Microbiome-Targeted Therapies: Developments and Recent Updates

The microbiome, a complex microbial community found in ecosystems like animals, plants, and humans, plays a crucial role in maintaining health and preventing diseases. These communities promote healthy growth, protect against infectious diseases, and support complex behavioural traits in animals like learning and memory. Human microbiota, also known as "the hidden organ," plays a pivotal role in maintaining physiological functions, such as nutrient extraction, biosynthesis, immune, endocrine, and nervous system interactions, and resistance to pathogen colonization. Research in microbiome therapies is advancing rapidly, leading to a new era of precision medicine where the gut microbiome becomes an integral part of the clinical landscape. Microbiome therapies play a vital role in impacting gut health by modulating the gut microbiota to achieve beneficial effects for the host. This research is paving the way for a new era of precision medicine, where the gut microbiome becomes an integral part of the clinical landscape.

The microbiome refers to the complex microbial communities that inhabit various ecosystems, including animals, plants, and humans, playing a crucial role in maintaining health and preventing diseases [1-3]. These communities consist of a wide array of microorganisms such as bacteria, fungi, archaea, viruses, and protozoa, with interactions that are essential for the well-being of their hosts [4]. The microbiome's functions include promoting healthy growth, protecting against infections, supporting immunity, and aiding in nutrient bioconversion and detoxification processes [2]. Microbiomes are generally beneficial to their animal and plant hosts, functioning to promote healthy growth, to protect against infectious disease, and, in some animals, to support complex behavioural traits, such as learning and memory. They also help protect against infectious diseases by strengthening the host's immune system. In some animals, microbiomes support complex behavioural traits like learning and memory, showcasing their diverse functions [3]. However, under some circumstances, the microbiome can cause or exacerbate poor health and disease. Environmental factors can influence the balance of the gut microbiota, impacting overall health and disease susceptibility [2]. With advancements in genome sequencing and meta-omics tools, researchers can now conduct in-depth analyses of microbiomes, accelerating the progress of microbiome research in various fields, from environmental sciences to medicine [1-3]. Overall, microbiomes are vital for the overall well-being of animals and plants, highlighting the intricate relationship between these microorganisms and their hosts. It is becoming increasingly clear that the human microbiota, also known as “the hidden organ”, possesses a pivotal role in numerous processes involved in maintaining the physiological functions of the host, such as nutrient extraction, biosynthesis of bioactive molecules, interplay with the immune, endocrine, and nervous systems, as well as resistance to the colonization of potential invading pathogens. In the last decade, the development of metagenomic approaches based on the sequencing of the bacterial 16s rRNA gene via Next Generation Sequencing, followed by whole genome sequencing via third generation sequencing technologies, has been one of the great advances in molecular biology, allowing a better profiling of the human microbiota composition and, hence, a deeper understanding of the importance of microbiota in the etiopathogenesis of different pathologies. In this scenario, it is of the utmost importance to comprehensively characterize the human microbiota in relation to disease pathogenesis, in order to develop novel potential treatment or preventive strategies by manipulating the microbiota. Therefore, this perspective will focus on the progress, challenges, and promises of the current and future technological approaches for microbiome profiling and analysis.

The human microbiome plays a crucial role in maintaining health and preventing disease by influencing processes like nutrient extraction, immune regulation, and resistance to pathogens [5,6]. Research highlights the impact of microbiome dysbiosis, caused by factors such as diet, lifestyle, and infections, on conditions like obesity, diabetes, and mental health [7]. Advances in metagenomic techniques have deepened our understanding of the microbiome's composition and its significance in various pathologies [6]. The human gut microbiome, a complex ecosystem of trillions of microorganisms, has become a topic of intense research in recent years due to its significant impact on human health and disease. This microbial community, which resides in the gastrointestinal tract, plays a crucial role in various physiological functions, including digestion, energy metabolism, and modulation of the immune system [8-11]. Emerging evidence suggests that an imbalance or disruption in the gut microbiome, known as dysbiosis, can contribute to the development of a wide range of diseases, such as inflammatory bowel diseases, metabolic disorders, an even neurological conditions [12]. Consequently, the potential to manipulate the gut microbiome for therapeutic purposes has garnered substantial interest from the scientific and medical communities [13].

