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Rapid biotransformation of STW 5 constituents by human gut microbiome from IBS- and non-IBS donors

ABSTRACT:

STW 5, a blend of 9 medicinal plant extracts, exhibits promising efficacy in treating functional gastrointestinal disorders, notably irritable bowel syndrome (IBS). Nonetheless, its effects on the gastrointestinal microbiome and the role of microbiota on the conversion of its constituents are still largely unexplored. This study employed an experimental ex vivo model to investigate STW 5's differential effects on fecal microbial communities and metabolite production in samples from individuals with and without IBS. Using 560 fecal microcosms (IBS patients, n=6; healthy controls, n=10), we evaluated the influence of pre-digested STW 5 and controls on microbial and metabolite composition at time points 0, 0.5, 4 and 24 h. Our findings demonstrate the potential of this ex vivo platform to analyze herbal medicine turnover within 4 h with minimal microbiome shifts due to abiotic factors. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products, such as 18β-glycyrrhetinic acid, davidigenin, herniarin, 3-(3-hydroxyphenyl)propanoic acid and 3-(2-hydroxy-4-methoxyphenyl)propanoic acid occurred. For davidigenin, 3-(3-hydroxyphenyl)propanoic acid and 18β-glycyrrhetinic acid, anti-inflammatory, cytoprotective or spasmolytic activities have been previously described. Notably, the microbiome-driven metabolic transformation did not induce a global microbiome shift, and the detected metabolites were minimally linked to specific taxa. Observed biotransformations were independent of IBS diagnosis, suggesting potential benefits for IBS patients from biotransformation products of STW 5.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

SUBMITTER: Timo Thumann

PROVIDER: MTBLS2398 | MetaboLights | 2024-05-07

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS2398	Other
	FILES	Other
	a_MTBLS2398_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS2398_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Mechanisms through which the microbiome communicates with the systemic immune system remain unclear. We have identified a family of microbiome Bacteroidota-derived lipopeptides – the serine-glycine (S/G) lipids, and specifically L654 – that are TLR2 ligands, access the systemic circulation, and potentially link the microbiome and systemic innate immunity. We have previously postulated that L654 and the S/G lipids regulate systemic innate immunity by entering the systemic circulation and mediating weak TLR2 interactions that maintain “normal” levels of innate immune signaling feedback inhibitors. In proof-of-concept studies, we reported that increasing systemic L654 levels in mice by administering exogenous L654 intravenously significantly diminishes systemic innate immune responses and attenuates murine autoimmunity. In the present study, our goal was to confirm the role of the microbiome in mediating this mode of immunoregulation by decreasing the microbiome-based production of S/G lipids. We now report that decreasing microbiome Bacteroidota in mice using a specific oral antibiotic/rest protocol reduces fecal and plasma S/G lipids levels and significantly enhances systemic innate immune responses. Replenishing systemic levels of S/G lipids after antibiotic treatment through exogenous administration of L654 returns innate immune responses to normal levels, confirming the regulatory role of S/G lipids in this mode of microbiome regulation. Finally, RNAseq analysis of splenic monocytes derived from antibiotic-treated and control mice with or without exogenous L654 prior to ex vivo stimulation demonstrates that the antibiotic/rest protocol and the concomitant decrease in microbiome S/G lipids and Bacteroidota has significant downregulatory effects on normal homeostatic pro-inflammatory pathways. These effects are also associated with downregulation of specific proinflammatory pathway inhibitors, which may suggest a potential mechanism underlying the enhancement in ex vivo innate immune stimulated responses of these monocytes. Overall, our results suggest that S/G lipids are microbiome-derived bacterial factors capable of regulating systemic innate immunity and as such are manipulatable targets with therapeutic potential for enhancing or decreasing innate immunity in the context of infectious, malignant, and autoimmune diseases.

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Rapid biotransformation of STW 5 constituents by human gut microbiome from IBS- and non-IBS donors

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