Essential oils as promising treatments for treating Candida albicans infections: research progress, mechanisms, and clinical applications

Candida albicans: (C. albicans) is a prevalent opportunistic pathogen that can cause severe mucosal and systemic fungal infections, leading to high morbidity and mortality rates. Traditional chemical drug treatments for C. albicans infection have limitations, including the potential for the development of drug resistance. Essential oils, which are secondary metabolites extracted from plants, have gained significant attention due to their antibacterial activity and intestinal regulatory effects. It makes them an ideal focus for eco-friendly antifungal research. This review was aimed to comprehensively evaluate the research progress, mechanisms, and clinical application prospects of essential oils in treating C. albicans infections through their antibacterial and intestinal regulatory effects. We delve into how essential oils exert antibacterial effects against C. albicans infections through these effects and provide a comprehensive analysis of related experimental studies and clinical trials. Additionally, we offer insights into the future application prospects of essential oils in antifungal therapy, aiming to provide new ideas and methods for the development of safer and more effective antifungal drugs. Through a systematic literature review and data analysis, we hope to provide insights supporting the application of essential oils in antifungal therapy while also contributing to the research and development of natural medicines. In the face of increasingly severe fungal infections, essential oils might emerge as a potent method in our arsenal, aiding in the effective protection of human and animal health.


