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Current status of microbiome-based therapeutics research and development
Korean J. Microbiol. 2023;59(3):159-172
Published online September 30, 2023
© 2023 The Microbiological Society of Korea.

Hyunna Jung and Hyosun Cho*

College of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea
Correspondence to: *E-mail: hyosun1102@duksung.ac.kr; Tel.: +82-2-901-8678; Fax: +82-2-901-8386
Received June 8, 2023; Revised August 18, 2023; Accepted August 23, 2023.
Abstract
Recently, several studies have demonstrated that imbalance in the microbiome is associated with several diseases such as cancer, diabetes, allergy, obesity, and infection. Microbiome-based therapeutics are a way to treat these diseases by regulating the human microbiome, which includes prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation. These are known to revert an imbalanced microbiome to a healthy state and subsequently contribute to maintaining the homeostasis of the intestinal environment and regulating the immune response. Therefore, microbiome-based therapeutics also improve or synergize the effectiveness of existing therapeutic reagents. However, the differences in efficacy seem to occur depending on various levels of microbiome classes, strains, and administration methods. This review provides a summary of the current research and development status in the field of microbiome-based therapeutics, especially focusing on probiotics, postbiotics, and fecal transplantation.
Keywords : fecal microbiota transplantation, microbiome-based therapeutics, postbiotics, probiotics
Body

The microbiome refers to all microorganisms in a particular environment and their genomes, especially, the human microbiome means all microorganisms such as bacteria, viruses, and fungi that inhabit the human body, and their genome and by-products (ISAPP, 2021). Microbiome-based therapeutics are a way to treat diseases by regulating the human microbiome (Gulliver et al., 2022).

Understanding the relationship between the microbiome and the host has shown the possibility that microbiome regulation can prevent or treat many diseases such as cancer, diabetes, allergy, obesity, and infection (Rouanet et al., 2020; Alam et al., 2023). For instance, the dominance of certain bacteria can promote energy storage and alter the metabolic pathways leading to obesity. This indicates that altering the gut microbiome can provide beneficial effects by reversing the bacterial imbalance that characterizes obesity (Zsálig et al., 2023). Specifically, it is known that one of the microbiome-based treatment strategies, the probiotics Lactobacillus rhamnosus GG has anti-obesity effects via increasing the proportion of Bacteroidetes and decreasing the proportion of Proteobacteria as well as upregulation of adiponectin (Cheng and Liu, 2020). Additionally, fecal microbiota transplantation is known to be an effective therapeutic method to treat recurrent Clostridioides difficile infection (Sandhu and Chopra, 2021). The VOWST and the REBYOTA are successful microbiome-based therapeutics using fecal microbiota transplantation and were approved by the FDA (Mullard, 2023).

Microbiome-based therapeutics also address issues associated with existing treatments, such as pathogen resistance to antibiotics, resistance to chemotherapy, drug unresponsiveness, and low specificity. Sivan et al. (2015) found that mice from different suppliers have different rates of tumor growth and that tumor growth of Jackson Laboratory (JAX) mice was slower and respond more effectively to anti-PD-L1 than in Taconic mice. Although these mice had the same genetic background, the microbiome composition was different, and the efficacy of anti-PD-L1 was enhanced when the fecal microbiome from a JAX mice was transplanted into Taconic mice. In particular, Bifidobacterium identified as important, and it has been reported that supplying Bifidobacterium can enhance anti-PD-L1 efficacy by re-activating dendritic cells to promote CD8+ T cell responses to combat tumors (Ma et al., 2019).

Microbiome-based therapeutics encompass various approaches including prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation (Gulliver et al., 2022). Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit (Valladares-Diestra et al., 2023). Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al., 2014). Synbiotics are a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host (Yildirim et al., 2023). Postbiotics are the preparation of inanimate microorganisms and/or their components that confers a health benefit on the host (Salminen et al., 2021). Last but not least, fecal microbiota transplantation can be defined as the transfer of minimally manipulated feces from healthy donors into a recipient’s gut to treat a disorder associated with gut microbiota alterations (Khoruts and Sadowsky, 2016).

