated (Fig. 2).
Fig. 2
Interaction between gut bacteria and Candida albicans. Red arrows indicate promotion, and green arrows indicate inhibition. Bacteroides species enhance the immune defense of the intestinal mucosa by promoting the colonic expression of HIF-1α and IL37-CRAMP, which in turn inhibit the growth of Candida albicans. Lactobacillus catabolicus breaks down tryptophan to produce indole aldehydes to increase immune defenses and thus inhibit the growth of Candida albicans. Bifidobacterium species inhibit the growth of Candida albicans by producing fermentation acids. Enterococcus faecalis inhibits Candida albicans growth by producing Entv, which inhibits Candida albicans hypha and biofilm formation. Clostridium difficile inhibits the yeast‒hypha morphological transition and biofilm formation of Candida albicans through the production of p-Cresol, which in turn inhibits Candida albicans growth (created at https://BioRender.com)
Effects of antibiotics on the gut microbiota
The discovery of penicillin by Alexander Fleming in 1928 provided a powerful weapon for human beings to fight infectious diseases. In recent years, the abuse of antibiotics has led to increasing drug resistance. In addition, the use of antibiotics could lead to fungal overgrowth [46, 47], which may cause serious fungal infections. Antibiotic treatment was reported to cause intestinal overgrowth of Candida albicans since the 1960 s [48, 49], possibly because antibiotic exposure leads to disorder of the gut bacterial community, which affects the interactions between Candida albicans and gut bacteria. Subsequently, Rachel Nettles et al. analyzed variations in the gut microbiome of mice following antibiotic treatment and reported alterations in the structure, diversity and abundance of gut bacteria and fungi as well as a partial correlation between the variations in bacteria and fungi [50]. Alterations in the metabolome and microbiome induced by the broad-spectrum antibiotic cefoperazone favors the growth and morphogenesis of Candida albicans and may play an important role in gastrointestinal colonization by Candida albicans [51].
SCFAs produced by gut microbial fermentation have protective effects against Candida infection by promoting the production of Foxp3 + regulatory cells (Tregs) and Th17 cells [52]; however, antibiotic treatment leads to a decrease in the production of Foxp3 + regulatory cells (Tregs) and IL-17 A, making it difficult for SCFAs to exert a protective effect during antibiotic treatment. Research on the cause for the reduction in Treg and IL-17 A levels could determine whether antibiotic treatment could serve as a new therapeutic strategy against Candida albicans infection.
Cyr1p, the adenylate cyclase of Candida albicans, is an essential component of the cAMP/protein kinase A (PKA) pathway, and activation of this enzyme triggers the expression of hypha-specific genes, which are critical for the invasiveness and virulence of Candida albicans [53, 54]. A team has identified numerous purified and synthetic cytosolic acyl dipeptides (MDPs), which are subunits of peptidoglycan (PGN), that promote the growth of Candida albicans hyphae. These MDPs are similar to the mammalian sensors Nod1 and Nod2, which recognize PGN through the leucine-rich repeat (LRR) domain. They activate Cyr1p by binding directly to its LRR domain, which in turn triggers mycelium-specific gene expression [55]. The gut is a natural habitat and invasion site for Candida albicans, and given that the gut is rich in PGN, the results of this study have important implications for further understanding the mechanisms of Candida albicans infection. In 2021, it was proposed that the application of β-lactam antibiotics triggers the release of large amounts of PGN subunits from bacteria, generating a PGN storm, which induces hyphal growth and the systemic spread of Candida albicans [56].
At the clinical level, the use of antibiotics is inevitable, so the necessary considerations must be taken to reduce their harm. The use of probiotics with potential antifungal activity or their metabolites prior to the application of antibiotics may play a role in preventing antibiotic-induced fungal infections.
Relationship between the immune system and gut microbiota disorders
Impact of the immune response on the gut microbiota
The immune response affects the gut microbiota in several ways, most notably through the inflammatory response and the production of cytokines and antibodies. The inflammatory response is a normal defense mechanism of the body and helps the body defend itself against pathogens and other stress factors; however, when the inflammatory response is too intense, it can trigger an inflammatory storm in the body and cause severe damage to the body. In inflammatory bowel disease, the inflammatory response in the gut weakens the intestinal barrier and increases intestinal permeability, triggering translocation of the gut microbiome and causing intestinal dysbiosis [57]. The intestinal tract, as the body’s largest immune organ, accounts for 70%−80% of immune cells. When pathogenic bacteria invade, immune cells produce cytokines, antibodies, etc., to help the body combat external threats [58].
