In recent decades, researchers have uncovered several connections between microbiota and the health of the host. The human microbiome encompasses all the bacteria and derived metabolites present within and on the human body.¹ The microbiota residing in the gut, oral cavity, nasal cavity, skin, and vagina maintain a delicate equilibrium that facilitates digestion, nutrient acquisition, and protection against pathogens, thereby, contributing to the homeostasis of the host.² The microbiome is not merely a passive observer; it actively influences multiple processes within the host body, including circadian rhythm, nutritional responses, metabolism, and immunity.³ The microbiome significantly impacts the programming and development of key components of the host’s innate and adaptive immune systems.^4,5

The relationship between therapeutics and microbiota is bidirectional, with each influencing the other. A recent pharmacological study found that approximately 25% of over 1,000 non-antibiotic drugs tested exhibited antibacterial properties when evaluated against 40 types of human gut flora.⁶ Another study revealed that out of 271 drugs tested on 76 human gut bacterial species, 176 significantly inhibited bacterial growth by more than 20%.⁷ Additionally, research employing high-throughput genomic analysis and mass spectrometry has identified causal links between microbiota and variations in microbiomes, which contribute to individual differences in drug metabolism.^4,8 These findings have profound implications for the identification and understanding of the non-target effects of a broad range of medications.

Microbiome therapy offers several advantages over conventional therapeutics. Microbes are indigenous inhabitants of the human body, and their therapeutic potential can be harnessed with minimal adverse side effects. Recent research demonstrates that Christensenella spp. can reduce symptoms of depression and anxiety. Additionally, Akkermansiamuciniphila has been shown to alleviate metabolic diseases and enhance the efficacy of metformin in cancer treatment. This microbe also protects against atherosclerosis by reducing intestinal permeability and inhibiting inflammation.^8,9 Lactobacillus johnsonii offers protective effects against cancer, while Bifidobacterium longum mitigates the severity of Crohn’s disease and restores the integrity of the mucus layer compromised by a high-fat diet.³ Oxalobacter formigenes maintains the balance of oxalic acid, thus preventing the formation of kidney stones, and Bacteroides species confer protection against obesity.^10,11

Numerous studies have established the crucial role of the microbiome in both health and disease. Microbiome-based therapies can be broadly categorized into three paradigms: 1) additive, 2) subtractive, and 3) modulatory therapies.¹² Additive therapy involves the enhancement of host microbiota through the introduction of specific strains of microorganisms, which may be natural or genetically modified, while subtractive therapy entails the targeted removal of pathogenic microorganisms from the microbiome to treat a disease. Modulatory therapy, on the other hand, involves the use of non-living substances, such as prebiotics, to alter or regulate the composition or behavior of the host microbiome. Probiotics and prebiotics represent the earliest forms of microbiome therapy and have been extensively studied.^13,14

Microbial diversity varies across different body sites, and the complexity and function of bacterial communities are influenced by factors such as health status, genetics, diet, and hygiene practices.⁵ The environmental and biological characteristics of each body habitat significantly influence the microbial richness and genetic diversity of the associated microbiomes.¹⁵ Although yeast and viruses are integral components of the human microbiome, most research has focused predominantly on host-associated bacteria. Microbial dysbiosis is associated with various human health conditions, including obesity, inflammatory bowel diseases (IBDs), autoimmune disorders (e.g., rheumatoid arthritis), and mental health issues such as stress and Alzheimer’s disease. Dysbiosis of the gut, oral, or skin microbiomes is also linked to conditions like periodontal disease, acne, and eczema.^16,17 In this review, we explore the most recent developments in microbiome-based medicines, different types, and the processes through which these medicines operate.

