# Microbiome-Based Interventions for Food Safety and Environmental Health
## 5 Challenges and Limitations Associated with MBT  
### Regulatory and Safety Concerns  
Despite significant advancements in MBT using various techniques like probiotics, prebiotics, synbiotics, and FMT to counteract dysbiosis and restore gut microbiota, this research area still faces challenges, such as the evolving regulatory landscape, and safety concerns arising from their unclear mechanism of action and the inherent risks of introducing live microorganisms into the human body [105; 106]. While the stable colonization of therapeutic organisms in the gut can enhance their effectiveness, it raises concerns about pharmacological control and the potential spread of genetically modified DNA to native microbiota due to natural horizontal gene transfer [107]. Also, although most genetically modified organisms (GMOs) developed in laboratories tend to be less competitive than their natural counterparts, there is a risk that these engineered organisms could escape into the environment and inadvertently colonize other areas such as natural ecosystems or agricultural environments [108]. This presents a challenge in MBT, as the unintended spread of GMOs could potentially disrupt natural ecosystems and interactions. Recent studies have shown the vast potential of MBT, as evidenced by scientific literature and media, with practices like FMT showing high efficacy in treating recurrent CDI [109], and probiotics, especially strains of _Lactobacillus rhamnosus_ and _Saccharomyces boulardii_, helping in reducing the duration and severity of diarrhea, including antibiotic-associated and infectious diarrhea [110]. However, FMT products pose safety risks due to the potential presence of uncharacterized pathogens that might pose threats to immunocompromised individuals, prompting the U.S. Food and Drug Administration (FDA) to issue multiple safety alerts regarding serious adverse events associated with their use [111]. Similarly, a study of _Lactobacillus_ bacteremia cases in ICU patients at Boston Children's Hospital by [112] found that those receiving _Lactobacillus rhamnosus_ strain GG (LGG) probiotics had a significantly higher risk of developing _Lactobacillus_ bacteremia compared to those who did not receive probiotics. Out of 22,174 ICU patients, 522 were given LGG probiotics (usually through a feeding tube), and 6 of these patients developed _Lactobacillus_ bacteremia, while only 2 of the 21,652 patients who did not receive LGG probiotics experienced the same condition. Until 2022, FMT and other microbiota-based therapies in Europe faced regulatory uncertainty because they were not classified as drugs. This lack of classification stemmed from the highly variable composition of gut microbiota samples, which made it challenging to standardize and regulate these therapies under existing drug frameworks [113]. The diverse nature of microbiota means that each FMT or microbiota-based product can differ significantly in its microbial content [114; 115], complicating efforts to apply conventional drug regulations and approval processes. As a result, these therapies existed in a regulatory gray area, lacking clear guidelines and standards for their use and oversight [113]. In the United States, the classification of MBT such as the use of stool in FMT as a drug and a biological product under traditional statutory declarations by regulatory bodies affects the required clinical trial rigor, safety evaluations, and manufacturing standards, creating significant regulatory challenges [116; 117]. This is exemplified by the FDA's 2013 decision to regulate stool for FMT as a biologic drug, necessitating an investigational new drug (IND) application for clinical trials [118]. Since clinical experience and preliminary data for FMT already showed its efficacy as treatment for recurrent or refractory CDI [119; 120], investigators and clinicians pushed back against the policy, arguing that the regulatory burden of maintaining an IND may prohibit many clinicians from offering a potentially life-saving therapy [121].