Exploring substrate–microbe interactions: a metabiotic approach toward developing targeted synbiotic compositions

Abstract

Gut microbiota is an important modulator of human health and contributes to high inter-individual variation in response to food and pharmaceutical ingredients. The clinical outcomes of interventions with prebiotics, probiotics, and synbiotics have been mixed and often unpredictable, arguing for novel approaches for developing microbiome-targeted therapeutics. Here, we review how the gut microbiota determines the fate of and individual responses to dietary and xenobiotic compounds via its immense metabolic potential. We highlight that microbial metabolites play a crucial role as targetable mediators in the microbiota-host health relationship. With this in mind, we expand the concept of synbiotics beyond prebiotics’ role in facilitating growth and engraftment of probiotics, by focusing on microbial metabolism as a vital mode of action thereof. Consequently, we discuss synbiotic compositions that enable the guided metabolism of dietary or co-formulated ingredients by specific microbes leading to target molecules with beneficial functions. A workflow to develop novel synbiotics is presented, including the selection of promising target metabolites (e.g. equol, urolithin A, spermidine, indole-3 derivatives), identification of suitable substrates and producer strains applying bioinformatic tools, gut models, and eventually human trials. In conclusion, we propose that discovering and enabling specific substrate–microbe interactions is a valuable strategy to rationally design synbiotics that could establish a new category of hybrid nutra-/pharmaceuticals.

Novel probiotic preparation with in vivo gluten-degrading activity and potential modulatory effects on the gut microbiota

“…In theory, probiotics are a promising strategy for gluten detoxification, in the sense of a synergistic interaction between bacteria and gluten, as recently described ( 13 ). Three main mechanisms are conceivable: hydrolysis of gluten into small non-immunogenic polypeptides, limited access of immunogenic polypeptides to the lamina propria and reduced epithelial permeability, and maintenance of the gut microbiota homeostasis, with regulation of both internal and adaptive immune systems ( 11 ).…”

“…Altogether gluten-related disorders show an increasing global trend, with a prevalence of approximately 5% of the worldwide population ( 6 ). Gluten is not fully digested in healthy individuals, but derived immunogenic epitopes promote disorders in predisposed people ( 13 , 30 ). Compliance with GFD so far is the most efficient way to treat CD and is also the most recommended therapy for other gluten-related disorders.…”

“…Glutenins and mainly gliadins contain at least 50 different crypted immunogenic peptides, which are resistant to further hydrolysis ( 1 ). This is mainly owing to an unusually high content of proline residues, which, because of the cyclic structure, hydrogen-free N-terminus, and side cis chains ( 12 , 13 ), form peptide bonds resistant to all mammalian gastrointestinal peptidases ( 12 , 14 ). Overall, the incomplete gluten hydrolysis slows down the digestion of healthy people ( 14 ).…”

Synbiotic Bacillus megaterium DSM 32963 and n-3 PUFA Salt Composition Elevates Pro-Resolving Lipid Mediator Levels in Healthy Subjects: A Randomized Controlled Study

“…We previously introduced a novel route towards endogenous n-3 PUFA conversion, based on a recently described concept of synbiotics that exploits specific metabolic properties of probiotic strains [36]. More precisely, our route applies the CYP102A1-dependent metabolic capacity of Bacillus megaterium to produce a range of SPMs and precursors from exogenously provided n3-PUFA in a strain-specific manner.…”

Omics approaches in understanding the benefits of plant-microbe interactions

“…Omics-based screening can identify these microbial-derived compounds and reveal their mechanisms of action, enabling the development of new antimicrobials or probiotics for infectious diseases, inflammatory disorders, and metabolic syndromes (Garia et al, 2024 ). Plant-microbe interaction omics can also help personalize medicine by revealing inter-individual microbial community variability and dietary component interactions (Wright et al, 2023 ; Speckmann et al, 2024 ).…”