Furthermore, the oral microbiome has been identified as pivotal in disease progression within the oral cavity, emphasizing the need for innovative detection methodologies and therapeutic strategies to maintain oral health [14]. Overall, the intricate relationship between the human microbiome and health underscores the importance of further research and interventions to harness its potential for personalized medicine and disease prevention [15]. As our understanding of the gut microbiome continues to evolve, the development of personalized, microbiome-based therapies holds great promise for the future of healthcare. By tailoring interventions to an individual's unique gut microbial profile, clinicians can potentially improve the diagnosis, treatment, and prevention of a wide range of diseases [10].

Ongoing research in this rapidly advancing field is paving the way for a new era of precision medicine, where the gut microbiome becomes an integral part of the clinical landscape. Since the 80s, research on the impact of host microbiota on drugs has led to the development of pharmacogenomics, which focuses on how human genetic variation affects drug action and effectiveness, resulting in toxicity effects and the "responder-no-responder" effect [15,16].

Microbiome therapeutics have emerged as a promising approach in addressing various human disorders by leveraging the role of gut microbes in human health [17]. The gut microbiome, in particular, has been identified as a potential target for personalized treatments, including in conditions like Parkinson's disease where dysbiosis plays a role [18]. Furthermore, the interaction between the microbiome and the immune system is crucial in the development of autoimmune disorders, highlighting the impact of dysbiosis on disease pathogenesis [19]. In addition to human health, the plant microbiome also plays a significant role in plant health through interactions in the rhizosphere, such as symbiotic relationships with rhizobia and mycorrhizae, ultimately affecting nutrient absorption and overall plant well-being [20]. Overall, microbiome-based therapies offer a novel and potentially effective strategy for managing a wide range of health conditions by modulating the microbial communities within the body. Microbiomes studies are increasingly being harnessed, especially in biomedicine for improved human health, and in agriculture for crop production. With the increasing evidence that modern lifestyles and excessive use of antimicrobials are degrading microbiomes, microbiome research is providing routes for novel microbial therapies to restore health-promoting microbiomes in humans, other animals, and plants.

Furthermore, the concept of precision medicine has been extended to the microbiome, with researchers exploring ways to develop targeted approaches for controlling microbial metabolic activity and their interactions with host tissues [21]. While these developments hold great promise, the process of developing microbiome-based therapies is time-consuming and complex, requiring a deep understanding of the intricate relationships between the microbiome, host, and disease [8].

As the field of microbiome research continues to evolve, the potential for personalized and precise microbiome-based treatments to improve human health and combat diseases is becoming increasingly apparent. The field of microbiome therapeutics aims to modulate microbiomes with various approaches, including genetically engineered probiotics, chemicals, peptides, and bacteriophages, to diagnose diseases and enhance therapeutic protein production [22]. Overall, microbiome therapeutics offer promising avenues for personalized care and novel treatment strategies in human disorders [17].

A key factor in the development of microbiome-targeted therapies is the recognition that the human gut microbiome is a complex and dynamic ecosystem, influenced by various factors such as diet, environment, and host genetics [21]. Antibiotics, in particular, can have a profound impact on the gut microbiome, leading to the depletion of microbial diversity and the proliferation of antibiotic-resistant pathogens [23]. Microbiome therapies have seen significant advancements in recent years, with a focus on leveraging the human microbiota to manage various health conditions.

Research has shown the microbiome's role in human health and disease, leading to the development of microbiome-based therapeutics. Microbiome therapies play a crucial role in impacting gut health by modulating the gut microbiota to achieve beneficial effects for the host. These therapies can be categorized into additive, subtractive, or modulatory approaches. Additive therapy: Additive therapy involves supplementing the host's microbiota with natural or engineered microorganisms, while subtractive therapy involves eliminating harmful microbiome members to cure diseases.

Modulatory therapies: Modulatory therapies use non-living agents, like probiotics to change the endogenous microbiome's composition. In addition to probiotics, other microbiome-based therapies, including the use of prebiotics, fecal microbiota transplantation, and targeted antimicrobial therapies, are being explored for their potential in treating. Probiotics are live microorganisms that, when administered in sufficient amounts, provide health benefits to the host, with different probiotics influencing the immune system differently, despite their wide range of potential health benefits. Prebiotics are fermented ingredients that alter the gastrointestinal microflora, promoting host health. These fibers, which cannot be digested by the host, are metabolized by the colonic microbiome, leading to the expansion of certain bacterial species and the release of metabolites like SCFAs. The combination of probiotics and prebiotics is termed ‘synbiotics’. A promising approach is the use of probiotics, such as Lactobacillus rhamnosus GG, which have been shown to promote a healthy gut microbiome and provide various health benefits [24]. These beneficial microorganisms can be administered as supplements or incorporated into foods to help restore the balance of the gut microbiome and mitigate the effects of dysbiosis [10]. Techniques like probiotics, prebiotics, synbiotics, and FMT have been explored to address dysbiosis-related issues and restore gut microbiota balance [25]. Efforts have been made to develop microbiota-directed therapeutics targeting gut microbiota for disease treatment and wellness maintenance, highlighting the need for advanced -omics approaches and ex vivo microbiome assays for evaluating biotherapeutics [26].