Although elucidating their exact mechanism of action remains to be addressed, it is known that they generally contribute to human health by maintaining intestinal homeostasis via the exclusion of pathogens and improving the tight junction protein expression (Huang et al., 2023a). Also, they regulate the innate and adaptive immune response via activating the immune cells including dendritic cells, NK cells, T lymphocytes, and B lymphocytes (Roy and Dhaneshwar, 2023). This review discusses microbiome-based therapeutics with a focus on probiotics, postbiotics, and fecal microbiota transplantation.

Probiotics

Definition

Probiotics were defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” by World Health Organization (WHO)/Food and Agriculture Organization (FAO) in 2001. However, a revised definition was introduced in 2014, stating that probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” (Hill et al., 2014). There are minor grammatical corrections, but there is no significant difference in meaning. This definition has been in use until recently (Fijan, 2023).

Safety

Several microbial strains, such as Bifidobacterium, Limosilactobacillus, are considered inherently safe because they have been used for a long time as food. This concept was established through the Food and Drug Administration (FDA)’s GRAS (Generally Recognized as Safe) designation, which is based on the fact that these strains have been used as ingredients in food or dietary supplements for an extended period and in large populations without any specific issues (Cordaillat-Simmons et al., 2020). GRAS is an abbreviation for “Generally Recognized As Safe”, the microorganisms or substances included in GRAS are those that have been approved by the FDA as generally safe under the conditions of their intended use, or unless the use of the substance is otherwise excepted from the definition of a food additive (US FDA, 2022a). Although most probiotic formulations utilize lactic acid bacteria with GRAS status (Kiepś and Dembczyński, 2022), concerns about the safety of probiotics have been consistently raised by clinicians, researchers, and policymakers. Consequently, ISAPP assembled expert panels in 2022 to provide the latest insights and recommendations regarding the safety of probiotics. Specifically, this annual meeting emphasizes the importance of conducting rigorous testing of probiotics as drugs when considering their application in the patient population (Merenstein et al., 2023). Indeed, a case study reported that there was a 61-year-old woman who is using an automated intracardiac defibrillator with a history of cardiovascular disease obtained Lactobacillus endocarditis after she intake a probiotic Lactobacillus (DeMarco et al., 2023).

Advantages and disadvantages

There are several advantages and disadvantages when using probiotics as microbiome-based therapeutics. As mentioned above, some microorganisms commonly used as probiotics such as Lactobacillus and Bifidobacterium are relatively safe because they have been used in a large population without any adverse effects. Furthermore, standardized mixtures of probiotics facilitate commercialization. However, most probiotics cannot colonize in the gut, resulting in their beneficial effects being temporary and necessitating continuous intake (Gulliver et al., 2022).

Recent researches on probiotics

Among recent cancer-targeted probiotics studies, studies on colorectal cancer have been the most published. A clinical study suggested that the consumption of Bifidobacterium youthis DSM 18351, Bifidobacterium longum DSM 16603, and Bifidobacterium bifidum DSM 22892 decreases the incidence of colorectal cancer (CRC) by improving the gut environment and regulating CRC-associated bacteria, such as Fusobacterium nucleatum (Liang et al., 2023). Dikeocha et al. (2023) found that the administration of Propionibacterium freudenreichii significantly reduced colonic aberrant foci and enhanced the diversity of gut microbiota in azoxymethane-induced CRC rats. Also, Lactobacillus acidophilus C4 and Saccharomyces cerevisiae QHNLD8L1 were shown to alleviate inflammatory bowel disease (Hu et al., 2023; Liu et al., 2023a). Lee et al. (2023) observed that Lactobacillus paracasei ATG-E1 suppressed neutrophil infiltration and the expression of inflammatory mediators on airway inflammation. In addition, Bifidobacterium longum showed beneficial effects in lithium pilocarpine-induced temporal lobe epilepsy in vivo model. In this study, B. longum was administered to rats daily at 109 CFU for 30 days and as a result, the amygdala nerve damage was reduced and the expression of anti-inflammatory and neuroprotective genes Il1rn and Pparg was increased in the B. longum administered group, which indicates that B. longum can be a promising drug for the treatment of epilepsy (Zubareva et al., 2023). Furthermore, Kang et al. (2023) reported the antibacterial and antibiofilm effects of Weissella cibaria strains against Streptococcus mutans. Streptococcus mutans is a causative bacterium of dental caries, and this study found that Weissella cibaria strains reduced the production of exopolysaccharides and downregulated virulence factors of S. mutans.

