Search for


search for




 

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.

References
  1. Ağagündüz D, Gençer Bingöl F, Çelik E, Cemali Ö, Özenir Ç, Özoğul F, and Capasso R. 2022. Recent developments in the probiotics as live biotherapeutic products (LBPs) as modulators of gut brain axis related neurological conditions. J. Transl. Med. 20, 460.
    Pubmed KoreaMed CrossRef
  2. Alam MZ, Maslanka JR, and Abt MC. 2023. Immunological consequences of microbiome-based therapeutics. Front. Immunol. 13, 1046472.
    Pubmed KoreaMed CrossRef
  3. Algieri F, Tanaskovic N, Rincon CC, Notario E, Braga D, Pesole G, Rusconi R, Penna G, and Rescigno M. 2023. Lactobacillus paracasei CNCM I-5220-derived postbiotic protects from the leaky-gut. Front. Microbiol. 14, 1157164.
    Pubmed KoreaMed CrossRef
  4. Allegretti JR, Mullish BH, Kelly C, and Fischer M. 2019. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. Lancet 394, 420-431.
    Pubmed CrossRef
  5. Amin M, Navidifar T, Saeb S, Barzegari E, and Jamalan M. 2023. Tumor-targeted induction of intrinsic apoptosis in colon cancer cells by Lactobacillus plantarum and Lactobacillus rhamnosus strains. Mol. Biol. Rep. 50, 5345-5354.
    Pubmed CrossRef
  6. Andresen V, Gschossmann J, and Layer P. 2020. Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial. Lancet Gastroenterol. Hepatol. 5, 658-666.
    Pubmed CrossRef
  7. Bae WY, Jung WH, Lee YJ, Shin SL, An YK, Kim TR, and Sohn M. 2023. Heat-treated Pediococcus acidilactici LM1013-mediated inhibition of biofilm formation by Cutibacterium acnes and its application in acne vulgaris: a single-arm clinical trial. J. Cosmet. Dermatol.. doi:10.1111/jocd.15809.
    Pubmed CrossRef
  8. Batista VL, da Silva TF, de Jesus LCL, Coelho-Rocha ND, Barroso FAL, Tavares LM, Azevedo V, Mancha-Agresti P, and Drumond MM. 2020. Probiotics, prebiotics, synbiotics, and paraprobiotics as a therapeutic alternative for intestinal mucositis. Front. Microbiol. 11, 544490.
    Pubmed KoreaMed CrossRef
  9. Budu O, Banciu CD, Soica C, Lighezan DF, Milan A, Prodea A, Mioc A, Mioc M, Mardale G, and Sima L. 2023. Lacticaseibacillus rhamnosus-A promising tool for colorectal cancer treatment. Processes 11, 781.
    CrossRef
  10. Chen Q, Fan Y, Zhang B, Yan C, Zhang Q, Ke Y, Chen Z, Wang L, Shi H, and Hu Y, et al. 2023a. Capsulized fecal microbiota transplantation induces remission in patients with ulcerative colitis by gut microbial colonization and metabolite regulation. Microbiol. Spectr. 11, e0415222.
    Pubmed KoreaMed CrossRef
  11. Chen K, Jin S, Ma Y, Cai L, Xu P, Nie Y, Luo L, Yu Q, Shen Y, and Ma W, et al. 2023b. Adjunctive efficacy of Lactis XLTG11 for acute diarrhea in children: a randomized, blinded, placebo-controlled study. Nutrition 111, 112052.
    Pubmed CrossRef
  12. Cheng YC and Liu JR. 2020. Effect of Lactobacillus rhamnosus GG on energy metabolism, leptin resistance, and gut microbiota in mice with diet-induced obesity. Nutrients 12, 2557.
    Pubmed KoreaMed CrossRef
  13. Cordaillat-Simmons M, Rouanet A, and Pot B. 2020. Live biotherapeutic products: the importance of a defined regulatory framework. Exp. Mol. Med. 52, 1397-1406.