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Relationship between immunological diseases and disorders of the gut microbiota
Immunity and the gut microbiota are complementary and dynamically balanced, and when one is out of balance, scales can tip, and immune-related diseases can occur. Current immune disorders that are clearly linked to the gut microbiota include inflammatory bowel disease, irritable bowel syndrome and colorectal cancer [57, 59]. In addition to bowel diseases, a wide range of extraintestinal diseases, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, have been covered [60‐62]. Most studies on the gut microbiota and immune-related diseases have focused on correlational analysis, but the causal relationship between them is not clear, which may be due to the limitations of research tools and the heterogeneity of the population’s gut microbiota. In the future, more attention should be given to exploring their causal relationship with a view to developing therapeutic measures on the basis of gut microecology.
Link between immunity and Candida albicans susceptibility
The immune system plays a central role in defending against Candida albicans infections, maintaining the body’s defence capabilities through both direct and indirect actions. Macrophages play a key role in the direct immune response. Not only can they directly phagocytose Candida albicans, but they can also activate the adaptive immune system through antigen presentation and further regulate the immune response by secreting cytokines, promoting T cell activation and proliferation [63]. Macrophages can change into different types. M1-type macrophages are especially good at fighting off Candida albicans infections. They do this by activating the NF-κB pathway to get rid of the infection [64]. However, IL-1Ra released by macrophages inhibits early neutrophil recruitment. Neutralising IL-1Ra may restore neutrophil function and correct the hyperinflammatory state. Conversely, increasing IL-1Ra secretion (e.g. through IFN-I) increases susceptibility to invasive candidiasis and mortality [65]. In addition, the activation status and exhaustion level of macrophages have also been found to be closely related to susceptibility to secondary fungal infections and their outcomes [66]. Neutrophils are important effector cells in the frontline defence against Candida albicans, responsible for directly killing pathogens [67]. They effectively eliminate Candida albicans by producing reactive oxygen species (ROS) and releasing antimicrobial peptides [68]. A key killing mechanism is the formation of neutrophil extracellular trap nets (NETs) to capture and kill fungi [69]. In Candida infections, NETs formation depends on oxidative stress and the activation of intracellular calcium signals [70]. It is worth noting that hematopoietic stem cells and progenitor cells stimulated by Candida albicans can generate ‘trained’ neutrophils with stronger mitochondrial ROS production capabilities, enhancing their defensive capabilities [71]. However, excessive NETs formation can lead to tissue damage and exacerbated inflammatory responses, so maintaining an appropriate balance of NETs formation is critical for host immune homeostasis [70]. The recruitment and function of neutrophils are also regulated by other immune cells and signaling pathways. For example, CCR5-mediated recruitment of NK cells to sites of infection (such as the kidneys) is essential for neutrophils to exert their optimal antimicrobial activity [72].
In recent years, the role of the gut microbiota and its metabolites in regulating the body’s defence against Candida albicans has received increasing attention. For example, tryptophan metabolites can directly regulate group 3 innate lymphoid cells (ILC3) in the colonic lamina propria, or indirectly regulate ILC3 secretion of IL-22 by affecting the intestinal microbiota, thereby enhancing the intestine’s resistance to Candida albicans invasion and barrier protection capacity [73]. Conversely, the use of antibiotics significantly disrupts this protective mechanism. Long-term exposure to antibiotics disrupts the structure and diversity of the gut microbiota, reduces IL-17 A levels, and impairs lymphocyte-dependent antifungal immunity (including IL-17 A- and GM-CSF-mediated pathways), thereby significantly increasing the host’s susceptibility to invasive candidiasis [74, 75]. FMT experiments have confirmed that restoring the intestinal microbiota can enhance IL-17 A production and restore protection against invasive candidiasis [76].
In addition, other factors and pathways also profoundly influence host susceptibility. The innate immune receptor MDA5 has been shown to enhance host susceptibility to invasive Candida albicans infection by promoting macrophage and renal cell apoptosis (regulating Noxa, Bcl2, and Bax expression) and inhibiting macrophage killing capacity (reducing iNOS expression), making it a potential therapeutic target [77]. Environmental factors such as smoking can damage the oral mucosal defence response by inducing Nrf2 negative regulation of NLRP3 inflammasomes, thereby increasing oral susceptibility to Candida albicans [78].
