Live Biotherapeutics: Key Insights on Microbial Therapies

Live biotherapeutics are an emerging class of microbial therapies designed to treat or prevent disease by modulating the human microbiome. Unlike traditional pharmaceuticals, these treatments use living microorganisms to improve health. With growing recognition of the microbiome’s role in various conditions, live biotherapeutics are gaining attention for their potential in gastrointestinal disorders, infections, and immune-related diseases.

Defining Characteristics And Composition

Live biotherapeutics differ from other microbiome-based interventions due to their precise formulation, regulatory classification, and therapeutic intent. Unlike probiotics, which are marketed as dietary supplements, live biotherapeutic products (LBPs) are classified as drugs and must meet stringent regulatory requirements for safety, efficacy, and manufacturing consistency. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regulate LBPs as biological products, subjecting them to rigorous clinical evaluation.

The composition of these therapies is carefully designed, typically consisting of a single strain or a defined consortium of strains with targeted therapeutic properties. For example, SER-109, developed for recurrent Clostridioides difficile infection, is composed of purified Firmicutes spores from healthy donors to ensure a controlled and reproducible microbial composition.

Manufacturing live biotherapeutics requires advanced bioprocessing techniques to maintain microbial viability and stability. Unlike standard probiotics, which may be freeze-dried or encapsulated without strict viability controls, LBPs must be produced under Good Manufacturing Practice (GMP) conditions to ensure consistency. This involves precise control over oxygen levels, pH, and nutrient availability during fermentation, as well as specialized cryopreservation or lyophilization methods. Regulatory agencies also mandate extensive characterization of these products, including whole-genome sequencing to confirm strain identity and potency assays to verify functional activity.

Microbial Species Commonly Used

Microbial species for live biotherapeutics are selected based on their ability to colonize, persist, and exert targeted effects. Commonly used bacteria include Clostridium, Bacteroides, Lactobacillus, and Bifidobacterium, which play critical roles in gut health and disease mitigation.

Clostridium species, particularly those in Clostridium cluster IV and XIVa, produce short-chain fatty acids (SCFAs) like butyrate, which support intestinal barrier integrity and regulate inflammation. Clostridium butyricum has been explored for treating gastrointestinal disorders by restoring microbial diversity and enhancing mucosal health. SER-109 has demonstrated efficacy in reducing recurrent Clostridioides difficile infections by reintroducing beneficial bacteria that inhibit pathogen overgrowth.

Bacteroides species, such as Bacteroides fragilis, contribute to microbial therapies by producing polysaccharide A, which modulates gut-associated metabolic processes. Their metabolic versatility makes them candidates for treating conditions linked to microbial imbalances, including metabolic syndrome and inflammatory bowel diseases.

Lactobacillus and Bifidobacterium species are also integral to live biotherapeutic development. Lactobacillus rhamnosus GG reinforces epithelial integrity, while Bifidobacterium longum enhances dietary fiber fermentation into bioactive metabolites. Unlike conventional probiotics, strains selected for live biotherapeutics undergo rigorous characterization to ensure measurable therapeutic benefits.

Mechanisms Within The Human Body

Once administered, live biotherapeutics interact with the host through complex processes that influence microbial composition and metabolic activity. Their effectiveness begins with their ability to survive transit through the gastrointestinal tract. Acid resistance, bile salt tolerance, and mucosal adhesion determine whether a strain can persist long enough to function. Certain bacterial species, such as Bacteroides and Clostridium, possess mechanisms enabling them to withstand stomach and small intestine conditions, ensuring they reach the colon.

Once in the gut, these microorganisms contribute to their therapeutic potential through metabolic interactions. Some strains produce bioactive compounds, such as SCFAs or bacteriocins, which promote beneficial bacterial growth while inhibiting harmful species. Clostridium butyricum, for instance, enhances butyrate production, which strengthens the intestinal barrier. Bacteroides fragilis ferments dietary polysaccharides into metabolites that support microbial diversity and maintain gut stability.

Live biotherapeutics also influence microbial interactions through competitive exclusion, where beneficial microbes outcompete pathogenic species for nutrients or attachment sites. In cases of recurrent Clostridioides difficile infection, SER-109 introduces Firmicutes spores that germinate into beneficial bacteria, restoring microbial balance and reducing pathogen colonization. This principle applies to other conditions where dysbiosis contributes to disease, such as antibiotic-associated diarrhea.

Distinctions From Conventional Probiotics

Live biotherapeutics and conventional probiotics differ in purpose, regulatory oversight, strain selection, and clinical validation. While probiotics are marketed as dietary supplements for general gut health, LBPs are pharmaceutical treatments for specific diseases. This distinction requires LBPs to undergo rigorous regulatory approval, including preclinical and clinical trials demonstrating safety, efficacy, and manufacturing consistency. In contrast, probiotics are evaluated primarily for general safety rather than disease-targeted outcomes.

LBPs include specific strains with documented effects on disease pathology, unlike probiotics, which often contain broadly beneficial species such as Lactobacillus and Bifidobacterium. For instance, SER-109, composed of Firmicutes spores, is designed to restore microbial balance in patients with recurrent Clostridioides difficile infections. Traditional probiotics lack the strain-specific functionality required to address complex microbiome-related diseases.

Standard Approaches To Strain Classification

Classifying microbial strains for live biotherapeutics ensures consistency, safety, and therapeutic viability. Unlike conventional probiotics, which are often identified at the species level without extensive characterization, LBPs undergo rigorous taxonomic and functional assessments. Whole-genome sequencing provides insight into genetic stability, antimicrobial resistance genes, and functional capabilities. Regulatory agencies mandate precise classification to prevent contamination, ensure reproducibility, and maintain efficacy.

Beyond genomic identification, strain classification involves assessing microbial viability, metabolic output, and host interactions. Advanced analytical techniques, such as metagenomic sequencing and mass spectrometry, determine whether a strain can survive in the human body and produce relevant bioactive compounds. For example, Clostridium species are classified based on SCFA production, while Bacteroides strains are evaluated for polysaccharide metabolism. These classifications inform dosing strategies, storage conditions, and formulation methods to maintain potency. Standardized classification protocols ensure live biotherapeutics deliver consistent therapeutic outcomes.