    Pubmed KoreaMed CrossRef
  14. Cuffaro B, Boutillier D, Desramaut J, Jablaoui A, Werkmeister E, Trottein F, Waligora-Dupriet AJ, Rhimi M, Maguin E, and Grangette C. 2023. Characterization of two Parabacteroides distasonis candidate strains as new live biotherapeutics against obesity. Cells 12, 1260.
    Pubmed KoreaMed CrossRef
  15. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, Turbett S, Chung RT, Chen YB, and Hohmann EL. 2019. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381, 2043-2050.
    Pubmed CrossRef
  16. DeMarco E, DePetrillo J, and Qadeer F. 2023. Meropenem resistant Lactobacillus endocarditis in an immunocompetent patient. SAGE Open Med. Case Rep. 11, 2050313X231152709.
    Pubmed KoreaMed CrossRef
  17. Dikeocha IJ, Al-Kabsi AM, Ahmeda AF, Mathai M, and Alshawsh MA. 2023. Investigation into the potential role of Propionibacterium freudenreichii in prevention of colorectal cancer and its effects on the diversity of gut microbiota in rats. Int. J. Mol. Sci. 24, 8080.
    Pubmed KoreaMed CrossRef
  18. DuPont HL, Suescun J, Jiang ZD, Brown EL, Essigmann HT, Alexander AS, DuPont AW, Iqbal T, Utay NS, and Newmark M, et al. 2023. Fecal microbiota transplantation in Parkinson's disease-a randomized repeat-dose, placebo-controlled clinical pilot study. Front. Neurol. 14, 1104759.
    Pubmed KoreaMed CrossRef
  19. Fijan S. 2023. Probiotics and their antimicrobial effect. Microorganisms 11, 528.
    Pubmed KoreaMed CrossRef
  20. Furuya-Kanamori L, Doi SAR, Paterson DL, Helms SK, Yakob L, McKenzie SJ, Garborg K, Emanuelsson F, Stollman N, and Kronman MP, et al. 2017. Upper versus lower gastrointestinal delivery for transplantation of fecal microbiota in recurrent or refractory Clostridium difficile infection: a collaborative analysis of individual patient data from 14 studies. J. Clin. Gastroenterol. 51, 145-150.
    Pubmed CrossRef
  21. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, and Wei SC, et al. 2018. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103.
    Pubmed KoreaMed CrossRef
  22. Groenewegen B, Terveer EM, Joosse A, Barnhoorn MC, and Zwittink RD. 2023. Fecal microbiota transplantation for immune checkpoint inhibitor-induced colitis is safe and contributes to recovery: two case reports. J. Immunother. 46, 216-220.
    Pubmed CrossRef
  23. Gulliver EL, Young RB, Chonwerawong M, D'Adamo GL, Thomason T, Widdop JT, Rutten EL, Rossetto Marcelino V, Bryant RV, and Costello SP, et al. 2022. Review article: the future of microbiome-based therapeutics. Aliment. Pharmacol. Ther. 56, 192-208.
    Pubmed KoreaMed CrossRef
  24. Han YY, Liu DD, and Li LH. 2020. PD-1/PD-L1 pathway: current researches in cancer. Am. J. Cancer Res. 10, 727-742.
    Pubmed KoreaMed
  25. Hashemi B, Abdollahi M, Abbaspour-Aghdam S, Hazrati A, Malekpour K, Meshgi S, and Kafil H. 2023. The effect of probiotics on immune responses and their therapeutic application: a new treatment option for multiple sclerosis. Biomed. Pharmacother. 159, 114195.
    Pubmed CrossRef
  26. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, and Salminen S, et al. 2014. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506-514.
    Pubmed CrossRef
  27. Hu Q, Yu L, Zhai Q, Zhao J, and Tian F. 2023. Anti-inflammatory, barrier maintenance, and gut microbiome modulation effects of Saccharomyces cerevisiae QHNLD8L1 on DSS-induced ulcerative colitis in mice. Int. J. Mol. Sci. 24, 6721.
