Synergy and oxygen adaptation for development of next-generation probiotics

Khan, Muhammad Idrees; Dwibedi, Chinmay; Sundh, Daniel; Pradhan, Meenakshi; Kraft, Jamie; Caesar, Robert; Tremaroli, Valentina; Lorentzon, Mattias; Bäckhed, Fredrik

doi:10.1038/s41586-023-06378-w

Cited by 68 publications

(23 citation statements)

References 58 publications

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“…Another potential probiotic candidate for enhancing immunotherapy outcomes could be Propionibacterium freudenreichii due to its ability to produce cobalamin. However, the most promising prospects lie in the potential development of probiotics based on F. prausnitzii for clinical use [60]. As noted above, this bacterium has been linked to the enhancement of antitumor immunity in numerous studies, including our own analysis.…”

Section: Discussionmentioning

confidence: 99%

Systemic Metabolic Depletion of Intestine Microbiome Undermines Melanoma Immunotherapy Effectiveness

Zakharevich,

Morozov,

Kanaeva

et al. 2023

Preprint

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Immunotherapy has proven to be a boon for patients grappling with metastatic melanoma, significantly enhancing their clinical condition and overall quality of life. A compelling connection was discovered between the composition of the intestinal microbiome and the effectiveness of immunotherapy substantiated in both animal models and human patients. Nonetheless, the precise biological mechanisms through which gut microbes influence melanoma treatment outcomes remain poorly understood. This study conducted a high-resolution metagenomic meta-analysis, employing cutting-edge bioinformatics techniques including genome-resolved metagenomics, strain profiling, comparative genomics, and metabolic reconstruction. According to the obtained results, the systemic metabolic depletion of the gut microbiome causes a lack of response to immunotherapy. Specifically, the presence of bacteria adept at utilizing polysaccharides, as well as those responsible for cobalamin, amino acids, and fatty acids production, decreased in patients who experienced unfavorable treatment outcomes. In contrast, patients who had successful outcomes after immunotherapy exhibited a prevalence of amino acids and cobalamin prototrophs, while autotrophy in these substances characterized the microbiomes of patients with unsuccessful outcomes. The metabolic reconstruction of short-chain fatty acid biosynthesis pathways did not differentiate bacteria linked to treatment outcomes based on their ability to produce acetate, butyrate, or propionate. However, the cobalamin-dependent Wood-Ljungdahl pathway of acetate synthesis was directly associated with immunotherapy effectiveness.

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Section: Discussionmentioning

confidence: 99%

Systemic Metabolic Depletion of Intestine Microbiome Undermines Melanoma Immunotherapy Effectiveness

Zakharevich,

Morozov,

Kanaeva

et al. 2023

Preprint

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“…In summary, using an approach such as the one we have presented here can be useful in selecting microbial species for testing in animal models, thus supporting a rational approach to developing “next-generation” probiotics. Efforts using selected combinations of microbial species designed to address specific dysbiosis are in the early stages (38, 39) but promise a new era in treating a variety of serious health conditions affecting a large portion of the population.…”

Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolites And Their Predicted Microbial Sources In Fecal Samples Of Healthy Individuals

Chappell,

Hoffman,

Lorenzi

et al. 2023

Preprint

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Gut microbiota produce tryptophan metabolites (TMs) important to homeostasis. However, measuring TM levels in stool and determining their microbial sources can be difficult. Here, we measured TMs from the indole pathway in fecal samples from 21 healthy adults with the goal to: 1) determine fecal TM concentrations in healthy individuals; 2) link TM levels to bacterial abundance using 16S and whole genome shotgun (WGS) sequencing data; and 3) predict likely bacterial sources of TM production. Within our samples, we identified 151 genera (16S) and 592 bacterial species (WGS). Eight TMs were found in ≥17 fecal samples, including four in all persons. To our knowledge, we are the first to report fecal levels for indole-3-lactate, indole-3-propionate, and 3-indoleacrylate levels in healthy persons. Overall, indole, indole-3-acetate (IAA), and skatole accounted for 86% of the eight TMs measured. Significant correlations were found between seven TMs and 29 bacterial species. Predicted multiple TM sources support the notion of a complex network of TM production and regulation. Further, the data suggest key roles forCollinsella aerofaciensand IAA, a metabolite reported to maintain intestinal homeostasis through enhanced barrier integrity and anti-inflammatory/antioxidant activities. These findings extend our understanding of TMs and their relationship to the microbial species that act as effectors and/or regulators in the healthy intestine and may lead to novel strategies designed to manipulate tryptophan metabolism to prevent disease and/or restore health to the dysbiotic gut.IMPORTANCETryptophan metabolites (TMs) of bacterial origin are increasingly recognized as important signaling molecules among gut microbiota and with the host. However, few reports exist for fecal TM levels in healthy humans, and reported levels vary widely. Further, the specific bacterial species producing TMs and the combinations of fecal TMs in healthy individuals are not well known. Our research combines 16S and whole genome shotgun sequencing of gut bacteria with a sensitive method (LC/MS) for measuring TMs and a reported method to predict which species are likely TM contributors. To our knowledge, this combination of analyses has not been reported elsewhere and will add significantly to the existing literature. Understanding TM levels and their sources in the healthy intestine are fundamental to elucidating how TMs contribute to maintaining homeostasis. Such knowledge of gut microbiota and their metabolic products will inform novel strategies to maintain intestinal health and prevent or treat dysbioses.

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“…Pre‐clinical experiments have shown it has a beneficial role in shaping the intestinal microbial flora, restoring metabolic homeostasis and alleviating inflammation 7 . However, F. prausnitzii is a strictly anaerobic microbe, and development of F. prausnitzii as a next‐generation probiotic still faces some technical hurdles 8 . Approaches to manipulate its intestinal abundance still largely rely on dietary intervention (e.g., high fibre intake) or faecal microbiota transplantation (FMT).…”

Section: Implication In Clinical Translationmentioning

confidence: 99%