FMT is the procedure to administer a solution of fecal matter from a healthy donor into the intestine of a recipient to change the recipient’s microbial composition and provide health benefits to the recipient³³ This process involves the selection of appropriate donors that do not have any family history of autoimmune, malignant, or metabolic diseases and any potential pathogens. The solution of the donor’s feces is prepared in water or normal saline, filtered, and administered through colonoscopy, nasogastric tube, nasojejunal tube, or esophagogastroduodenoscopy.³⁴ FMT has traditionally been used in ancient China and Indigenous Australian culture for healing purposes (Figure 2). Nevertheless, its potential as a modern treatment has only been acknowledged over the last two to three decades.³⁵

FMT is safe and effective in treating patients with Clostridium difficile infection (CDI) in more than 70 clinical studies, with reported success rates ranging from 85% to 95%. FMT is thought to increase the diversity and abundance of bacteria in the gastrointestinal system through C. difficile and avert reinfection.³⁶

A study conducted by Philips et al.³⁷ has shown that patients with severe alcohol-associated hepatitis due to long-term, high-dose alcohol consumption may potentially derive the largest degree of benefit from this novel FMT therapy. He conducted one of the first pilot trials comparing the effects of FMT on eight male patients with severe alcohol-associated hepatitis to a group of 18 controls with the same condition who received standard-of-care treatment over 7 days.³⁷ The FMT arm showed a substantial improvement in liver disease severity indices and survival rates compared to the conventional treatment arm. These findings indicate that FMT enhances longevity beyond the benefits provided by existing treatments and might serve as a cost-effective means of facilitating liver transplantation. Another research has shown that the FMT may have the ability to decrease alcohol demand and intake, as well as prevent long-term hospitalizations associated with alcohol use disorders.³⁸

In this unblinded, randomized controlled crossover study, the typical therapy group had a 50% recurrence rate, while the FMT arm showed no recurrence. FMT therapy demonstrated not only long-term safety and efficacy, with effects maintained for 1 year, but also resulted in an increased variety of microorganisms in the engrafted feces and the number of helpful bacteria Lactobacillaceae and Bifidobacteriaceae.³⁸ Further, FMT is a successful treatment method for antibiotic-induced dysbiosis in C. difficile infections. It has exhibited high efficacy in treating patients with recurrent C. difficile infections.³⁹ Many clinical studies are being conducted to assess FMT potentials to reduce or eliminate antibiotic-resistant bacteria in the digestive system.⁴⁰ Alcoholic hepatitis and cirrhosis are both associated with a shortage of mucosa-associated invariant T lymphocytes. The recovery of these T-cells was found in patients after FMT. ⁴¹

Researchers are now studying the potential application of FMT therapy in immunological-related disorders because of the microbiome’s substantial impact on the immune system. These disorders include acute graft-versus-host disease (GVHD), Type I diabetes, and multiple sclerosis. The outcomes of these investigations have shown variability; overall, they have shown promise, especially in the management of GVHD.⁴² A recent study indicated that gut microbiota plays a crucial role in metabolizing foreign medicines and regulating immune responses, which has significant implications for cancer therapy. For example, FMT can enhance the efficacy of immunotherapy and alleviate the adverse effects of chemotherapy. These results indicate that microbiome-based treatments have the potential to become the primary method to tailor anticancer medicines in the future.⁵

The global decline in the efficacy of antibiotics has fostered interest in looking for other alternative strategies for prophylaxis and control of infectious diseases. Recently, technological advancements, like next-generation sequencing and electron microscopy, have sparked a revival in phage therapy research. Phage therapy is the use of bacteriolytic phages to treat bacterial infections.⁴³ The use of bacteriophages as solitary therapeutic agents dates back more than 100 years.⁴⁴ As an alternative treatment, phage therapy is being supported due to several advantages phages have over antibiotics, including self-amplification, biofilm degradation, host-specificity, and low toxicity to humans.⁴⁵ This therapy could not only be administered as a sole alternative to antibiotics but also as a combination with them.⁴⁶ A recent study demonstrated synergistic potential and a reduced acquisition of resistance in bacteria.⁴⁷

In a clinical trial, phage cocktails specifically prepared against difficult-to-treat E. coli, Staphylococcus aureus, and Pseudomonas aeruginosa infections, as well as multidrug-resistant bacterial diseases such as methicillin-resistant S. aureus or Acinetobacter baumannii, have shown promise. It has been demonstrated that active phages contribute to positive outcomes of therapy by colonizing the host following FMT.⁴⁸ Another study suggested that the effectiveness of the sterile filtrate of FMT in patients with CDI may be partially due to phages.⁴⁹ Host specificity of the phage offers an opportunity to specifically reduce the population of infection-causing pathogen bacteria, preserving beneficial microbiota. Therefore, the composition and role of indigenous microbiota must be taken into consideration while planning phage therapy.⁴⁷