Introduction
Candida albicans (C.albicans) is the most common and important type of Candida, belonging to the yeast genus.Its cells are round or oval in shape, typically ranging between 3 and 5 microns in diameter.It usually exists in the form of yeast and can form mycelium under appropriate conditions.Widely distributed in the natural environment, C. albicans is a common symbiotic fungus that often coexists with humans and animals as part of the normal microbial community (Moran et al., 2011).Infections caused by C. albicans occur when the body's immune system is compromised, resulting in conditions such as oral candidiasis (Millsop and Fazel, 2016;Vila et al., 2020), vaginal candidiasis (Gonçalves et al., 2016;Rodríguez-Cerdeira et al., 2019), skin and nail candidiasis (Jautová et al., 2001 Espinosa-Hernández et al., 2020), and severe systemic fungal infections (Blanco and Garcia, 2008).Factors contributing to infection include a compromised immune system (e.g., HIV/ AIDS, organ transplantation, chemotherapy), antibiotic usage, diabetes, pregnancy, and extended catheter or ventilator use.Oral candidiasis is a prevalent C. albicans infection, especially among young individuals and animals with weakened immune systems.It presents as white patches or spots on the oral mucosa and tongue, accompanied by symptoms like bad breath, loss of appetite, and difficulty eating.Vaginal candidiasis can affect the genitourinary system of animals, leading to symptoms such as urinary tract inflammation, frequent urination, urgency to urinate, hematuria, vaginal inflammation, and mastitis.Symptoms of skin and nail candidiasis may include redness, swelling, itching, desquamation, and ulcers at the affected site, causing discomfort and itching in animals.In some cases, C. albicans infections can progress to blood infections, resulting in severe symptoms like fever, weakness, loss of appetite, anemia, and organ failure, thereby posing a serious threat to the animal's life and health (Miceli et al., 2011).
The main antifungal drugs used for treating infections of C. albicans are as follows: (1) Azole antifungal drugs (Polyazoles): Azole drugs serve as the initial choice for treating the infections caused by C. albicans.Common polyazole drugs such as Fluconazole, Itraconazole, and Posaconazole inhibit growth and replication by disrupting yeast ketones synthesized by the cell wall of C. albicans; (2) Polyene antifungal drugs (Polyketides): Polyenes target the cell membrane of C. albicans, leading to membrane rupture and cell death.Widely used polyene drugs include Neomycin B (Amphotericin B) and the liposomal form Amphotericin B lipid complex (ABLC), typically employed in severe infections of C. albicans; (3) Novel antifungal drugs: In recent years, several novel antifungal agents have emerged to address refractory or drug-resistant infections of C. albicans, including Isaviconazole and Voriconazole, offering a wider spectrum of antifungal activities suitable for complex infections of C. albicans (Kathiravan et al., 2012;Cowen et al., 2015;Houšť et al., 2020).
However, the use of antibiotics pose a number of challenges.The improper and overuse of antibiotics has resulted in an escalation of bacterial resistance to these drugs.Consequently, bacteria that could typically be effectively treated with antibiotics are becoming less sensitive to the drugs, leading to infections that are difficult to cure (Balkis et al., 2002).Antibiotics not only eliminate pathogenic bacteria but also disrupt the natural microbial community within the human body.This disruption can lead to an imbalance in the gut microbiota, heightening the risk of other infections, and may impact the immune system and overall health.Residues of antibiotics enter the environment, including soil and water bodies, exerting adverse effects on ecosystems.These residues may interact with environmental bacteria, fostering the development of drug resistance in bacteria, and potentially causing harmful effects on aquatic organisms and other members of the ecosystem.Therefore, the new environmentally friendly methods which can either substitute or decrease antibiotic usage are necessary.
Essential oil is a secondary metabolite usually extracted from flowers, leaves, roots, fruits, or bark of plants through distillation, cold pressing, or solvent extraction (Valdivieso-Ugarte et al., 2019;Spisni et al., 2020).Based on a strong aroma and active ingredients (Mancianti and Ebani, 2020), it is featured by antibacterial properties that can inhibit or eradicate various microorganisms, including bacteria, fungi, and viruses (Bakkali et al., 2008).The antibacterial efficacy of different essential oils varies, stemming from their unique chemical compositions.Numerous essential oils contain volatile compounds such as phenols, alcohols, esters, aldehydes, and ketones (Dhifi et al., 2016) capable of inhibiting or eradicating microorganisms.In addition, essential oil, as a natural product, is characterized by its safety, efficiency, absence of residue, lack of resistance, good tolerance within the animal body, and minimal toxic side effects, rendering it one of the most promising antibiotic alternatives.Unlike some chemical medications, the antibacterial activity of essential oils is the result of multiple components working together.This complex combination of ingredients makes it difficult for microbes to develop microbial resistance against essential oils, thereby reducing this risk.Beyond their antibacterial effects, some essential oils also offer gut-regulating effects.They aid in balancing intestinal flora, promoting the growth of beneficial bacteria, suppressing harmful bacterial proliferation, and thereby maintaining intestinal health.These attributes hold significant implications for the prevention and treatment of infections and diseases associated with the dysregulation of gut flora.