The conventional probiotics studies were focused on the strains of probiotics, whereas, current probiotics studies are directed towards research for the prevention and treatment of diseases using probiotics (Kim, 2020). This transition has led to terminological confusion regarding the use of probiotics as food, dietary supplements, and therapeutic substances. To address this confusion, FDA established the live biotherapeutic products (LBP) category (Ağagündüz et al., 2022). According to FDA, LBP is a biological product that (1) contains live organisms, (2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings, and (3) is not a vaccine (US FDA, 2016). As with other products intended for the prevention or treatment of disease, LBP should be registered as a drug product to reach the market in the US and Europe (Cordaillat-Simmons et al., 2020).

LBP and probiotics both contain live organisms, but they differ in their intended use and regulation. LBP is classified as a medical therapeutic reagent, whereas probiotics are typically regulated as food supplements. Another key distinction lies in the target population: probiotics are commonly used by healthy individuals who aim to prevent diseases, while LBPs are specifically intended for patients requiring treatment (Cordaillat-Simmons et al., 2020).

The safety evaluation of LBP poses certain challenges. Unlike other medicines, LBPs are not intended to directly target specific organs or receptors. Instead, they provide health benefits to the host indirectly by interacting with microorganisms or modulating the host-microorganism relationship. As a result, the mode of action of LBPs may not be entirely clear, making risk prediction and assessment more difficult. To ensure safety, researchers must thoroughly conduct risk analysis and safety assessments (Rouanet et al., 2020). Recent studies on probiotics are summarized in Table 1.

Recent researches on probiotics
Strain Study Target Ref.
Cancer
Lactobacillus plantarum ATCC 14917 in vitro
(Caco-2)
Colorectal cancer Amin et al. (2023)
Lactobacillus rhamnosus ATCC 7469
Lacticaseibacillus rhamnosus in vitro
(HaCaT, HT-29, HCT-116)
Colorectal cancer Budu et al. (2023)
Propionibacterium freudenreichii in vivo
(SD rats)
Colorectal cancer Dikeocha et al. (2023)
Lactobacillus plantarum in vivo
(C57BL/6J)
Colorectal cancer Yang et al. (2023a)
Bifidobacterium adolescentis Clinical Colorectal cancer Liang et al. (2023)
+Bifidobacterium longum+Bifidobacterium bifidum
Bifidobacterium infantis Clinical Colorectal cancer Huang et al. (2023b)
+Lactobacillus acidophilus
+Enterococcus faecalis+Bacillus cereus
Lactobacillus+Bifidobacterium+Enterococcus Clinical Breast cancer Thu et al. (2023)
Infectious or inflammatory diseases
Lactobacillus acidophilus C4 in vivo
(C57BL/6)
Inflammatory bowel disease Liu et al. (2023a)
Saccharomyces cerevisiae QHNLD8L1 in vivo
(C57BL/6N)
Ulcerative colitis Hu et al. (2023)
Lactobacillus paracasei ATG-E1 in vivo
(BALB/c)
Airway inflammation Lee et al. (2023)
Etc.
Weissella cibaria in vitro
(Streptococcus mutans)
Oral health Kang et al. (2023)
Bifidobacterium longum in vivo
(Wistar)
Epilepsy Zubareva et al. (2023)
Parabacteroides distasonis in vivo
(C57BL/6JRj)
Obesity Cuffaro et al. (2023)
Bifidobacterium animalis sp. lactis XLTG11 Clinical Acute diarrhea Chen et al. (2023b)

Postbiotics

Definition

Postbiotics were defined as “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host” by ISAPP in 2021 (Salminen et al., 2021). Postbiotics include short-chain fatty acids (SCFA), exopolysaccharides, proteins, and cell wall fragments that are produced by the microorganism (Thorakkattu et al., 2022). Importantly, postbiotics do not necessarily have to be produced by probiotics (Salminen et al., 2021).

