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Harnessing the Power of Microbiome-Based Therapies
Microbiome-based therapies restore healthy microbes and metabolic networks to promote health by manipulating microbial communities and restoring balance.
In recent years, the microbiome — a vast community of microorganisms inhabiting the human body — has emerged as a compelling area of research with immense therapeutic potential. The complex interplay between the microbiome and human health is now being studied, and scientists are exploring innovative microbiome-based therapeutics to revolutionize healthcare.
The Microbiome
The human microbiome comprises trillions of microorganisms, including bacteria, viruses, fungi, and other microbes, residing primarily in the gut, skin, and other mucosal surfaces. These microbes are crucial in various physiological processes, such as digestion, immune system modulation, and nutrient absorption. Disruptions in the delicate balance of the microbiome, known as dysbiosis, have been linked to various diseases, including metabolic disorders, autoimmune conditions, and mental health disorders.
Microbiome-Based Therapeutics
Microbiome-based therapeutics seek to restore the healthy microbial populations that reside on or within the host and the downstream metabolic networks that the microbiome directs by manipulating microbial communities to restore balance and promote health.
There are five main categories of microbiome-based therapies: prebiotics, fecal microbiota transplantation (FMT), probiotics, live biotherapeutics, and postbiotics.
Prebiotics
Prebiotics are non-digestible dietary fibers that selectively promote the growth and activity of beneficial bacteria in the gut while inhibiting the growth of harmful pathogens.
Because prebiotics are resistant to digestive processes in the upper gastrointestinal tract, they are not broken down by acids, bile salts, or digestive enzymes, allowing them to reach the colon intact. In the colon, they serve as substrates for fermentation by beneficial bacteria, producing short-chain fatty acids (SCFAs).
Short-chain fatty acids are crucial for lowering blood glucose levels, addressing insulin resistance, reducing inflammation, and promoting the secretion of glucagon-like peptide 1 (GLP-1) in the host. These functions contribute to the observed improvement in metabolic diseases like type 2 diabetes and obesity.
For example, butyrate and propionate, produced by gut bacteria, exhibit anti-inflammatory properties and play a vital role in maintaining gut health. Studies show that prebiotics can reduce inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-12, TNF-α, and IFN-γ and enhance the natural intestinal barrier by increasing the mucinous layer and tight junctions between epithelial cells.
Researchers are currently exploring synthetic versions of these metabolites as potential therapeutics for various inflammatory disorders.
FMT
Fecal microbiota transplantation, sometimes called bacteriotherapy, involves collecting feces from a healthy individual and introducing it into a patient's intestinal tract. This procedure aims to restore the recipient's gut bacterial diversity and the associated metabolites known as the metabolome.
While fecal microbiota transplantation is viewed as a less sophisticated type of live microbiome-based therapy due to the transplanted material usually being an undefined mixture of microbes, it has demonstrated remarkable efficacy in addressing recurrent Clostridioides difficile (formerly known as Clostridium difficile) infections (rCDIs) — a leading cause of healthcare-associated infections with a high relapse rate.
Globally, the general incidence of healthcare-associated CDIs is an estimated 2.24 infections per 1,000 admissions annually. Intensive care units and internal medicine wards exhibit substantially higher rates than community-associated CDIs, with 11.08 and 10.80 infections per 1,000 admissions annually, respectively. Moreover, CDIs demonstrate a notable relapse rate of 20–30%, leading to prolonged hospital stays and a significant economic burden, contributing to healthcare costs ranging from $5.4 to $6.3 billion annually in the US.
C. difficile is known to cause diarrhea and inflammation of the colon, and recurrent infections occur when a patient experiences multiple episodes of C. difficile infection after completing a course of treatment. C. difficile infections often result from disruptions in the normal gut microbiota, commonly associated with antibiotics. While initial infections can be treated with antibiotics, some individuals are prone to experiencing recurrent episodes. This recurrence may be attributed to factors such as persistent spores of C. difficile in the environment, alterations in the patient's gut microbial composition, or other underlying health conditions.
According to a 2023 Cochrane Review, FMT is significantly more effective than antibiotics in treating recurrent rCDIs. The review analyzed six randomized clinical trials involving 320 patients. It concluded that FMT is likely to lead to a substantial increase in the resolution of rCDI symptoms in immunocompetent patients compared to antibiotic treatment. The review also indicated that FMT may result in fewer adverse events and reduce overall mortality rates.
