Project description:Tan2012 - Antibiotic Treatment, Inoculum Effect The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies. This model is described in the article: The inoculum effect and band-pass bacterial response to periodic antibiotic treatment. Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L. Mol Syst Biol. 2012 Oct 9; 8:617 Abstract: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes. This model is hosted on BioModels Database and identified by: MODEL1208300000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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 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.

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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