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Microbiome-based therapies
Probiotics
Probiotics are a group of microorganisms that are beneficial to the human body. They are commonly used to regulate the balance of the gut microbiome and exert a positive influence on human intestinal health via effects on the host immune system [79, 80]. Contrary to the previous understanding, probiotics are not exclusively bacteria; an increasing number of fungi are now recognized as having a role in regulating the gut microbiome [81]. The most commonly utilized bacterial probiotics are Lactobacillus and Bifidobacterium species. They are employed to facilitate the treatment of Candida albicans infections, which include vaginal candidiasis and oral candidiasis [82‐86]. The use of these treatments for candidiasis in the gastrointestinal tract has not been extensively investigated. In 2021, a research team discovered that a Lactobacillus mixture functioned as a fungicide by inducing macrophages to orient toward a phenotype characterized by a c-type lectin receptor. This process controls gastrointestinal candidiasis while preserving gastrointestinal tract integrity by modulating the microbiota and inflammation [87]. The main fungal probiotic commonly used today is Saccharomyces cerevisiae [88], which not only induces coaggregation of Candida, thereby inhibiting its adhesion to epithelial cells, but also inhibits some of the major virulence factors of Candida albicans. These include the ability to switch from the yeast to the hyphal form and the ability to express several aspartic proteases. The result of this is accelerated fungal clearance, which in turn shortens the course of candidiasis [89]. Clinical screening of probiotics is highly important, as it ensures their safety and efficacy, and contributes evidence from subsequent human-based clinical studies. Assessing the risks and benefits for patients and developing individualized protocols for probiotic use are particularly important.
Prebiotics
Prebiotics are defined as substrates that confer health benefits when utilized by host microorganisms in a selective manner [90]. They not only promote the growth of probiotics in the human gut but also stimulate the immune system. The most commonly studied prebiotics include oligofructose (FOS), galacto-oligosaccharides (GOS), isomaltose (IMO), oligo-xylulose (XOS) and lactoferrin [91‐93]. Lactoferrin, a defense protein of the innate immune system, increases resistance to Candida albicans by inhibiting the metabolic activity of its biofilm and the transition from the yeast to hyphal form [94]. GOS can help protect against infections caused by Candida albicans by enhancing the effect of Lactobacillus plantarum in the laboratory. This makes GOS a promising prebiotic [95]. In addition to the use of prebiotics alone, an increasing number of studies have employed a combination of prebiotics and probiotics to intervene in Candida albicans infections. The combined use of prebiotics and probiotics may produce a synergistic effect, which is effective in reducing the incidence and recurrence of Candida infections by optimizing the intestinal microecology and enhancing immune functions. Probiotics and inulin-based fructan synthesis have been found to significantly inhibit the growth and biofilm formation of clinically isolated Candida albicans [96, 97]. Although preliminary studies have suggested that prebiotics show great potential in the resistance to Candida albicans infections, more mechanistic studies and clinical trials are needed to validate their safety and efficacy.
Dietary interventions
The human intestinal microbiome is not fixed, and its composition is influenced by a variety of factors, including age, environment, diet, and the immune response. Dietary interventions are a relatively gentle means of altering the microbiota, with some dietary components maintaining a healthy disease-fighting microbiota and others leading to microbiota imbalances that compromise gut barrier function and immunity [98]. In the context of Candida albicans infections, there is a long-standing association between carbohydrate diets and strong intestinal colonization by Candida albicans [99, 100]; in contrast, coconut oil [101], sodium houttuyfonate derived from Houttuynia cordata Thunb [102], capric acid and caprylic acid [103], and medium-chain triglycerides [104] have all been shown to be effective in reducing Candida albicans colonization in the gut. Dietary interventions mostly exert anti-infective effects by directly or indirectly affecting the microbial community, and there is potential to use dietary interventions as complementary interventions for Candida albicans infections in future studies.
Fecal microbiota transplantation
FMT is a procedure whereby the feces of a healthy individual are transplanted into the intestines of a patient with a disease affecting the gut microbiome, with the aim of restoring the structure of the microbiome and thereby treating the disease. The initial application of FMT in the clinical management of intractable Clostridium difficile infections demonstrated encouraging outcomes. Consequently, an expanding body of research has employed FMT as a therapeutic modality in the treatment of diverse infectious disorders, with a concomitant investigation of the underlying mechanisms. The application of FMT during intestinal Candida albicans infection significantly reduces Candida colonization and further prevents disseminated candidiasis [76, 105]. Although these findings suggest that FMT is a potentially approach for treating Candida albicans infections, the safety and population efficacy assessments need to be further refined.
