Profiling rhythmicity of bile salt hydrolase activity in the gut lumen with a rapid fluorescence assay

Kombala, Chathuri; Agrawal, Neha; Nixon, Agne; Karatsoreos, Ilia N.; Dongen, Hans P. A. Van; Brandvold, Kristoffer R.

doi:10.1039/d2ob02257e

Cited by 4 publications

(6 citation statements)

References 63 publications

(80 reference statements)

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“…Our findings appear to be consistent with a report that four days of simulated shift work dampens insulin sensitivity, a marker of risk for metabolic disease, which may be mediated by internal desynchronization between circadian- and behavior-driven rhythms like that found in our study. Data from experiments focused specifically on meal timing suggest a specific role for the prior schedule of food intake in our study, potentially mediated by shifted circadian rhythmicity in functional enzymatic activity of the gut microbiome …”

Section: Discussionmentioning

confidence: 86%

“…Data from experiments focused specifically on meal timing 42 suggest a specific role for the prior schedule of food intake in our study, potentially mediated by shifted circadian rhythmicity in functional enzymatic activity of the gut microbiome. 43 Indeed, recent studies have shown that the temporal pattern of food intake during the prior shift days may serve as a peripheral clock source. 2,42 In our study, food intake was equally distributed across the 24 h of the constant routine when the blood samples were taken but was shifted to the night in the prior simulated night shift days, thus providing a shifted peripheral clock signal.…”

Section: ■ Discussionmentioning

confidence: 99%

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Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

McDermott,

Jacobs,

Merrill

et al. 2024

J. Proteome Res.

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Circadian misalignment due to night work has been associated with an elevated risk for chronic diseases. We investigated the effects of circadian misalignment using shotgun protein profiling of peripheral blood mononuclear cells taken from healthy humans during a constant routine protocol, which was conducted immediately after participants had been subjected to a 3-day simulated night shift schedule or a 3-day simulated day shift schedule. By comparing proteomic profiles between the simulated shift conditions, we identified proteins and pathways that are associated with the effects of circadian misalignment and observed that insulin regulation pathways and inflammation-related proteins displayed markedly different temporal patterns after simulated night shift. Further, by integrating the proteomic profiles with previously assessed metabolomic profiles in a network-based approach, we found key associations between circadian dysregulation of protein-level pathways and metabolites of interest in the context of chronic metabolic diseases. Endogenous circadian rhythms in circulating glucose and insulin differed between the simulated shift conditions. Overall, our results suggest that circadian misalignment is associated with a tug of war between central clock mechanisms controlling insulin secretion and peripheral clock mechanisms regulating insulin sensitivity, which may lead to adverse long-term outcomes such as diabetes and obesity. Our study provides a molecular-level mechanism linking circadian misalignment and adverse long-term health consequences of night work.

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Section: Discussionmentioning

confidence: 86%

Section: ■ Discussionmentioning

confidence: 99%

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

McDermott,

Jacobs,

Merrill

et al. 2024

J. Proteome Res.

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“…Using this cholic acid-based ABP, we profiled BSH activities within gut microbes and identified active BSH enzymes within healthy and colitic mouse gut microbiomes. Additional approaches have been developed using chemical probes containing a fluorogenic or luminogenic group to monitor BSH activity (Brandvold et al, 2019; Khodakivskyi et al, 2021; Kombala et al, 2023; Sveistyte et al, 2020), alternative covalent warheads to profile and inhibit BSH activity (Adhikari et al, 2020; Brandvold et al, 2021), and photoaffinity labels to identify bile acid-binding proteins (Forster et al, 2022; Liu et al, 2022; Yang et al, 2022, 2023; Zhuang et al, 2017). Despite the number of emerging chemical tools to study BSH activities, the substrate preferences within the BSH family at a metaproteome level remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases

Han,

Pendleton,

Singh

et al. 2024

Preprint

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The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

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“…Luminogenic and fluorogenic probes have been developed to detect BSH activity that comprise luciferin or quenched fluorophore bile acid conjugates, respectively, in which the imaging agent is activated upon bile acid deconjugation. [22][23][24][25] However, these approaches are not able to distinguish between BSH activities or substrate preferences from different bacteria in a complex sample.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the increasingly recognized importance of BSH in human health and disease, chemical tools to image their activities and probe their functions within the gut microbiome have recently begun to emerge. Luminogenic and fluorogenic probes have been developed to detect BSH activity that comprise luciferin or quenched fluorophore bile acid conjugates, respectively, in which the imaging agent is activated upon bile acid deconjugation [22–25] . However, these approaches are not able to distinguish between BSH activities or substrate preferences from different bacteria in a complex sample.…”

Section: Introductionmentioning

confidence: 99%

Bile Salt Hydrolase Activity‐Based Probes for Monitoring Gut Microbial Bile Acid Metabolism

Han,

Xu,

Conwell

et al. 2024

ChemBioChem

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Bile acids are bioactive metabolites that are biotransformed into secondary bile acids by the gut microbiota, a vast consortium of microbes that inhabit the intestines. The first step in intestinal secondary bile acid metabolism is carried out by a critical enzyme, bile salt hydrolase (BSH), that catalyzes the gateway reaction that precedes all subsequent microbial metabolism of these important metabolites. As gut microbial metabolic activity is difficult to probe due to the complex nature of the gut microbiome, approaches are needed to profile gut microbiota‐associated enzymes such as BSH. Here, we develop a panel of BSH activity‐based probes (ABPs) to determine how changes in diurnal rhythmicity of gut microbiota‐associated metabolism affects BSH activity and substrate preference. This panel of covalent probes enables determination of BSH activity and substrate specificity from multiple gut anerobic bacteria derived from the human and mouse gut microbiome. We found that both gut microbiota‐associated BSH activity and substrate preference is rhythmic, likely due to feeding patterns of the mice. These results indicate that this ABP‐based approach can be used to profile changes in BSH activity in physiological and disease states that are regulated by circadian rhythms.

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Profiling rhythmicity of bile salt hydrolase activity in the gut lumen with a rapid fluorescence assay

Abstract: Diurnal rhythmicity of cellular function is key to survival for most organisms on earth. Many circadian functions are driven by the brain, but regulation of a separate set of peripheral...

Cited by 4 publications

References 63 publications

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases

Bile Salt Hydrolase Activity‐Based Probes for Monitoring Gut Microbial Bile Acid Metabolism

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