Antibacterial effect of essential oils
Essential oils typically consist of a variety of aldehydes, phenols, alcohols, and other chemical molecules.They are divided into two categories of compounds: terpenes (such as carvacrol and thymol) and phenylallens (such as cinnamaldehyde and eugenol), with terpenes being the predominant.Essential oil is hydrophobic and can penetrate the cell membrane of Gram-positive bacteria to enter the cell's interior, exerting their antibacterial effect by disrupting enzyme production and protein denaturation (Pandey et al., 2017).Lipid soluble hydrophobic groups, such as hydroxyl and carbonyl groups in the structure of aldehyde phenols in essential oils, can interact with proteins within bacterial cell membranes, leading to structural and functional alterations in the membranes, membrane expansion and increased permeability, thereby eliciting antibacterial effects (Omonijo et al., 2018).The primary phenolic elements in essential oils, carvacrol, and thymol, which are isomers, are pivotal in modulating the balance of intestinal flora by changing the permeability of cell membrane and inhibiting the secretion of bacterial endotoxin.
Essential oils have antifungal properties and can inhibit or kill C. albicans.Ebani et al. studied the antibacterial activity of Litsea cubeba (Lour.)Pers.Essential oil, Origanum vulgare L. subsp.Hirtum essential oil, Origanum majorana L. essential oil, Thymus vulgaris L. essential oil, and their mixtures against pathogenic bacteria and C. albicans.They found that essential oil had different degrees of growth inhibition on the tested strains and C. albicans (Ebani et al., 2016).Hammer et al. found that concentrations of 0.25%-1.0%(v/v) of Melaleuca alternifolia (Maiden and Betche) Cheel oil and its components changed the permeability and fluidity of C. albicans (Hammer et al., 2004).Through a study on the antibacterial activity of M. alternifolia (Maiden and Betche) Cheel essential oil on 81 strains of C. albicans, it was found that the minimum inhibitory concentration for 90% of C. albicans was 0.25% (v/v) (Hammer et al., 1998).D'Auria et al. used Lavandula angustifolia Mill essential oil and its main components to inhibit C. albicans and found that the essential oil and its main components could inhibit the formation of bud tubes and mycelium extension of C. albicans, and had antibacterial and bactericidal activities as well (D'auria et al., 2005).Behmanesh et al. studied the inhibitory effect of L. angustifolia Mill essential oil on C. albicans in vitro and found that after 48 h of cultivation with L. angustifolia Mill essential oil, the number of fungal cells was low, indicating its antifungal effects (Behmanesh et al., 2015).Pinto et al. studied the components of Syzygium aromaticum (L.) Merr.and L.M.Perry essential oil and its antifungal activity and found that the essential oil and its main component eugenol could inhibit the formation of C. albicans bud tubes and had good antifungal activity (Pinto et al., 2009) (Banu et al., 2018).Filipowicz et al. studied the antifungal activity of Juniperus communis L. essential oil and found that it contained the highest concentration of (−)-α-pinene, p-cymene, and β-pinene, which had good antifungal properties.The MIC against C. albicans was 0.3 μg/ mL (Filipowicz et al., 2003).Manoharan et al. studied the antibacterial activity of Cedrus deodara (Roxb.ex D. Don) G. Don essential oil on C. albicans and found that a 0.01% concentration of essential oil could reduce the biofilm formation of C. albicans by 87%.A 0.1% concentration of essential oil could completely stop the biofilm formation, indicating that C. deodara (Roxb.ex D. Don) G. Don essential oil has significant anti-C.albicans biofilm activity (Manoharan et al., 2017).Mahboubi et al. studied the chemical composition and antibacterial activity of Mentha piperita L. essential oil and found that it has a bactericidal effect on C. albicans (MIC = MLC = 0.125 μL/mL) (Mahboubi and Kazempour, 2014).
Essential oils usually contain dozens or even hundreds of chemical components.Their antibacterial activity is closely related to their chemical composition, especially some highly active chemical components.The antibacterial activity of essential oils primarily depends on their chemical functional groups.In 1996, Charai et al. reported that the activity of functional groups in plant essential oils was as follows: phenols (with the highest activity) > alcohols > aldehydes > ketones > esters > hydrocarbons (Charai et al., 1996).In 2003, Kalemba et al. summarized the antibacterial activity of functional groups in plant essential oils based on hundreds of previous studies as follows: phenols > cinnamaldehyde > alcohols > aldehydes = ketones > esters > hydrocarbons (Kalemba and Kunicka, 2003).Additionally, the same plant essential oils may show varying antibacterial and antifungal activities, suggesting that their diverse chemical components present in these oils contribute to different antibacterial and antifungal mechanisms.Table 1 presents essential oils against C. albicans, along with their main components.

