Next-Generation Probiotics Targeting Clostridium difficile through Precursor-Directed Antimicrobial Biosynthesis

Abstract

Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified to be a promising candidate for adjunct therapy. Human-derived bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the gene locus were potent reuterin producers, with 17938 inhibiting growth at a level on par with the level of growth inhibition by vancomycin. Targeted mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of with glycerol was effective against colonization in complex human fecal microbial communities, whereas treatment with either glycerol or alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with elicited changes in the composition and function of the human microbial community that preferentially targets outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of , and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials.

Suppressive effect ofLactobacillus fermentumLim2 onClostridioides difficile027 toxin production

“…; Spinler et al . ; Najarian et al . ) and prevention of C. difficile colonization via competitive exclusion (Dicks et al .…”

Health promoting activities of probiotics

“…Another researcher found that only co‐delivery of L. reuteri with glycerol could effectively fight against C. difficile colonization. Treatment with either glycerol or L. reuteri could not efficaciously inhibit outgrowth of C. difficile (Spinler et al, ).…”

An overview of microbiome based strategies on anti‐obesity

“…By analyzing the microbiome between healthy and diseased individuals, a variety of bacteria have been found to correlate with diseases . Meanwhile, some bacteria were found being more abundant in the healthy population and might have potential to be used as probiotics . These newly discovered bacteria, originated from the microbiome‐based analysis, could be referred to as the “next‐generation probiotics.” Indeed, the amelioration of culture system, including the development of bioreactors, formulation of new isolation protocol, and modification of culture media, also contribute to the discovery of next‐generation probiotics.…”

“…Meanwhile, some bacteria were found being more abundant in the healthy population and might have potential to be used as probiotics . These newly discovered bacteria, originated from the microbiome‐based analysis, could be referred to as the “next‐generation probiotics.” Indeed, the amelioration of culture system, including the development of bioreactors, formulation of new isolation protocol, and modification of culture media, also contribute to the discovery of next‐generation probiotics. The development of metabolomics, an advanced technique for analyzing both the composition of metabolites from microbes and host, allows the researchers to establish the potential link between microbes and host, and provides the possible mechanisms for further investigation .…”

“…These newly discovered bacteria, originated from the microbiome‐based analysis, could be referred to as the “next‐generation probiotics.” Indeed, the amelioration of culture system, including the development of bioreactors, formulation of new isolation protocol, and modification of culture media, also contribute to the discovery of next‐generation probiotics. The development of metabolomics, an advanced technique for analyzing both the composition of metabolites from microbes and host, allows the researchers to establish the potential link between microbes and host, and provides the possible mechanisms for further investigation . All these improvements enable the researchers to select the next‐generation probiotics more efficiently, either from the traditional sources such as intestinal content and dairy food or from the unconventional sources such as fermented foods, grain, vegetables, fruit, honey‐comb, and soil .…”