    Pubmed KoreaMed CrossRef
  28. Huang C, Hao W, Wang X, Zhou R, and Lin Q. 2023a. Probiotics for the treatment of ulcerative colitis: a review of experimental research from 2018 to 2022. Front. Microbiol. 14, 1211271.
    Pubmed KoreaMed CrossRef
  29. Huang F, Li S, Chen W, Han Y, Yao Y, Yang L, Li Q, Xiao Q, Wei J, and Liu Z, et al. 2023b. Postoperative probiotics administration attenuates gastrointestinal complications and gut microbiota dysbiosis caused by chemotherapy in colorectal cancer patients. Nutrients 15, 356.
    Pubmed KoreaMed CrossRef
  30. ISAPP, International Scientific Association for Probiotics and Prebiotics. 2021. Microbiomes. Retrieved on May 31, 2023. https://isappscience.org/for-scientists/resources/microbiome/.
  31. Jørgensen SMD, Hansen MM, Erikstrup C, Dahlerup JF, and Hvas CL. 2017. Faecal microbiota transplantation: establishment of a clinical application framework. Eur. J. Gastroenterol. Hepatol. 29, e36-e45.
    Pubmed CrossRef
  32. Kang CE, Park YJ, Kim JH, Lee NK, and Paik HD. 2023. Probiotic Weissella cibaria displays antibacterial and anti-biofilm effect against cavity-causing Streptococcus mutans. Microb. Pathog. 180, 106151.
    Pubmed CrossRef
  33. Khanna S, Sims M, Louie TJ, Fischer M, LaPlante K, Allegretti J, Hasson BR, Fonte AT, McChalicher C, and Ege DS, et al. 2022. SER-109: an oral investigational microbiome therapeutic for patients with recurrent Clostridioides difficile infection (rCDI). Antibiotics 11, 1234.
    Pubmed KoreaMed CrossRef
  34. Khoruts A and Sadowsky MJ. 2016. Understanding the mechanisms of faecal microbiota transplantation. Nat. Rev. Gastroenterol. Hepatol. 13, 508-516.
    Pubmed KoreaMed CrossRef
  35. Kiepś J and Dembczyński R. 2022. Current trends in the production of probiotic formulations. Foods 11, 2330.
    Pubmed KoreaMed CrossRef
  36. Kim JW. 2020. Direction and new concept in probiotics R&D. Curr. Top. Lact. Acid Bact. Probiotics 6, 9-16.
    CrossRef
  37. Kim S, Kim GH, and Cho H. 2021. Postbiotics for cancer prevention and treatment. Korean J. Microbiol. 57, 142-153.
  38. Lahtinen P, Jalanka J, Mattila E, Tillonen J, Bergman P, Satokari R, and Arkkila P. 2023. Fecal microbiota transplantation for the maintenance of remission in patients with ulcerative colitis: a randomized controlled trial. World J. Gastroenterol. 29, 2666-2678.
    Pubmed KoreaMed CrossRef
  39. Lee YS, Park GS, Ko SH, Yang WK, Seo HJ, Kim SH, Jeong N, and Kang J. 2023. Lactobacillus paracasei ATG-E1 improves particulate matter 10 plus diesel exhaust particles (PM10D)-induced airway inflammation by regulating immune responses. Front. Microbiol. 14, 1145546.
    Pubmed KoreaMed CrossRef
  40. Liang JQ, Zeng Y, Lau EYT, Sun Y, Huang Y, Zhou T, Xu Z, Yu J, Ng SC, and Chan FKL. 2023. A probiotic formula for modulation of colorectal cancer risk via reducing CRC-associated bacteria. Cells 12, 1244.
    Pubmed KoreaMed CrossRef
  41. Liu Q, Jian W, Wang L, Yang S, Niu Y, Xie S, Hayer K, Chen K, Zhang Y, Guo Y, and Tu Z. 2023a. Alleviation of DSS-induced colitis in mice by a new-isolated Lactobacillus acidophilus C4. Front. Microbiol. 14, 1137701.