Safety

Although probiotics are generally considered safe, concerns have been raised regarding their use in vulnerable populations such as immune-suppressed patients or infants, as they consist of live organisms. These concerns include the potential for microbial translocation and transfer of antibiotic-resistance genes (Mosca et al., 2022). In contrast, postbiotics, being inactivated forms of live microorganisms, are free from these risks. Consequently, postbiotics are expected to have a better safety profile than probiotics (Ma et al., 2023). However, in a clinical study, there was also a report that heat-killed Bifidobacterium bifidum administration caused abdominal pain in irritable bowel syndrome patients (Andresen et al., 2020).

Advantages and disadvantages

In addition to the safety benefits of postbiotics, there are several advantages when using postbiotics as microbiome-based therapeutics. First, the beneficial effect of postbiotics is not dependent on the viability of microorganisms (Mosca et al., 2022). Second, postbiotics exhibit increased stability under environmental conditions such as pH and temperature, and they have a longer shelf life compared to probiotics (Kim et al., 2021). This makes their storage and transportation more convenient. Third, postbiotics can be used in conjunction with antibiotics (Mosca et al., 2022). For these reasons, there is growing recognition that investing in postbiotics, which are easier to control and standardize, is more promising (Yunes et al., 2022). However, it’s important to note that the quality of postbiotics can be influenced by the process used to inactivate microorganisms (such as air drying, freeze drying, ultrasonication, high pressure, etc.), which may result in postbiotics having different functions than expected. Therefore, a careful validation process is required to produce consistent and safe postbiotics (Ma et al., 2023).

Recent researches on postbiotics

Vallino et al. (2023) noted that the cell-free supernatant of Lactiplantibacillus plantarum exhibited inhibitory effects on IL-6-induced cancer cell growth by targeting the ERK and S6 pathways. Pakbin et al. (2023) and Xu et al. (2023) reported that Saccharomyces boulardii has a cytotoxic effect on the AGS cells and a relieving effect on ulcerative colitis, respectively. A clinical study showed that heat-killed Pediococcus acidilactici alleviated symptoms of acne vulgaris, which is a common skin disease characterized by chronic inflammation from excessive Cutibacterium acnes. This study reported that in subjects who applied a product containing P. acidilactici to the skin for 4 weeks, the TCA cycle and lipase activity of Cutibacterium acnes were reduced, as well as the formation of biofilm was inhibited to reduce acne vulgaris symptoms (Bae et al., 2023). Wu et al. (2023) and Liu et al. (2023b) investigated the effectiveness of heat-killed Lactobacillus plantarum and pasteurized Akkermansia muciniphila against Salmonella infection, respectively. L. plantarum protected IPEC-J2 cells by activating autophagy to remove Salmonella enterica in vitro (Wu et al., 2023). In addition, A. muciniphila secreted antimicrobial peptides and activated macrophages from Salmonella enterica infection (Liu et al., 2023). There were a couple of studies that reported the effect of postbiotics on intestinal health, and these studies showed that postbiotics could improve intestinal health by strengthening intestinal tight junctions (Algieri et al., 2023; Xie et al., 2023; Zhang et al., 2023a). Additionally, Ye et al. (2023) demonstrated that the cell-free supernatant of Lactobacillus plantarum could alleviate acute liver injury. In this study, in mice with acute liver injury induced by a single administration of 50% ethanol, Lactobacillus plantarum administration resulted in decreased levels of alanine aminotransferase and aspartate aminotransferase in the serum, and increased superoxide dismutase activity. Recent studies on postbiotics are summarized in Table 2.