Probiotics
Probiotics are live microorganisms, including Lactobacillus, Bifidobacterium, and Saccharomyces, that confer health benefits to the host when administered in adequate amounts. They can produce antimicrobial peptides, enhance mucus production, regulate mucosal immune functions, and augment or restore specific microbial populations in the body. Recent advances in strain selection, formulation, and delivery systems have allowed for the development of targeted probiotic therapies for conditions such as irritable bowel syndrome (IBS) and allergic diseases.
Studies have indicated that probiotics can improve IBS symptoms, such as stool frequency, gut transit time, and stool consistency. One specific strain, Bacillus coagulans strain LBSC (DSM17654), has shown efficacy in alleviating multiple IBS symptoms such as bloating, abdominal pain, constipation, diarrhea, nausea, vomiting, and stomach rumbling. It has been deemed safe for consumption and associated with improved quality of life in IBS patients.
Additionally, some studies have shown the beneficial effects of probiotics in treating allergic diseases. Although probiotics do not cure allergies, administration can reduce allergy symptoms' morbidity and duration. Researchers have found that the efficacy of probiotics is influenced by factors such as the composition and activity of the individual's intestinal microbiota and the metabolites produced by the probiotic species. Therefore, prior knowledge of the individual's intestinal microbiota status before probiotic use could enhance effectiveness.
Live Biotherapeutics
Live biotherapeutics are refined forms of microbiome-based therapeutics consisting of specific bacterial species or combinations designed to provide clinical benefits for targeted diseases. They are distinct from probiotics and are isolated from fecal bacterial populations.
Live biotherapeutics offer a safer alternative to fecal transplant mixtures, although identifying a single or combination of bacteria with comparable effects to fecal transplants remains challenging. Nonetheless, they show promise in treating dysbiosis-related diseases.
On April 26, 2023, the US FDA approved Seres Therapeutics’ live microbiome capsule Vowst (fecal microbiota spores, live-brpk). Vowst, previously called SER-109, is the first orally administered fecal microbiota product approved for preventing rCDIs in individuals aged 18 and above. Phase 3 clinical trials have conclusively shown that SER-109 significantly decreases the likelihood of infection recurrence compared to a placebo. These compelling results highlight the potential of SER-109 as a pioneering microbial therapy, marking a significant advancement in the field.
In addition, Memorial Sloan Kettering Cancer Center and Seres Therapeutics have joined forces to conduct clinical research on SER-155. This investigational fermented microbiome therapeutic is designed to be taken orally. It aims to lower the risk of gastrointestinal infections, bacteremia, and graft versus host disease (GvHD) in immunocompromised patients, including those undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, SER-155 is in Phase 1b of clinical trials.
In collaboration with Nestlé Health Science, Seres Therapeutics is also researching SER-287 and SER-301 for treating ulcerative colitis.
Postbiotics
Postbiotics are soluble, bioactive compounds microbes produce during fermentation, including cell wall components, enzymes, and metabolic byproducts. These compounds can have direct health benefits without requiring live microbial cells.
An example of well-studied microbial-derived metabolites includes secondary bile acids, actively tested for their therapeutic effects. In mouse models, secondary bile acids exhibit anti-inflammatory effects on immune cells and alleviate intestinal inflammation of colitis. Several studies are underway to evaluate the therapeutic effect of a secondary bile acid called ursodeoxycholic acid in IBD, a predisposing factor for colitis-associated cancer.
Researchers note that high concentrations of secondary bile acids can promote colorectal tumorigenesis by causing oxidative stress and DNA damage in the epithelium. Because of this, postbiotic therapy is designed to identify and isolate the downstream metabolites produced by beneficial bacteria in the microbiome and administer them to treat diseases while avoiding any detrimental side effects. Postbiotic therapeutics offer the potential for chemical modifications to minimize unintended interactions and enhance their desired therapeutic effects.
Representing a previously untapped frontier in healthcare, the microbiome has the potential to transform the treatment trajectory for numerous diseases. Microbiome-based therapeutics offer a novel way to restore microbial balance and promote health. Recent successes in clinical trials and first-of-a-kind FDA approvals demonstrate the progress in this field.
As research and understanding of the microbiome deepen, it opens possibilities for personalized medicine and targeted interventions tailored to an individual's unique microbial composition. However, challenges remain, including the need for standardized manufacturing processes, rigorous clinical trials, and regulatory frameworks to ensure safety and efficacy.