    Pubmed KoreaMed CrossRef
  42. Liu J, Liu H, Liu H, Teng Y, Qin N, Ren X, and Xia X. 2023b. Live and pasteurized Akkermansia muciniphila decrease susceptibility to Salmonella Typhimurium infection in mice. J. Adv. Res.. doi: 10.1016/j.jare.2023.03.008.
    Pubmed KoreaMed CrossRef
  43. Lu YT, Yuan XL, Wang M, He ZH, Li HZ, Wang J, and Li Q. 2022. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J. Hematol. Oncol. 15, 47.
    Pubmed KoreaMed CrossRef
  44. Ma WD, Mao QX, Xia WJ, Dong GC, Yu CH, and Jiang F. 2019. Gut microbiota shapes the efficiency of cancer therapy. Front. Microbiol. 10, 1050.
    Pubmed KoreaMed CrossRef
  45. Ma L, Tu H, and Chen T. 2023. Postbiotics in human health: a narrative review. Nutrients 15, 291.
    Pubmed KoreaMed CrossRef
  46. Mazziotta C, Tognon M, Martini F, Torreggiani E, and Rotondo JC. 2023. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cells 12, 184.
    Pubmed KoreaMed CrossRef
  47. Merenstein D, Pot B, Leyer G, Ouwehand AC, Preidis GA, Elkins CA, Hill C, Lewis ZT, Shane AL, and Zmora N, et al. 2023. Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes 15, 2185034.
    Pubmed KoreaMed CrossRef
  48. Merrick B, Allen L, Masirah M, Zain N, Forbes B, Shawcross DL, and Goldenberg SD. 2020. Regulation, risk and safety of faecal microbiota transplant. Infect. Prev. Pract. 2, 100069.
    Pubmed KoreaMed CrossRef
  49. Mosca A, Abreu Y, Abreu AT, Gwee KA, Ianiro G, Tack J, Nguyen TVH, and Hill C. 2022. The clinical evidence for postbiotics as microbial therapeutics. Gut Microbes 14, 2117508.
    Pubmed KoreaMed CrossRef
  50. Mullard A. 2023. FDA approves second microbiome-based C. difficile therapy. Nat. Rev. Drug Discov. 22, 436. https://doi.org/10.1038/d41573-023-00081-1.
    CrossRef
  51. Nagpal R, Kumar A, Kumar M, Behare PV, Jain S, and Yadav H. 2012. Probiotics, their health benefits and applications for developing healthier foods: a review. FEMS Microbiol. Lett. 334, 1-15.
    Pubmed CrossRef
  52. NIH, National Institutes of Health. 2022a. 28-Day Daily-dose Crossover Study of the Safety and Tolerability of SB-121 (Lactobacillus Reuteri With Sephadex® and Maltose) in Subjects, Ages 15 to 45 Years, Diagnosed With Autistic Disorder. ClinicalTrials.gov Identifier: NCT04944901. https://clinicaltrials.gov/ct2/show/NCT 04944901.
  53. NIH, National Institutes of Health. 2022b. Probiotics: Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/.
  54. NIH, National Institutes of Health. 2023a. A Study of Live Biotherapeutic Product MRx0518 With Hypofractionated Radiation Therapy in Resectable Pancreatic Cancer. ClinicalTrials.gov Identifier: NCT04193904. https://www.clinicaltrials.gov/ct2/show/NCT04193904.
  55. NIH, National Institutes of Health. 2023b. EO2040 in Combination With Nivolumab, for Treatment of Patients With Minimal Residual Disease of Colorectal Cancer (CLAUDE). Clinical Trials.gov Identifier: NCT05350501. https://clinicaltrials.gov/ct2/show/NCT05350501.
  56. NIH, National Institutes of Health. 2023c. GEN-001 in Combination With Avelumab for Patients With PD-L1 Positive Gastric Cancer. ClinicalTrials.gov Identifier: NCT05419362. https://clinicaltrials.gov/ct2/show/NCT05419362.
  57. NIH, National Institutes of Health. 2023d. Investigational Microbiota Restoration Therapeutic for Hepatic Encephalopathy. Clinical Trials.gov Identifier: NCT04155099. https://clinicaltrials.gov/ct2/show/NCT04155099.