Recent researches on postbiotics
Strain Study Target Ref.
Cancer
Lactiplantibacillus plantarum OC01
(Cell-free supernatant)
in vitro
(HCT116, HT29)
Colorectal cancer Vallino et al. (2023)
Saccharomyces boulardii
(Cell-free supernatant)
in vitro
(AGS)
Gastric cancer Pakbin et al. (2023)
Infectious or inflammatory diseases
Lactobacillus plantarum
(Heat-killed)
in vitro
(IPEC-J2)
Salmonella enterica infection Wu et al. (2023)
Akkermansia muciniphila
(Pasteurized)
in vivo
(C57BL/6J)
Salmonella enterica infection Liu et al. (2023b)
Saccharomyces boulardii
(Cell-free supernatant)
in vivo
(C57BL/6J)
Ulcerative colitis Xu et al. (2023)
Pediococcus acidilactici LM1013
(Heat-killed)
Clinical Acne vulgaris Bae et al. (2023)
Intestinal Health
Lacticaseibacillus paracasei
(Heat-killed)
in vitro
(Caco-2)
Intestinal health Xie et al. (2023)
Lactobacillus paracasei CNCM I-5220
(Short chain fructooligosaccharides)
in vitro (Caco-2) Leaky gut syndrome Algieri et al. (2023)
in vivo (C57BL/6J)
Pichia kudriavzevii FZ12
(Cell-free supernatant)
in vivo
(Cross bred piglets)
intestinal health Zhang et al. (2023a)
Etc.
Ligilactobacillus salivarius LS03
(Cell-free supernatant)
in vitro
(Fusobacteriumnucleatum, Porphyromonas gingivalis)
Oral health Zanetta et al. (2023)
Lactobacillus paracasei ET-22
(Heat-killed)
in vitro
(Streptococcus mutans)
Dental caries Zhao et al. (2023)
Lactobacillus plantarum AB161
(Cell-free supernatant)
in vivo
(C57BL/6)
Acute alcohol-induced liver injury Ye et al. (2023)
Lacticaseibacillus paracasei GMNL-653
(Heat-killed)
Clinical Scalp health Tsai et al. (2023)

Fecal Microbiota Transplantation

Definition

Fecal microbiota transplantation (FMT) is a method that injects stool samples from a healthy donor into the intestinal tract of a recipient. This method aims to normalize the composition and function of the recipient’s gut microbiome (Khoruts and Sadowsky, 2016). The most commonly used technique for FMT is injecting a feces suspension through a colonoscopy into the tip of the ileum and the ascending colon (Jørgensen et al., 2017).

Safety

FMT has been associated with certain risks and side effects, including transient diarrhea, abdominal cramps or pain, low-grade fever, bloating, flatulence, and constipation (Park and Seo, 2021). However, these are short-term risks related to the methodology of the procedure, such as the use of endoscopy, rather than problems with FMT itself. Studies have indicated that FMT can be safely applied even in high-risk patients, such as those who are immunosuppressed, without excessive side effects (Merrick et al., 2020).

Although FMT is a well-established method, there have been rare cases where it has resulted in adverse events. This report describes a case where a recipient died due to bacteremia caused by an extended-spectrum beta-lactamase (ESBL)-producing E. coli strain present in the donor’s feces (DeFilipp et al., 2019). Therefore, to perform safer and more successful FMT, careful donor selection and protocol standardization are required (Allegretti et al., 2019).

Advantages and disadvantages

Although the range of products to which probiotics are added is increasing (Nagpal et al., 2012), probiotic products contain a limited number of genera of microorganisms, such as Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, Escherichia, and Bacillus (NIH, 2022b). In contrast, FMT transfers intact fecal microbiota from a healthy donor to the recipient, providing a broader range of microbial diversity and complexity compared to probiotic products. This diversity can potentially provide a more comprehensive and varied microbial ecosystem, which may be beneficial for certain conditions associated with dysbiosis or disrupted gut microbiota. Furuya-Kanamori et al. (2017) found that the lower gastrointestinal (LGI) delivery route of FMT is more effective than the upper gastrointestinal (UGI) delivery route in recurrent or refractory Clostridium difficile infection patients. Given that most probiotic and postbiotic products are taken orally, FMT, which can be injected directly into the patient’s intestines, may be more useful in certain cases.