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Precision fecal microbiota transplantation
Advancements in technology and the uncontrollable factors inherent to FMT have prompted a heightened focus on precision FMT, encompassing the transplantation of bacteria, viruses, fungi, and other active constituents in isolation [106‐108]. Currently, there are two main methods for transplanting bacteria: washed microbiota transplantation and bacterial spore treatment. The former refers to the use of washed fecal microbiota preparations to transplant enriched bacteria and maximize the elimination of bacterial fragments, viruses, fungi, parasite eggs, etc [106].; the latter refers to the purification of nontoxic bacterial spores in capsules. One such preparation is SER-109, a preparation consisting of purified Firmicutes bacterial spores, which has been found to be effective in reducing recurrence rates and improving safety in the treatment of C. difficile infections [109]. Enteroviruses are composed primarily of phages, which play a pivotal role in preserving the stability of the gut microbiome. The process of fecal virome transplantation (FVT) involves the filtration of feces using filters with a pore size smaller than bacterial cells to remove bacteria. This procedure emphasizes the transplantation of the virome via feces [110]. To date, the effectiveness of FVT in the treatment of obesity, diabetes, and Clostridium difficile infection has been suggested, but further research is needed to provide a robust theoretical and practical basis for its use in these contexts. However, a theoretical basis and practical guidance regarding precision fecal transplantation in the treatment of fungal infections are lacking. This may be a fruitful area for future research.
RCT of microecological therapies for fungal infections
Currently, fungal infections, especially Candida albicans infections, are highly endemic. However, the side effects of the long-term use of antifungal drugs are significant, and resistance is becoming increasingly common; thus, we are forced to innovate new strategies for treating fungal infections. Given the increasing number of studies on gut bacterium‒fungus interactions, could microbiome-based therapies be used as new treatments for antifungal infections? We summarize recent relevant randomized controlled studies to better understand this relationship, and hopefully, in the future, it could be used to complement or as an alternative to antifungal treatment.
In 2014, in a double-blind randomized trial, researchers randomized patients wearing oral prostheses into two groups; the probiotic group was treated with a daily blend of probiotic capsules (comprising Lactobacillus rhamnosus HS111, Lactobacillus acidophilus HS101, and Bifidobacterium bifidum) poured onto the palatal surfaces of the maxillary prostheses, whereas the placebo group was treated with the same treatment using placebo capsules. Five weeks later, oral mucosal Candida infection levels were significantly lower in the probiotic group than in the placebo group, suggesting that the mixed probiotic product may be effective in preventing oral mucosal Candida infections [111]. In 2018, a randomized, double-blind, placebo-controlled study was conducted in which women with recurrent vulvovaginal candidiasis were administered capsules of Lactobacillus plantarum P17630 or placebo orally. The results revealed a significant difference in LBG scores on day 0 and day 45. On day 90, there was no improvement in the group that received the placebo, whereas the group that received the probiotic exhibited a significant improvement. Furthermore, the oral probiotic Lactobacillus plantarum P17630 was found to enhance intravaginal acidic lactobacillus colonization (as evidenced by increased vaginal LBG scores) and effectively prevent episodes of vulvovaginal candidiasis [112]. Similarly, in several studies, the use of probiotics to complement antifungal treatment for vaginal candidiasis has provided significant symptomatic relief while reducing the recurrence rate [113‐115] Probiotics alone are not as effective as fluconazole in controlling the recurrence of vaginal candidiasis [116]. At present, clinical trials on the use of probiotics for the treatment of oral, gastrointestinal and vaginal Candida infections have made some progress, but most clinical trials on the use of probiotics in the gastrointestinal tract have focused on the prevention of Candida albicans infections in neonates (Table 1). There is a lack of relevant trials conducted in the remaining population, and since the gut microbiome of neonates is very different from that of adults, more relevant clinical trials in the remaining population are needed to support this view. In addition, there are no population-based randomized controlled trials of the use of FMT for the treatment of Candida albicans infections, which is an important gap to fill, and FMT may have a better chance of becoming an adjunct or alternative to probiotics in the treatment of antifungal infections owing to the greater microecological similarity of feces to the human gut.