  58. NIH, National Institutes of Health. 2023e. Safety and Efficacy of the Bacteriophage Preparation, ShigActive™, in a Human Experimental Model of Shigellosis. ClinicalTrials.gov Identifier: NCT05182749. https://clinicaltrials.gov/ct2/show/NCT05182749.
  59. Pakbin B, Allahyari S, Dibazar SP, Zolghadr L, Chermahini NK, Brück WM, Brück TB, and Mahmoudi R. 2023. Effects of probiotic Saccharomyces boulardii supernatant on viability, nano-mechanical properties of cytoplasmic membrane and pro-inflammatory gene expression in human gastric cancer AGS cells. Int. J. Mol. Sci. 24, 7945.
    Pubmed KoreaMed CrossRef
  60. Park SY and Seo GS. 2021. Fecal microbiota transplantation: is it safe?. Clin. Endosc. 54, 157-160.
    Pubmed KoreaMed CrossRef
  61. Pietrzak B, Tomela K, Olejnik-Schmidt A, Mackiewicz A, and Schmidt M. 2020. Secretory IgA in intestinal mucosal secretions as an adaptive barrier against microbial cells. Int. J. Mol. Sci. 21, 9254.
    Pubmed KoreaMed CrossRef
  62. Rodig NM, Weatherly M, Kaplan AL, Ballal SA, Elisofon SA, Daly KP, and Kahn SA. 2023. Fecal microbiota transplant in pediatric solid organ transplant recipients. Transplantation 107, 2073-2077.
    Pubmed CrossRef
  63. Rouanet A, Bolca S, Bru A, Claes I, Cvejic H, Girgis H, Harper A, Lavergne SN, Mathys S, and Pane M, et al. 2020. Live biotherapeutic products, a road map for safety assessment. Front. Med. 7, 237.
    Pubmed KoreaMed CrossRef
  64. Roy S and Dhaneshwar S. 2023. Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: current perspectives. World J. Gastroenterol. 29, 2078-2100.
    Pubmed KoreaMed CrossRef
  65. Salminen S, Collado MC, Endo A, Hill C, Lebeer S, Quigley EMM, Sanders ME, Shamir R, Swann JR, Szajewska H, and Vinderola G. 2021. The international scientific association of probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. 18, 649-667.
    Pubmed KoreaMed CrossRef
  66. Sandhu A and Chopra T. 2021. Fecal microbiota transplantation for recurrent Clostridioides difficile, safety, and pitfalls. Therap. Adv. Gastroenterol. 14, 17562848211053105.
    Pubmed KoreaMed CrossRef
  67. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, and Alegre ML, et al. 2015. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084-1089.
    Pubmed KoreaMed CrossRef
  68. Stojanov S, Berlec A, and Strukelj B. 2020. The influence of probiotics on the Firmicutes/Bacteroidetes ratio in the treatment of obesity and inflammatory bowel disease. Microorganisms 8, 1715.
    Pubmed KoreaMed CrossRef
  69. Thorakkattu P, Khanashyam AC, Shah K, Babu KS, Mundanat AS, Deliephan A, Deokar GS, Santivarangkna C, and Nirmal NP. 2022. Postbiotics: current trends in food and pharmaceutical industry. Foods 11, 3094.
    Pubmed KoreaMed CrossRef
  70. Thu MS, Ondee T, Nopsopon T, Farzana IAK, Fothergill JL, Hirankarn N, Campbell BJ, and Pongpirul K. 2023. Effect of probiotics in breast cancer: a systematic review and meta-analysis. Biology 12, 280.
    Pubmed KoreaMed CrossRef
  71. Tsai WH, Fang YT, Huang TY, Chiang YJ, Lin CG, and Chang WW. 2023. Heat-killed Lacticaseibacillus paracasei GMNL-653 ameliorates human scalp health by regulating scalp microbiome. BMC Microbiol. 23, 121.