Recent researches on fecal transplantation

Intestinal inflammation has been the most targeted in FMT. A clinical trial investigated the therapeutic effects of FMT on ulcerative colitis patients. The study found that capsulized FMT treatment led to clinical remission in 57.1% of UC patients (Chen et al., 2023a). Additionally, this treatment improved microbial richness and reduced levels of opportunistic pathogens such as Escherichia coli and Salmonella enterica (Chen et al., 2023a). These findings suggest that FMT could be a potential treatment option for UC, as it positively influenced the gut microbiota composition and reduced the presence of harmful pathogens. However, according to the study of Lahtiene et al. (2023), there was no significant difference in UC relapses between the control and FMT groups after a single FMT. anticancer treatment, especially immune checkpoint inhibitors (ICIs) can induce immune-related adverse events such as immune-mediated enterocolitis (IMC). Groenewegen et al. (2023) reported two cases about two patients with cancer suffering from IMC. After FMT, both patients showed similar microbial diversity and richness compared to healthy donor levels. BALB/c mice with colorectal cancer that received fecal transplants from healthy mice showed a recovery of gut dysbiosis and improvement of immune response (Yu et al., 2023). This suggests that FMT has a beneficial impact on the gut microbiota and immune system in the context of colorectal cancer. Patients with Parkinson’s disease who received FMT showed improvement in constipation and gut motility index. Their subjective motor symptoms were also improved by FMT although objective motor symptoms were not, considering that most Parkinson’s disease patients suffer from chronic constipation, FMT can be a solution to gut motility in Parkinson’s patients (DuPont et al., 2023). Recent studies on FMT are summarized in Table 3.

Recent researches on fecal transplantation
Study Target Ref.
Cancer
in vivo
(BALB/c)
Colorectal cancer Yu et al. (2023)
Infectious or inflammatory diseases
Clinical Ulcerative colitis Chen et al. (2023a)
Clinical Immune-mediated enterocolitis Groenewegen et al. (2023)
Clinical Ulcerative colitis Lahtinen et al. (2023)
Clinical Recurrent Clostridioides difficile infection Rodig et al. (2023)
Etc.
in vivo
(C57BL/6NCrSIc)
Obesity Zhang et al. (2023b)
Clinical Parkinson’s disease DuPont et al. (2023)
in vivo
(C57BL/6J)
Type 2 diabetes Yang et al. (2023b)

Current Status of Microbiome-based Therapeutics in the Industrial Field

It is indeed significant that REBYOTATM, developed by Ferring Pharmaceuticals, became the first FDA-approved microbiome-based treatment for preventing recurrent Clostridioide difficile infection (rCDI) in October 2022. REBYOTATM is a liquid formulation that contains 1 × 108–5 × 1010 colony forming units (CFU)/ml of fecal microbes including > 1 × 105 CFU/ml of Bacteroides and is administered by rectum administration (US FDA, 2022b). This approval marks a milestone in the field of microbiome-based therapies. Similarly, VOWST, developed by Seres Therapeutics, received FDA approval in April 2023 for the treatment of rCDI (US FDA, 2023). Unlike REBYOTATM, VOWST is a capsule that is orally administered, developed in a form that is more convenient to apply (Khanna et al., 2022).

In addition to these approvals, ongoing clinical trials are exploring the application of microbiome-based therapies in various areas (Table 4). Genome & Company is evaluating the combination of GEN-001 and Avelumab (BAVENCIO®) in patients with PD-L1 positive gastric cancer, with a phase 2 clinical trial currently underway. Scioto Biosciences, Inc. has completed phase 1 clinical trials assessing the safety and tolerability of Lactobacillus Reuteri SB-121 in individuals diagnosed with autism.

Current status of microbiome-based therapeutics in the industrial field
Company Name Intervention/treatment Target Country Status Ref.
Ferring Pharmaceuticals REBYOTA Drug Recurrent Clostridioides difficile infection Switzerland FDA approval
(November 30, 2022)
US FDA (2022b)
Seres Therapeutics, Inc. VOWST Biological Recurrent Clostridioides difficile infection United States FDA approval
(April 26, 2023)
US FDA (2023)
Genome & Company GEN-001 Drug Gastric cancer Republic of Korea Phase 2 NIH (2023c)
Scioto Biosciences, Inc. SB-121 Drug Autism spectrum disorder United States Phase 1 completed NIH (2022a)
Ochsner Health System RBX7455 Biological Hepatic encephalopathy United States Phase 2 NIH (2023d)
Enterome EO2040 Drug Colorectal cancer France Phase 2 NIH (2023b)
Intralytix, Inc ShigActiveTM Biological Shigellosis United States Phase 1/2a NIH (2023e)
Active, not recruiting
4D Pharma plc MRx0518 Drug Resectable pancreatic cancer United Kingdom Phase 1 NIH (2023a)

