Unlocking the Full Potential of Probiotics: Refocusing on Microbial Demands
The human-associated intestinal microbiome has been extensively studied over the past decade, revealing its critical role in human physiology. The vast community of microorganisms residing in the gastrointestinal tract is now recognized as an additional organ due to its profound impact on health. This understanding has led to increased medical interest in bacteriotherapy, the deliberate use of bacteria or their products to treat diseases. Bacteriotherapy encompasses two main approaches: fecal microbial transfer, where donor stool or its derivatives are administered to treat illnesses, and probiotics. Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These benefits are achieved through interactions with the immune system, production of desired metabolites, cross-feeding with existing microorganisms, and increasing the bacterial load. Probiotics are typically administered in doses of up to 10^10 viable microorganisms, adding to the estimated 10^14 bacteria already present in the human gastrointestinal tract. Upon administration, probiotics exert transient effects without permanent colonization, with wash-out periods of 2 to 4 weeks commonly used in clinical trials.
The term “probiotics” encompasses a wide range of microorganisms, including both prokaryotic bacteria and eukaryotic yeast, each with distinct properties. This diversity complicates the evaluation of probiotic efficacy, as health benefits and modes of action vary significantly across strains. To unlock the full potential of probiotics, it is essential to adopt a microbial perspective, focusing on the impact of specific bacterial strains on the existing microbial ecosystem. This approach emphasizes the strain-specificity of probiotic features, which is often overlooked despite its importance. Strain-specific effects have been well-documented in vitro and in animal models. For example, Bifidobacterium longum has been shown to inhibit acute colitis in mice in a strain-specific manner, while Lactobacillus murinus exhibits strain-specific anti-inflammatory properties in a Caco-2 cell model. Similarly, different strains of Akkermansia muciniphila demonstrated similar anti-inflammatory effects in vitro, but strain-specific properties were observed in vivo in mouse models of chronic colitis. These examples highlight the strain-specificity of probiotic features and underscore the challenges of translating animal model data to clinical settings.
In vitro experiments often fail to replicate the complex microbial network of the human intestinal tract, where cross-feeding, co-exclusion, and inhibition between bacteria play crucial roles in the structure and function of the microbial “organ.” The Simulator of the Human Intestinal Microbial Ecosystem (SHIME) offers a more realistic in vitro model by pre-inoculating with human intestinal samples. However, since the intestinal microbial community is subject-specific, individual pre-screening is necessary to assess the receptivity of a patient’s microbial community to a probiotic strain. In mice, the resistance of the indigenous microbial community to probiotic colonization has been demonstrated, and similar subject-dependent colonization has been observed in humans. This resistance can be linked to microbiome features and local immune responses, as well as underlying host factors such as genetic background and nutritional habits. Nutritional habits influence the availability of specific substrates in the intestines, which can either directly or indirectly support the probiotic’s nutritional needs. Genetic background also plays a role, with cohort studies uncovering links between human genetics and microbiome composition. For example, a decrease in Roseburia has been associated with genetic risk variants for inflammatory bowel disease, suggesting that pre-selecting patients without these variants could improve the assessment of butyrate-producing Roseburia strains in ulcerative colitis treatment.
The therapeutic use of probiotics is broadly supported for the prevention of antibiotic-associated diarrhea, as evidenced by a large meta-analysis. Antibiotic-associated diarrhea results from the destabilization of the intestinal ecosystem, making patients more prone to pathogen infections and fungal overgrowth. Probiotics help repopulate the intestines with chosen microbial strains, competing with potential pathogens for intestinal niches. However, this niche competition can also hinder the recovery of the intestinal microbiome after antibiotic treatment. Autologous fecal transfer has been proposed as a therapeutic alternative to speed up microbiome reconstruction, but this approach is cumbersome and not feasible in cases of bowel infections. Autologous microbial communities inherently meet the prerequisites for effective bacteriotherapy by providing a host-specific, functional ecosystem with established metabolic interactions.
In conclusion, the term “probiotics” covers a diverse range of microorganisms with inter-individual effects based on the indigenous microbial ecosystem and host features. To fully integrate probiotics into evidence-based therapy, it is essential to match the desired probiotic features with the needs of the probiotic strain to thrive in the human host. This requires acknowledging underlying host factors and enhancing environmental conditions for the selected probiotic. Pre-selecting patients based on their microbial and genetic profiles will enable the evaluation of specific strains in receptive hosts. This combined approach will help identify truly health-promoting microorganisms in targeted patient groups, advancing the field of personalized probiotic therapy.
doi.org/10.1097/CM9.0000000000000849
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