Microbiome engineering has entered a new era with the advent of synthetic biology, as it enables the construction of tailor-made microbial strains with important therapeutic applications. Whole-genome editing with CRISPR-Cas9 is being extensively used to genetically engineer microbial genomes, thereby improving or obtaining various bacterial characteristics that can be used to treat diseases.⁵⁰ Genetically engineered bacterial strains are used to produce the cytokine interleukin-22, which plays a key role in maintaining gut barrier integrity and helps to control immune responses. The administration of this engineered bacterial strain to models of IBD not only resulted in a reduction in gut inflammation but also a considerable improvement in mucosal lining. These results suggest that it could serve as a therapy for Crohn’s and other conditions such as ulcerative colitis.⁵¹

The gut microbiota produces a wide variety of compounds that are used both by the host as well as by other microorganisms. These interactions between the organisms, termed host–microbe and microbial community interactions, are important to shaping the host microbial symbiosis and the establishment of stable microbiota communities to promote host health.^7,11 Microbiome mimetics are interventions that replicate the interactions between the microbiome and host, leading to beneficial therapeutic outcomes. These include traditional therapies, bacteria-derived products, small molecules, or host-derived products.⁵² The majority of the health benefits conferred by the administration of probiotics and prebiotics are due to the production of components like functional proteins, microbial fractions, secreted polysaccharides, cell lysates, teichoic acid, and pili-type structures,^23,53 which gave rise to the concept of “postbiotics,” the newest member of the “biotics” family. Other studies used the terms “paraprobiotics,” “non-viable microbial cells,” and “fermented infant formulas” (FIFs) for postbiotics. Postbiotics are fermentation compounds that can be used in combination with nutritional components to provide health benefits.⁵⁴ The two most common classes of postbiotics are para-probiotics, which are non-viable components of bacteria (bacterial proteins and polysaccharides), and FIFs, which are purified products produced after the infant formula is fermented by lactic acid-producing or other bacteria.⁵⁵ Postbiotics are based on proteins, lipids, carbohydrates, metabolites, vitamins, organic acids, cell wall components, and other molecules secreted during fermentation. Hence, their composition could vary by methods used for food processing such as heat, pressure, sonication, and irradiation, and it can affect the efficacy of postbiotics (Table 1).⁵⁶

Short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate produced by bacterial fermentation are the most commonly used postbiotics. It has been found that SCFAs have beneficial effects on the mucosal immune system and are also found to be efficient in delaying the onset of type 1 diabetes mellitus in mice.^55,57 Future microbiome therapies may include the augmentation of dietary intervention to provide beneficial effects through microbiota that will help to bring closer the concept of personalized treatment by integrating the knowledge from food and microbiology.

Microbiome-based therapeutics include prebiotics, probiotics, live microorganisms, microbiome mimetics, and others. All of them have their unique composition and mode of action in the host body. Using modern techniques such as bioinformatics, genetic engineering, metagenomics, and metabolomics can give a whole new direction to this therapy. We can experience oral, FMT, and site- specific microbiome medicines. In the near future, there is a huge potential for person- and disease-specific, genetically modified microbiome therapeutics. This can revolutionize the treatment methods and the overall health management. The main obstacles currently encountered include identifying clinical conditions that may be effectively treated with microbiome-based medications and developing suitable approaches to discover, improve, and evaluate potential therapeutics. Although targeted therapeutics, such as modified bacteria, postbiotics, and phages, have been tested in several preclinical settings, their full effectiveness and safety remain to be evaluated. Most current studies focus on short-term outcomes; there are limited clinical data on the safety and effectiveness of long-term use of microbiome-based therapies. We are of the view that there is a need for post-market surveillance and long-term risk assessment of these therapies. Without these data, regulatory approval and patient confidence in microbiome-based therapies will remain limited. More randomized controlled trials on larger cohorts are needed to build a durable foundation for the wider adoption of microbiome therapeutics.