Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infection in Mice

Zhang, Yiming; Shaikh, Nurmohammad; Ferey, J; Wankhade, Umesh D.; Chintapalli, Sree V.; Higgins, Cassandra B.; Crowley, Jan R.; Heitmeier, Monique R.; Stothard, Alicyn I; Mihi, Belgacem; Good, Misty R.; Higashiyama, Takanobu; Swarts, Benjamin M.; Hruz, Paul W.; Shankar, Kartik; Tarr, Phillip I.; DeBosch, Brian J.

doi:10.1053/j.gastro.2019.11.295

Cited by 28 publications

(35 citation statements)

References 69 publications

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“…Secondly, it was shown that compared to a water control, oral dosing with trehalose increased the risk of disease 3-fold [ 50 ]. Additionally, a recent study [ 52 ] has shown that feeding trehalose or lactotrehalose (a trehalase-resistant form of trehalose) did not promote growth of C. difficile CD027 in mice, and actually reduced the levels of markers of inflammation in gut issues. It is not clear why the results of this study are different to the previously reported effects of trehalose on the potentiation of C. difficile disease.…”

Section: Introductionmentioning

confidence: 99%

Trehalose and bacterial virulence

Vanaporn

Titball

2020

Virulence

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Trehalose is a disaccharide of two D-glucose molecules linked by a glycosidic linkage, which plays both structural and functional roles in bacteria. Trehalose can be synthesized and degraded by several pathways, and induction of trehalose biosynthesis is typically associated with exposure to abiotic stress. The ability of trehalose to protect against abiotic stress has been exploited to stabilize a range of bacterial vaccines. More recently, there has been interest in the role of this molecule in microbial virulence. There is now evidence that trehalose or trehalose derivatives play important roles in virulence of a diverse range of Gram-positive and Gram-negative pathogens of animals or plants. Trehalose and/or trehalose derivatives can play important roles in host colonization and growth in the host, and can modulate the interactions with host defense mechanisms. However, the roles are typically pathogen-specific. These findings suggest that trehalose metabolism may be a target for novel pathogen-specific rather than broad spectrum interventions.

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Section: Introductionmentioning

confidence: 99%

Trehalose and bacterial virulence

Vanaporn

Titball

2020

Virulence

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“…18,19 Both of these adapted trehalose utilization mechanisms were shown to provide in vitro growth advantages to C. difficile, which led to the hypothesis that escalating consumption of trehalose by humans may have contributed to the spread and virulence of these epidemic C. difficile strains over the past two decades. 18,19,23 However, the available evidence from mouse infection models 18,19,24 is mixed and, along with human epidemiology data, 25,26 does not unequivocally support this hypothesis. Whereas some reports 18,19 suggested that trehalose enhanced RT027 disease severity via toxin elevation, these data are counterbalanced by mouse infection models showing that trehalose did not increase RT027 disease severity, bacterial burden, toxin level, or colorectal inflammation.…”

Section: Importance Of Trehalose To Bacterial Physiology and Virulencementioning

confidence: 99%

“…Whereas some reports 18,19 suggested that trehalose enhanced RT027 disease severity via toxin elevation, these data are counterbalanced by mouse infection models showing that trehalose did not increase RT027 disease severity, bacterial burden, toxin level, or colorectal inflammation. 24 Further investigation is needed to assess the potential contributions of trehalose metabolism to C. difficile infection and, correspondingly, its potential as a therapeutic target. In the meantime, these studies illustrate the diversity of trehalose metabolic pathways that occur and evolve in bacteria, even between different strains of the same species, and also call attention to the possibility that trehalose consumption can impact the trehalose-metabolizing population of the human microbiota.…”

Section: Importance Of Trehalose To Bacterial Physiology and Virulencementioning

confidence: 99%

“…In pursuit of this goal, we have worked in collaboration with the DeBosch group to develop degradation-resistant LactoTre as a potential therapeutic for treating cardiometabolic diseases. 24,[140][141][142] Excitingly, in comparison to native trehalose, LactoTre exerts comparable or enhanced metabolic effects without contributing to C. difficile RT027 growth or virulence in vivo. 24,142 To support these efforts from the synthetic side, we initially produced LactoTre via a 5-step chemical synthesis route because this analogue is inaccessible via TreT catalysis.…”

Section: Inhibiting C Difficile Trehalose Utilization With Degradation-resistant Trehalose Analoguesmentioning

confidence: 99%

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The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

et al. 2020

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“…The bioavailability of ingested trehalose is low [ 8 , 9 ] and may depend on bacteria colonization [ 10 ]. Nevertheless, trehalose-based diets in mice have positive cardiometabolic [ 4 , 11 , 12 ], neuroprotective [ 13 ], and anti-inflammatory properties [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Trehalose Reduces Nerve Injury Induced Nociception in Mice but Negatively Affects Alertness

et al. 2021

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Trehalose, a sugar from fungi, mimics starvation due to a block of glucose transport and induces Transcription Factor EB- mediated autophagy, likely supported by the upregulation of progranulin. The pro-autophagy effects help to remove pathological proteins and thereby prevent neurodegenerative diseases such as Alzheimer’s disease. Enhancing autophagy also contributes to the resolution of neuropathic pain in mice. Therefore, we here assessed the effects of continuous trehalose administration via drinking water using the mouse Spared Nerve Injury model of neuropathic pain. Trehalose had no effect on drinking, feeding, voluntary wheel running, motor coordination, locomotion, and open field, elevated plus maze, and Barnes Maze behavior, showing that it was well tolerated. However, trehalose reduced nerve injury-evoked nociceptive mechanical and thermal hypersensitivity as compared to vehicle. Trehalose had no effect on calcium currents in primary somatosensory neurons, pointing to central mechanisms of the antinociceptive effects. In IntelliCages, trehalose-treated mice showed reduced activity, in particular, a low frequency of nosepokes, which was associated with a reduced proportion of correct trials and flat learning curves in place preference learning tasks. Mice failed to switch corner preferences and stuck to spontaneously preferred corners. The behavior in IntelliCages is suggestive of sedative effects as a “side effect” of a continuous protracted trehalose treatment, leading to impairment of learning flexibility. Hence, trehalose diet supplements might reduce chronic pain but likely at the expense of alertness.

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Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infection in Mice

Cited by 28 publications

References 69 publications

Trehalose and bacterial virulence

Trehalose and bacterial virulence

The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

Trehalose Reduces Nerve Injury Induced Nociception in Mice but Negatively Affects Alertness

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