    Pubmed KoreaMed CrossRef
  72. US FDA, U.S. Food and Drug Administration. 2016. Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Early-Clinical-Trials-With-Live-Biotherapeutic-Products--Chemistry--Manufacturing--and-Control-Information--Guidance-for-Industry.pdf.
  73. US FDA, U.S. Food and Drug Administration. 2022a. Generally Recognized as Safe (GRAS). Retrieved on May 31, 2023. https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras.
  74. US FDA, U.S. Food and Drug Administration. 2022b. REBYOTA. Retrieved on May 31, 2023. https://www.fda.gov/vaccines-blood-biologics/vaccines/rebyota.
  75. US FDA, U.S. Food and Drug Administration. 2023. VOWST. Retrieved on May 31, 2023. https://www.fda.gov/vaccines-blood-biologics/vowst.
  76. Valladares-Diestra KK, Vandenberghe LPD, Vieira S, Goyzueta-Mamani LD, de Mattos PBG, Manzoki MC, Soccol VT, and Soccol CR. 2023. The potential of xylooligosaccharides as prebiotics and their sustainable production from agro-industrial by-products. Foods 12, 2681.
    Pubmed KoreaMed CrossRef
  77. Vallino L, Garavaglia B, Visciglia A, Amoruso A, Pane M, Ferraresi A, and Isidoro C. 2023. Cell-free Lactiplantibacillus plantarum OC01 supernatant suppresses IL-6-induced proliferation and invasion of human colorectal cancer cells: Effect on β-catenin degradation and induction of autophagy. J. Tradit. Complement. Med. 13, 193-206.
    Pubmed KoreaMed CrossRef
  78. Wu Y, Hu A, Shu X, Huang W, Zhang R, Xu Y, and Yang C. 2023. Lactobacillus plantarum postbiotics trigger AMPK-dependent autophagy to suppress Salmonella intracellular infection and NLRP3 inflammasome activation. J. Cell. Physiol. 238, 1336-1353.
    Pubmed CrossRef
  79. Xie Z, Zhang G, Liu R, Wang Y, Tsapieva AN, Zhang L, and Han J. 2023. Heat-killed Lacticaseibacillus paracasei repairs lipopolysaccharide-induced intestinal epithelial barrier damage via MLCK/MLC pathway activation. Nutrients 15, 1758.
    Pubmed KoreaMed CrossRef
  80. Xu X, Wu J, Jin Y, Huang K, Zhang Y, and Liang Z. 2023. Both Saccharomyces boulardii and its postbiotics alleviate dextran sulfate sodium-induced colitis in mice, association with modulating inflammation and intestinal microbiota. Nutrients 15, 1484.
    Pubmed KoreaMed CrossRef
  81. Yang X, Cao Q, Ma B, Xia Y, Liu M, Tian J, Chen J, Su C, and Duan X. 2023a. Probiotic powder ameliorates colorectal cancer by regulating Bifidobacterium animalis, Clostridium cocleatum, and immune cell composition. PLoS ONE 18, e0277155.
    Pubmed KoreaMed CrossRef
  82. Yang W, Xia Z, Zhu Y, Tang H, Xu H, Hu X, Lin C, Jiang T, He P, and Shen J. 2023b. Comprehensive study of untargeted metabolomics and 16S rRNA reveals the mechanism of fecal microbiota transplantation in improving a mouse model of T2D. Diabetes Metab. Syndr. Obes. 16, 1367-1381.
    Pubmed KoreaMed CrossRef
  83. Ye W, Chen Z, He Z, Gong H, Zhang J, Sun J, Yuan S, Deng J, Liu Y, and Zeng A. 2023. Lactobacillus plantarum-derived postbiotics ameliorate acute alcohol-induced liver injury by protecting cells from oxidative damage, improving lipid metabolism, and regulating intestinal microbiota. Nutrients 15, 845.
    Pubmed KoreaMed CrossRef
  84. Yeşilyurt N, Yılmaz B, Ağagündüz D, and Capasso R. 2021. Involvement of probiotics and postbiotics in the immune system modulation. Biologics 1, 89-110.