Intestinal regulation of essential oils
The normal gut microbiota typically can suppress the proliferation of C. albicans.However, when the body's immune system is compromised, antibiotics are used long-term, a poor diet is followed, or other diseases are present, the balance of gut microbiota may be disrupted.This disruption can result in an overgrowth of C. albicans, leading to conditions like Candida enteritis and related diseases.Several associations between C. albicans overgrowth and gut health issues include: (1) Candida Enteritis: This condition, marked by symptoms such as abdominal pain, diarrhea, indigestion, loss of appetite, weight loss, and inflammation, can negatively impact gut health (Rusu et al., 2020); (2) Leaky gut: Overgrowth of C. albicans may trigger "leaky gut", characterized by damage and increased permeability of the intestinal mucosa, allowing harmful substances such as bacteria and toxins to enter the bloodstream, causing inflammation, immune system dysfunctions, and other health complications (Panpetch et al., 2020); (3) Effects on immune system: The overgrowth of C. albicans might disrupt immune system functions, interfering with immune cell activities and responses, subsequently elevating the risk of infections.Additionally, excessive growth of C. albicans can produce toxins that adversely affect the immune system (Tong and Tang, 2017); (4) Nutrient absorption problems: The overgrowth of C. albicans can impede the normal absorption of the intestine, affecting the nutritional status and overall health of the host (Martins et al., 2014).
Candida albicans infection may lead to an imbalance in the gut microbiota, which refers to a change in the proportion of beneficial and harmful bacteria in the microbiota.Under normal circumstances, the intestinal flora maintains a state of balance, with beneficial bacteria such as Lactobacillus and Bifidobacterium, inhibiting the growth of harmful bacteria, supporting the health of the intestinal mucosa, and providing nutritional support.However, C. albicans infection may result in an increase in harmful bacteria and a decrease in beneficial bacteria, potentially causing an imbalance in the flora.Given that C. albicans infection is a fungal infection, the number of fungi in the gut may increase significantly during infection, negatively impacting the diversity of flora, which signifies the richness and balance of various microorganisms in the flora (Cheng et al., 2023).Infection can cause alterations in the flora and an increase in dominant bacteria, ultimately lowering overall diversity (Wang et al., 2021).Furthermore, C. albicans infection may alter bacterial attachment and adhesion.The fungus can attach to the intestinal mucosa and form biofilms, creating a conducive environment for its growth and reproduction.This process may interfere with the ability of other bacteria to attach and adhere to the intestinal tract.The infection might also influence the intestinal immune system, potentially leading to an abnormal immune response triggering the activation of immune cells and an increase in inflammatory responses, further disrupting the balance of intestinal flora (Zeise et al., 2021).The impacts of C. albicans infection on intestinal flora are shown in Table 2.
Intestinal flora refers to the microbial community in the human digestive system, playing a critical role in human health and immune function.Imbalances in intestinal flora are associated with the occurrence and development of various diseases.Essential oils are believed to contain diverse active ingredients that could potentially influence gut microbiota and health, but further research is necessary to understand these mechanisms.The compounds found in essential oils can act as prebiotics, providing nutrients and a growth-friendly environment for beneficial bacteria.These ingredients can be used by beneficial bacteria in the gut to promote their growth and reproduction.For example, dietary fiber, a common prebiotic, shares similarities with certain components in essential oils such as natural polysaccharides.Kondapalli et al. conducted oral tests of Ocimum sanctum L., Zingiber officinale Roscoe, and Piper nigrum L. essential oil on healthy rats and found that the three essential oils had high prebiotic potential and could promote the growth of beneficial intestinal bacteria (Lactobacillus and Bifidobacterium) (Kondapalli et al., 2022).Babu et al. found that O. sanctum L., Z. officinale Roscoe, and P. nigrum L. extracts contain high concentrations of polyphenols, which have a proliferation effect on some intestinal microbiota and have high probiotic potential (Babu et al., 2018).Phenolic compounds or polyphenols are widely existing secondary metabolites in the plant kingdom, which can maintain the balance of intestinal microorganisms by stimulating the growth of beneficial bacteria (such as Lactobacillus and Bifidobacterium) and inhibiting pathogenic bacteria, and play a prebiotic role, thus contributing to the maintenance of intestinal health (Dueñas et al., 2015).Oligosaccharides in plant extracts have a prebiotic effect and contribute to the growth of Lactobacillus and Bifidobacterium and the inhibition of Bacteroides (Markowiak and Śliżewska, 2017).Leong et al. studied the regulatory effects of Pogostemon cablin (Blanco) Benth essential oil on intestinal microbiota in mice and found that P. cablin (Blanco) Benth essential oil had significant prebiotic-likes effects (Leong et al., 2019).Some of the ingredients in essential oils have antibacterial activity that can inhibit the growth and reproduction of harmful gut bacteria, thereby mitigating their   Hashim et al., 2017).components within essential oils can regulate the acid-base balance of the intestine, influencing microecological environment of the gut.Some beneficial bacteria thrive in acidic environments, while harmful bacteria prefer alkaline environments.By adjusting the pH of the gut, essential oils can create a favorable environment for the growth of beneficial bacteria and inhibit the proliferation of harmful bacteria.Giannenas et al. evaluated the effects of dietary supplementation of benzoic acid or thymol and its essential oil mixture on growth performance of Turkey, and found that essential oil mixture decreased the pH values of the caecal content, increased lactic acid bacteria, and decreased coliform group (Giannenas et al., 2014).Dibner et al. studied the nutrition and metabolism of organic acids on intestinal flora and found that organic acids can reduce the pH values of intestinal digesta and participate in antibacterial activity (Dibner and Buttin, 2002).Moreover, specific components in essential oils have anti-inflammatory properties that aid in promoting intestinal health by reducing inflammatory responses.Ocimum basilicum L. essential oil, for instance, has been shown to mitigate tissue damage and myeloperoxidase (MPO) activity caused by colitis (Rashidian et al., 2016).Foeniculum vulgare Mill.Essential oil has been found to reduce histological lesions from colitis and impact the expression of MPO, tumor necrosis factor α, and nuclear factor-κB mucosal mRNA levels (Rezayat et al., 2018).Furthermore, some essential oils show positive effects on the growth and activity of beneficial bacteria, leading to an increase in beneficial bacteria populations while decreasing harmful ones.This reduction in intestinal oxidative stress is crucial for maintaining intestinal health.Research indicates that the number of Lactobacillus jejuni increased, while the number of Enterococcus and E. coli decreased in piglets treated with a carvhol-thymol mixture (Wei et al., 2017).
Similarly, the administration of carvall essential oil to broilers showed a reduction in Salmonella and E. coli populations in their intestines (Liu et al., 2018).Sahoo et al. added Curcuma longa L. and Z. officinale Roscoe to the diets of broilers, it was observed that the growth of several pathogenic bacteria in the chickens' intestines was restricted, ultimately contributing to balanced intestinal microflora and improved feed utilization (Sahoo et al., 2019).The regulatory effects of essential oils on gut health are shown in Supplementary Table S1.