ISAPP defined probiotics in 2013 as live microorganisms that, when administered in sufficient amounts, provide health benefits to the host [27]. Probiotics, based on naturally occurring microbes, have been shown to remedy various diseases, have been utilized to restore the balance of gut microbes and promote digestive well-being [28-32]. Probiotics and prebiotics are the first generation of microbiome therapies, based on the belief that naturally occurring human-associated microbes offer numerous health benefits [10,33-37]. Oral ingestion of Lactobacillus spp., E. coli, and Bifidobacterium spp. has been shown to cure various diseases [37-40]. Recent efforts aim to enhance their benefits through recombinant expression of therapeutic biomolecules. Probiotics were utilized to support gut microbiota balance in the 1970s. "Live bacteria that bestow a health benefit on the host" is how the 2001 Expert Committee for the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) defined pro-biotics [41].

Probiotics and prebiotics, through the introduction of beneficial bacteria and fuel for these microbes, respectively, help in maintaining a diverse and strong gut ecosystem, aiding in digestion, nutrient absorption, and immune function.

Probiotics are live microorganisms that, when given in sufficient doses, benefit their hosts' health. The phrase also refers to well-studied, safe gut symbiotic bacteria (certain strains or combinations of strains) whose disappearance could have a detrimental effect on a host's health [41]. Although probiotics have been effectively used safely for many years, their benefits to the economy were not realized until the early 1900s. It was projected that food firms, nutraceutical companies, and probiotic manufacturing companies will dominate the $46.55 billion worldwide probiotic industry by 2020. Probiotic microorganisms derived mostly from the gastrointestinal system or traditionally fermented foods like kefir grains, yoghurt, and pickles are included in these products. Therefore, a few numbers of species, particularly Lactobacillus and Bidoxobacterium, provide the majority of probiotics used and provided in probiotic clinical studies and commercial probiotic manufacture [42].

Probiotics may provide these advantages in a number of ways, including by reducing pathogens or their metabolites, modifying mucosal immunity, or enhancing mucosal integrity, according to research conducted in vitro in addition to animal models [41]. The risk associated with probiotics is decreased since they are defined and grown in a clean culture [43]. Probiotics and synbiotics can effectively lower diabetics' fasting blood sugar levels, most likely through the restoration of the disturbed ecology, corresponding to a recent meta-analysis [44-46].Probiotics have been demonstrated to enhance intestinal epithelial barrier function, produce lactic acid and bacteriocins, reduce the pH of the gut, and modulate the body's immune system through these pathways [42].

Probiotics, including Lactobacillus, Bifidobacterium, Escherichia coli, Enterococci, and Weissella, improve intestinal barrier function, increase IgA levels, restore gut microbiome homeostasis, and reduce gastrointestinal pathogens. These bacteria are crucial for human health, maintaining gut homeostasis, supporting immune system function, and protecting against pathogens. In vitro and clinical trials have examined the beneficial effects of probiotics on host health and their role in various diseases [47,48].Probiotic categories include dietary supplements, medicines, live biological agents, medical food, and functional foods. Precision probiotics combine common microorganisms and bacteriophages to alter microbiota [49]. Recombinant microbes have been shown to effectively treat metabolic diseases like obesity and diabetes. Daily feeding of probiotic E. coli reduced obesity, adiposity, and food intake in mice, with protective effects lasting weeks after bacterial treatment cessation [50]. Lactobacillus gasseri was used to deliver GLP-1, a protein that converts intestinal epithelial cells into insulin-producing ones, increasing the number of insulin-producing cells and reducing hyperglycemia in a rat model [51]. Danino, et al. [52] developed a non-invasive biosensor for cancer metastasis, using E. coli's natural translocation to the liver and bacterial enzymatic activity to excrete compounds detected in urine.