Table 1
RCT of probiotics to treat Gastrointestinal fungal infections
Subjects | Sample size | Experimental/control groups | Conclusion |
|---|---|---|---|
Preterm babies born at 32 weeks with a birthweight of 1500 g | 150 for both experimental and control group | Lactobacillus Royale/Mycobacteria | Both groups had comparable efficacy in preventing fungal colonization and invasive candidiasis, and the probiotic group showed significantly lower values than the antifungal group for the septicemia infection rate, feeding intolerance and length of hospital stay [117] |
Children aged 3 months to 12 years admitted to the PICU for up to 18 months and treated with antibiotics for more than 48 h | 344 in the experimental group and 376 in the control group | Probiotic blend (EUGI) - Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Bifidobacterium, Saccharomyces boulardii, Streptococcus thermophilus; 7 consecutive days/no treatment | Children treated with probiotic blends were less likely to develop Candida infections [118] |
Children aged 3 months to 12 years who have been in the PICU and taken antibiotics for at least 48 h | 75 for both the experimental and control groups | Probiotic blend (EUGI) - Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Bifidobacterium, Saccharomyces boulardii, Streptococcus thermophilus; 7 consecutive days/placebo lactose | There was no significant difference in the incidence of candidemia between the two groups, while the probiotic group had a reduced rate of Candida colonization [119] |
Very low birthweight (< 1500 g) preterm babies | 40 for both the experimental and control groups | Breast milk with added probiotics (Lactobacillus rhamnosus) for 6 weeks/only breast milk | The probiotic group exhibited significantly reduced incidence and intensity of intestinal Candida colonization in very-low-birth-weight neonates [120] |
Preterm babies with birthweight < 2500 g and gestational age < 37 weeks | Three groups of 83 | Lactobacillus Royale/Lactobacillus rhamnosus/no treatment | Candida gastrointestinal colonization was significantly lower in the probiotic group than in the control group [121] |
Preterm babies with a gestational age of ≤ 32 weeks and birthweight ≤ 1500 g | 91 in the experimental group and 90 in the control group | Saccharomyces boulardii/mycotoxin | Gastrointestinal fungal colonization did not differ between the two groups, and feeding intolerance, clinical sepsis and septic episodes were significantly lower in the probiotic group than in the mycobacterial group [122] |
Preterm babies < 37 weeks gestation; birthweight < 2,500 g | 56 for both the experimental and control groups | Probiotics/placebo | Probiotics reduced intestinal fungal colonization and invasive fungal sepsis [123] |
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Conclusions
Since 2007, when the Human Microbiome Project (HMP) was initiated at the National Institutes of Health (NIH) in the United States of America, it has greatly contributed to research on the molecular mechanisms of bacterial and fungal interactions. Complex interactions between bacteria and fungi occur in the mammalian gastrointestinal tract, but the exact mechanisms are not yet fully understood. Although the mechanisms of probiotic‒fungal interactions are not yet fully understood, antifungal effects associated with these interactions have been observed in vivo, in vitro and in clinical studies.
FMT is a procedure in which the fecal microbiota of a healthy individual is transferred into a patient with the aim of enhancing the gut microbiome and thereby ameliorating the symptoms of a disease. The core mechanism of FMT, an emerging antifungal strategy, involves the inhibition of the overproliferation of opportunistic fungi (e.g., Candida spp.) by reestablishing the intestinal microecological balance. However, there remain multiple risks associated with the clinical application of this technique: first, there is a possibility of FMT leading to the transmission of drug resistance genes or unscreened pathogens, leading to secondary infections; second, there is a risk of invasive fungal infections or bacteremia being induced in immunosuppressed patients owing to dysbiosis. At present, clinical evidence is largely confined to small-sample studies, and there is a need for validation of standardized donor screening, optimization of mycobacterial preparations and long-term safety. Overall, FMT has theoretical advantages and preliminary practical value in antifungal therapy, but the benefits and potential harms need to be balanced by strict risk management and individualized protocol design.
Upon further consideration, the gut microbiota has been determined to encompass a variety of microorganisms, including but not limited to bacteria, viruses, fungi, and archaea. Consequently, the question arises as to which specific microbial taxa are responsible for the observed effects. In recent years, there has been an increased focus on the potential applicability of precision transplantation in the treatment of disease. For example, the use of washed microbiota transplantation, bacterial spore treatment, and FVT has been demonstrated to have considerable potential in the treatment of certain diseases. Furthermore, these transplantation procedures have the capacity to reduce the risk of infection by diminishing the incidence of unscreened pathogens. However, the fungal community has received minimal attention, and indeed, the development of numerous diseases is associated with alterations in the intestinal fungal microbiome. Moreover, fungi play pivotal roles in the efficacy of FMT.
In the future, more attention should be given to the role of precision fungal transplantation in repairing the intestinal fungal community and adjusting the balance of the gut microbiome to reduce the impact of fungal disorders on the development of diseases and to provide new strategies for treating antifungal infections.
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Acknowledgements
We extend our gratitude to Professor Jun Li for guidance and valuable suggestions in writing this paper. We also appreciate the drawing tools provided by BioRender.
Declarations
Competing interests
The authors declare no competing interests.
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