Mechanisms of Microbiome-based Therapeutics

Despite various studies that have demonstrated the therapeutic effect of probiotics, postbiotics, and fecal transplantation, uncovering their exact mode of action is still challenging. Moreover, the therapeutic effects of probiotics and postbiotics are thousands of different by bacterial strain, dose, and form (Huang et al., 2023a). In the case of fecal transplantation, the efficacy may vary depending on the donor’s microbiome taxa diversity (Zou et al., 2022). In this section, we review the possible therapeutic mechanisms of probiotics, postbiotics, and fecal transplantation (Fig. 1).

Fig. 1. Potential mechanism of action of probiotics, postbiotics, and fecal transplantation.

Modulation of the homeostasis of the gut microbiome and enforcement of the intestinal barrier function

Probiotics consumption can modulate the relative abundance of Firmicutes and Bacteroides (Huang et al., 2023a). It is well known that the imbalance ratio between Firmicutes and Bacteroides is related to disease. Raised Firmicutes/Bacteroides (F/B) ratio is observed with obesity, reduced F/B ratio is observed with inflammatory bowel disease (IBD) (Stojanov et al., 2020). Probiotics can impede the colonization of pathogenic bacteria through competitive exclusion and inhibit the pathogenic bacteria by secreting the substances such as bacteriocins and defensins (Batista et al., 2020; Roy and Dhaneshwar, 2023). In addition, adhesive molecules, such as polysaccharides and peptidoglycan, which are secreted by probiotics can enhance mucus production, expression of tight junction proteins (ZO-1, occludin, and claudin-1), and thicken the intestinal barrier in turn resist the pathogens (Huang et al., 2023a). The SCFA, the most representative postbiotics, may also contribute to intestinal homeostasis. Particularly, one of the most important SCFA is butyrate. Butyrate is the main trophic source for enterocytes and they play a role to repair the intestinal epithelium. Besides, it also has an anti-inflammatory effect as it reduces the expression of pro-inflammatory cytokines and prevents the overactivation of nuclear factor kappa B (NF-κB) (Thorakkattu et al., 2022).

Involvement in the immune response

Probiotics and postbiotics improve innate and adaptive immune responses by affecting immune cells and regulating immune responses. The interaction between probiotics and intestinal cell occurs in both intestinal epithelium and lamina propria. First, probiotics can increase secretory immunoglobulin A (sIgA) production by inducing B lymphocytes to mature into sIgA-producing plasma cells (Roy and Dhaneshwar, 2023). Moreover, this article alluded to the possibility that oral administration of probiotics probably induces the production of interleukin-6 (IL-6) and thereby establishes a lamina propria environment that allows clonal expansion of B lymphocytes, resulting in increased IgA production (Mazziotta et al., 2023). The fact that sIgA inhibits the colonization of pathogenic bacteria and viruses by binding to surface antigens of them (Pietrzak et al., 2020) is consistent with the mechanism described above. Secondly, probiotics are recognized by dendritic cells and can activate the CD8+ and CD4+ T lymphocytes as well as lead to the differentiation of CD4+ T lymphocytes into Th1, Th2, and Th17. Th1 cells secrete interferon-gamma (IFNγ), and engage in cell-mediated immunity, while Th2 cells that produce interleukin 4 (IL-4) involve humoral immunity (Mazziotta et al., 2023). Additionally, probiotics stimulate the macrophages and induce the production of tumor necrosis factor-α (TNF-α) and interleukin 12 (IL-12), subsequently, IL-12 activates natural killer (NK) cells. Apart from that, probiotics also increase the number of regulatory T cells and these secrete the anti-inflammatory cytokines, such as interleukin 10 (IL-10), transforming growth factor-β (TGF-β) (Hashemi et al., 2023). It has been reported that the immunomodulatory mechanism of postbiotics is similar to that of probiotics. As opposed to probiotics, the fact that the activity of postbiotics does not depend on the viability of bacteria and shows similar effects supports the aforementioned advantages of postbiotics (Yeşilyurt et al., 2021). Probiotics and postbiotics induce both anti-inflammatory and pro-inflammatory responses. This seems contradictory at first glance, but it indicates that they do an important role in balancing intestinal homeostasis in various contexts (Lu et al., 2022).