    CrossRef
  85. Yildirim GK, Dinleyici M, Vandenplas Y, and Dinleyici EC. 2023. Effects of synbiotic supplementation on intestinal microbiota composition in children and adolescents with exogenous obesity: (Probesity-2 trial). Gut Pathog. 15, 36.
    Pubmed KoreaMed CrossRef
  86. Yu H, Li XX, Han X, Chen BX, Zhang XH, Gao S, Xu DQ, Wang Y, Gao ZK, and Yu L, et al. 2023. Fecal microbiota transplantation inhibits colorectal cancer progression: reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses. Front. Microbiol. 14, 1126808.
    Pubmed KoreaMed CrossRef
  87. Yunes RA, Poluektova EU, Belkina TV, and Danilenko VN. 2022. Lactobacilli: legal regulation and prospects for new generation drugs. Appl. Biochem. Microbiol. 58, 652-664.
    Pubmed KoreaMed CrossRef
  88. Zanetta P, Squarzanti DF, di Coste A, Amoruso A, Pane M, and Azzimonti B. 2023. Growth conditions influence Lactobacillus cell-free supernatant impact on viability, biofilm formation, and co-aggregation of the oral periodontopathogens Fusobacterium nucleatum and Porphyromonas gingivalis. Biomedicines 11, 859.
    Pubmed KoreaMed CrossRef
  89. Zhang Z, Guo Q, Wang J, Tan H, Jin X, Fan Y, Liu J, Zhao S, Zheng J, and Peng N. 2023a. Postbiotics from Pichia kudriavzevii promote intestinal health performance through regulation of Limosilactobacillus reuteri in weaned piglets. Food Funct. 14, 3463-3474.
    Pubmed CrossRef
  90. Zhang LL, Jin Q, Chai DQ, Kuang TR, Li CL, Guan YJ, Liu L, Wang WX, and Deng WH. 2022. The correlation between probiotic use and outcomes of cancer patients treated with immune checkpoint inhibitors. Front. Pharmacol. 13, 937874.
    Pubmed KoreaMed CrossRef
  91. Zhang M, Sasaki H, Yang T, Chen J, Li R, Yi C, Li J, He M, and Yi SQ. 2023b. Fecal microbiota transplantation from Suncus murinus, an obesity-resistant animal, to C57BL/6NCrSIc mice, and the antibiotic effects in the approach. Front. Microbiol. 14, 1138983.
    Pubmed KoreaMed CrossRef
  92. Zhao Z, Wu J, Sun Z, Fan J, Liu F, Zhao W, Liu WH, Zhang M, and Hung WL. 2023. Postbiotics derived from L. paracasei ET-22 inhibit the formation of S. mutans biofilms and bioactive substances: an analysis. Molecules 28, 1236.
    Pubmed KoreaMed CrossRef
  93. Zsálig D, Berta A, Tóth V, Szabó Z, Simon K, Figler M, Pusztafalvi H, and Polyák E. 2023. A review of the relationship between gut microbiome and obesity. Appl. Sci. 13, 610.
    CrossRef
  94. Zou B, Liu SX, Li XS, He JY, Dong C, Ruan ML, Xu L, Bai T, Huang ZH, and Shu SN. 2022. Long-term safety and efficacy of fecal microbiota transplantation in 74 children: a single-center retrospective study. Front. Pediatr. 10, 964154.
    Pubmed KoreaMed CrossRef
  95. Zubareva OE, Dyomina AV, Kovalenko AA, Roginskaya AI, Melik-Kasumov TB, Korneeva MA, Chuprina AV, Zhabinskaya AA, Kolyhan SA, and Zakharova MV, et al. 2023. Beneficial effects of probiotic Bifidobacterium longum in a lithium-pilocarpine model of temporal lobe epilepsy in rats. Int. J. Mol. Sci. 24, 8451.
    Pubmed KoreaMed CrossRef

September 2024, 60 (3)
Full Text(PDF) Free

Social Network Service
Services

Author ORCID Information