Prebiotics are substrates used by host microorganisms to provide health benefits, with a substance, physiological effect, and microbiota-mediated mechanism [53]. They can be found naturally or synthesized in various forms like inulin, oligosaccharides, lactulose, pyrodextrins, dietary fibers, and resistant starches [54]. Prebiotics, which are non-digestible fibers that selectively promote the growth of beneficial gut bacteria, can also be used to modulate the gut microbiome and improve overall gut health [8]. Moreover, fecal microbiota transplantation, which involves the transfer of gut microbiota from a healthy donor to a recipient, has shown promising results in the treatment of recurrent Clostridioides difficile infections and inflammatory bowel diseases [55]. Prebiotics have shown potential in treating various diseases by modulating the gut microbiome, including IBD. They enhance the gut microbiome's composition and reduce inflammation. Plant-based prebiotics, including fibers like inulin, resistant starch, and rice bran, can help treat Parkinson's disease by promoting beneficial bacteria growth in the gut. Prebiotic metabolism produces SCFAs that reduce inflammation and improve motor function [56]. Prebiotics also have beneficial effects on diabetes and obesity [57].

Synbiotic products are the combination of probiotics and prebiotics, initially enhanced by synergistic synbiotics. Today, most symbiotic products are complementary synbiotics, a mixture of live microorganisms and substrates used by host microorganisms, independently conferring health benefits. Gomez Quintero, et al. [58] review recent examples of complementary and synergistic synbiotics.

Recombinant therapies often use safe bacterial chassis, primarily probiotics or bacteria used in food production. However, natural commensals like clostridial or Bacteroides species may be prime candidates for microbiota-based therapies. The ability of these organisms to colonize target environments may enhance therapeutic efficacy, but raises questions about pharmacology and control. The spread of genetically modified DNA to endogenous microbiota members may also be a concern due to natural horizontal gene transfer [59].

In response to these challenges, researchers have explored the potential of alternative approaches, such as fecal microbiota transplantation (FMT) and the use of postbiotics, which are compounds produced by microbial metabolism [8,60]. Postbiotics have shown promise in targeting the host-microbe-pathogen interface, rescuing biotic and immune imbalances, and reducing inflammation, thereby providing new therapeutic opportunities.

Faecal microbiota is a complex, dynamic organism influenced by environmental factors, including diet. Faecal Microbiota Transplantation (FMT) involves introducing minimally modified microbes from human donors to recipients to restore or replace native microbiota. FMT has been successful in treating Clostridium difficile infection (CDI), a serious illness causing 14,000 deaths annually and over 250,000 hospitalizations [49]. FMT is the most effective treatment for rCDI and treating various digestive disorders. However, FMT raises moral, social, and regulatory issues, including selecting donors to prevent disease transmission, conducting long-term studies, and obtaining informed consent. FMT, a clinically proven treatment for recurrent Clostridioides Difficile Infection (rCDI) [61-63]. has shown promise in improving anti-PD-1 response in immunotherapy-refractory cancer patients, indicating that targeting the microbiome could enhance precision cancer therapy efficacy [64,65]. It could also lead to the transmission of mental diseases and deceptive claims about health improvement [42,66]. FMT is a procedure that involves transplanting an ecosystem of gut bacteria from a pre-screened fecal sample into the upper intestinal tract. Inadequate gut flora can lead to health conditions, often due to antibiotic therapy. This can be caused by C. difficile bacteria, frozen feces, freeze-dried stool, or advanced products like synthetic stool capsules [43].

FMT has shown benefits in conditions like inflammatory bowel disease and chronic liver disorders by restoring the equilibrium of the gut microbiota. Additionally, antibiotics can target specific gut microorganisms to impede their growth, potentially inducing clinical remission in conditions like pouchitis and influencing the response to other therapies in inflammatory bowel disease. These microbiome therapies collectively contribute to the management and treatment of various gastrointestinal diseases by promoting a healthy gut microbiome.

The use of Fecal Microbiota Transplantation (FMT) has emerged as a potential therapeutic approach in gastrointestinal, hepatic, and extraintestinal disorders, showcasing the ability to transfer the entire intestinal ecosystem [67].

The human microbiome grew over the past few decades into a biomarker that may characterize a person's health, offer a prognosis, and forecast how well a treatment will work. The success of FMT as a C. difficile treatment has sparked research and regulation of microbiome-based therapies. With three therapies approved by regulatory bodies and increasing clinical trials worldwide, these therapies are likely to remain. However, further research is needed to understand their mechanisms of action and develop new formulations for scalability and safety. The relationship between gut microbiome and immune system modulation, along with the development of bioinformatic tools like AI, could lead to patient-tailored solutions. Acknowledging this rapidly evolving field is crucial for developing optimal solutions.

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