Clinical application
The primary applications of essential oils in infections of C. albicans mainly involve the treatment of oral and skin infections.
Here are the main applications of essential oils in these areas are as follows: (1) Oral infection: (Ⅰ) M. alternifolia (Maiden and Betche) Cheel oil: M. alternifolia (Maiden and Betche) Cheel oil can be used as an oral mouthwash to treat oral infections of C. albicans.Its antifungal and antibacterial properties can reduce the growth and spread of C. albicans; (Ⅱ) S. aromaticum (L.); Merr.and L.M.Perry essential oil: S. aromaticum (L.) Merr.and L.M.Perry essential oil is effective in managing oral infections of C. albicans due to its potent antifungal and antibacterial effects.
(  Frontiers in Pharmacology frontiersin.org09 It's important to note that the application of essential oils should follow the appropriate dilution ratio and application method.In cases of oral essential oils can be diluted and used as a Regarding skin infections, essential oils should be mixed with a carrier oil and gently applied to the affected area.It is best to perform a skin sensitivity test before usage and it is essential to adhere to the recommended guidelines for application.Although essential oils show some potential in the treatment of infections of C. albicans, further research is necessary to validate their effectiveness and safety.The mechanism diagrams of the Intestinal regulation of essential oils and Clinical application are shown in Figure 1.