Recent studies have highlighted the relationship between immune checkpoint inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) / anti-programmed death-ligand 1 (PD-L1) and the gut microbiome. PD-1 is an inhibitor of adaptive and innate immune responses and is expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs), and monocytes. In tumor cells, PD-L1 is expressed as an adaptive immune mechanism to evade antitumor responses (Han et al., 2020). Several researchers have found that the number, type, and composition of the gut microbiota of cancer patients are strongly related to the efficacy of anti-PD-1 therapy and patients’ survival rate (Lu et al., 2022). Gopalakrishnan et al. (2018) found that the gut microbiota could modulate the effectiveness of anti–PD-1 immunotherapy in melanoma patients. Patients with a gut microbiota composed of high species diversity and a predominance of beneficial bacteria such as Ruminococcaceae showed enhanced antitumor immune responses mediated by improved effector T cell function. On the other hand, patients with a gut microbiota composed of low species diversity and a high relative abundance of Bacteroidales show impaired antitumor immune responses mediated by weakened antigen presentation capacity. One study also found that probiotics significantly improved overall survival and objective response rates in cancer patients treated with ICI. Furthermore, patients with non-small cell lung cancer treated with ICI plus probiotics were shown to achieve significantly longer progression-free survival (Zhang et al., 2022).

Conclusion and Prospect

This review provides a concise summary of the three main strategies within microbiome-based therapeutics: probiotics (live biotherapeutic products), postbiotics, and fecal transplantation (Table 5). Numerous studies have been conducted on these strategies, indicating their potential effectiveness in preventing and treating various diseases. The industry is actively involved in the development of microbiome-based therapeutics, with new products being achieved. However, further research is necessary to elucidate the precise mechanisms of microbiome-based therapeutics. Further, the effects of microbiome-based therapeutics vary widely at the strain level, even though they are uniform within the same species and genus. Therefore additional researches on investigating the strain-specific effects are needed.

Advantages and disadvantages of probiotics, postbiotics, and fecal transplantation
Type Description Advantages Disadvantages
Probiotics Live bacteria - Easy to commercialize - Hard to colonize on the host’s gut
- Steady intake is required
Postbiotics Killed bacteria or their metabolite - Relatively safe - Beneficial function may change during inappropriate processing
- More stable
- Independent on the viability of microorganisms
- Available with antibiotics
Fecal transplantation Live bacteria included in healthy donor’s feces - Be supplied with a broader range of microbial diversity and complexity - The annoyance of the transplant process
- The therapeutic efficacy is dependent on the gut microbiome of the donor

적 요

최근 여러 연구에서 마이크로바이옴 불균형이 암, 당뇨, 알레르기, 비만 및 감염 등의 질환과 관련이 있음이 입증되었으며, 질병을 치료하기 위해 불균형 상태인 마이크로바이옴을 균형잡힌 마이크로바이옴으로 회복시키기 위한 다양한 전략이 시도되고 있다. 마이크로바이옴 기반 치료는 마이크로바이옴을 조절하여 질병을 예방 또는 치료하고자 하는 방법으로 프리바이오틱스, 프로바이오틱스, 신바이오틱스, 포스트바이오틱스, 분변 이식 치료제 제품이 포함된다. 이들은 체내 마이크로바이옴의 균형 회복을 통해 장환경의 항상성 및 면역조절에 기여하며 또한 기존 치료제의 효과를 향상 시키거나 상승효과를 가지는 것으로 알려져 있으나 마이크로바이옴 치료제의 종류, 균종 및 투여 방법에 따른 효능의 차이가 보이기도 한다. 본 총설은 마이크로바이옴 기반 치료제 중 프로바이오틱스, 포스바이오틱스 및 분변이식 치료제를 중심으로 최근의 연구개발 현황을 살펴보고자 한다.

Acknowledgments

None.

Conflict of Interest

Hyosun Cho is Editor of KJM. She was not involved in the review process of this article. Also, Authors have no conflicts of interest to report.

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