Challenges and prospects
As environmental regulations become more stringent, there is a growing consensus on the need to reduce and replace resistance.People are growing more health-conscious and environmentally aware, leading to a surge in interest in promoting natural and ecofriendly plant essential oils as a burgeoning research Frontier and focal point of study.Presently, numerous scholars both domestically and internationally have conducted extensive research on essential oils, focusing particularly on their physical and chemical properties, biological activities, mechanisms of action, etc.However, the majority of studies regarding the antibacterial activity of essential oils are conducted based on the MIC of these oils against bacteria or fungi.There is no systematic and thorough exploration into the antibacterial kinetics and mechanisms related to essential oils, indicating considerable groundwork to be undertaken.Specifically, understanding the mechanisms behind the antibacterial and antifungal effects of essential oils, exploring potential synergistic antibacterial properties among different oils, and investigating the relationship between chemical components require further investigation.
Essential oils represent a promising biological resource sourced from a wide variety of origins, known for their low toxicity and minimal side effects.The future industrialization of essential oils should not be confined to specific sectors such as traditional medicine, food, or daily necessities.Instead, it should incorporate a multidisciplinary, multi-directional, and versatile approach into its development.With the continuous advancement of various separation and detection technologies, the composition, structure, and functions of plant essential oils are becoming increasingly elucidated, leading to expanded applications and developmental opportunities in areas such as medicine, healthcare products, disease and pest prevention, food, and environmental protection (Rath, 2007;Pavela and Benelli, 2016).

Conclusion
Essential oils have demonstrated their ability to combat the infections of C. albicans through various antibacterial mechanisms and by regulating intestinal flora.Further research and clinical trials on essential oils are imperative to comprehensively assess their efficacy and safety as a viable treatment approach for the infections caused by C. albicans.
) Skin infection: (Ⅰ) M. alternifolia (Maiden and Betche) Cheel oil: M. alternifolia (Maiden and Betche) Cheel oil can be topically applied to address skin infections of C. albicans such as candida dermatitis.It can be directly applied to affected areas, possessing antifungal and antibacterial effects; (Ⅱ) L. angustifolia Mill.Essential oil: L. angustifolia Mill.Essential oil is effective in treating skin infections of C. albicans.With its antifungal and anti-inflammatory properties, it can alleviate itching and reduce inflammatory responses; (Ⅲ) C. verum J. Presl essential oil: C. verum J. Presl essential oil can be topically used to manage skin infections of C. albicans.Despite its antifungal and antibacterial activity, caution should be exercised to prevent skin irritation; (Ⅳ) Other essential oils: F. vulgare Mill.Essential oil, Salvia rosmarinus Spenn.Essential oil, Cupressus funebris Endl.Essential oil, C. citratus (DC.)Stapf essential oil, and Eucalyptus robusta Sm.Essential oil are also beneficial for the topical treatment of skin infections of C. albicans.They possess antifungal and antibacterial properties that can relieve symptoms and aid in wound healing.

FIGURE 1
FIGURE 1Mechanism diagrams of the Intestinal regulation of essential oils and Clinical application. ;

TABLE 1
Essential oils against C. albicans along with their main components.

TABLE 1 (
Continued) Essential oils against C. albicans along with their main components.

TABLE 1 (
Continued) Essential oils against C. albicans along with their main components.

TABLE 2
The impacts of C. albicans infection on intestinal flora.

TABLE 2 (
Continued) The impacts of C. albicans infection on intestinal flora.
(L.) Spreng.Essential oil has a good antibacterial effect on E. coli, Staphylococcus aureus, and methicillin-sensitive staphylococcus aureus (