E. coli Lipopolysaccharide: Acute oral toxicity study in mice

Harper, Marc S.; Carpenter, Carol; Klocke, Doris; Carlson, Gabrielle A.; Davis, Tom; Delaney, Bryan

doi:10.1016/j.fct.2011.04.025

Cited by 9 publications

(8 citation statements)

References 26 publications

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“…In contrast, oral administration of LPS is less common, perhaps because it is non-toxic to healthy mice even at doses 16.5X greater than that used here (Harper et al, 2011). Consistent with this report, we did not observe obvious signs of sickness, including changes in body position (hunched back, lying on side, or prone), sustained eye closure, piloerection, dragging or elevated tail position, or failure to respond to finger stroke of the back (Brown et al, 2005, Hines et al, 2013).…”

Section: Methodsmentioning

confidence: 89%

“…Systemic LPS induces the well-studied phenomena of sickness behavior (Asarian and Langhans, 2010), which includes anorexia, anhedonia, and taste aversion to sucrose (Cross-Mellor et al, 2004). Little is known about the behavioral consequences of ingested LPS, which is significantly less toxic than systemic LPS (Harper et al, 2011, Inagawa et al, 2011). Inhibiting sweet taste input to the CNS can alter preference for sweet taste stimuli, and ingestion of LPS-tainted solutions may have the same effect (Treesukosol et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice

Zhu

McCluskey

2014

Neuroscience

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A fundamental role of the taste system is to discriminate between nutritive and toxic foods. However, it is unknown whether bacterial pathogens that might contaminate food and water modulate the transmission of taste input to the brain. We hypothesized that exogenous, bacterially-derived lipopolysaccharide (LPS), modulates neural responses to taste stimuli. Neurophysiological responses from the chorda tympani nerve, which innervates taste cells on the anterior tongue, were unchanged by acute exposure to LPS. Instead, neural responses to sucrose were selectively inhibited in mice that drank LPS during a single overnight period. Decreased sucrose sensitivity appeared 7 days after LPS ingestion, in parallel with decreased lingual expression of Tas1r2 and Tas1r3 transcripts, which are translated to T1R2+T1R3 subunits forming the sweet taste receptor. Tas1r2 and Tas1r3 mRNA expression levels and neural responses to sucrose were restored by 14 days after LPS consumption. Ingestion of LPS, rather than contact with taste receptor cells, appears to be necessary to suppress sucrose responses. Furthermore, mice lacking the Toll-like receptor (TLR) 4 for LPS were resistant to neurophysiological changes following LPS consumption. These findings demonstrate that ingestion of LPS during a single period specifically and transiently inhibits neural responses to sucrose. We suggest that LPS drinking initiates TLR4-dependent hormonal signals that downregulate sweet taste receptor genes in taste buds. Delayed inhibition of sweet taste signaling may influence food selection and the complex interplay between gastrointestinal bacteria and obesity.

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Section: Methodsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice

Zhu

McCluskey

2014

Neuroscience

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“…While endotoxin limits for parenteral drugs have been established (19), there is no defined oral endotoxin limit dose. Oral administration of E. coli endotoxin to mice at a dose of up to 10 6 EU/mouse produced no evidence of toxicity (20). A different situation is encountered when oral phages infect the intestinal pathogen in the guts of diarrhea patients and release endo-and enterotoxins from the lysed pathogen in patients with a compromised gut barrier.…”

Section: Discussionmentioning

confidence: 99%

Amplification and Purification of T4-Like Escherichia coli Phages for Phage Therapy: from Laboratory to Pilot Scale

Bourdin

Schmitt

Guy

et al. 2014

Appl Environ Microbiol

115

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We investigated the amplification and purification of phage preparations with respect to titer, contamination level, stability, and technical affordability. Using various production systems (wave bags, stirred-tank reactors, and Erlenmeyer flasks), we obtained peak titers of 10 9 to 10 10 PFU/ml for T4-like coliphages. Phage lysates could be sterilized through 0.22-m membrane filters without titer loss. Phages concentrated by differential centrifugation were not contaminated with cellular debris or bacterial proteins, as assessed by electron microscopy and mass spectrometry, respectively. Titer losses occurred by high-speed pelleting of phages but could be decreased by sedimentation through a sucrose cushion. Alternative phage concentration methods are prolonged medium-speed centrifugation, strong anion-exchange chromatography, and ultrafiltration, but the latter still allowed elevated lipopolysaccharide contamination. T4-like phages could not be pasteurized but maintained their infectivity titer in the cold chain. In the presence of 10 mM magnesium ions, phages showed no loss of titer over 1 month at 30°C.

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“…For the clinical trial, the requested purity was defined as an absence of contaminating non‐T4 coliphages (e.g., induced prophages from the production E. coli strain) and bacterial cell debris by electron micrographic (EM) observation in the final T4‐like clinical phage cocktail. An absence of bacterial endotoxin (LPS) requested for phage cocktails targeted for burn wounds in the Phagoburn PT trial (http://www.phagoburn.eu) was not requested for oral PT cocktails, since the gut is tolerant to LPS . A phage cocktail consisting of nine different T4‐like phages was stable over at least 2 years under refrigeration temperatures.…”

Section: Production Stability and Safetymentioning

confidence: 99%

From bench to bed and back again: phage therapy of childhood Escherichia coli diarrhea

Sarker

Brüssow

2016

Annals of the New York Academy of Sciences

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Over the last 20 years, the Nestlé Research Center in Switzerland and the International Center for Diarrhoeal Diseases Research in Bangladesh have explored the efficacy of alternative biological agents for the treatment of diarrheal diseases. This paper reviews the work of this collaborative effort, particularly on Escherichia coli phage therapy (PT), and discusses the development of the project, starting with the isolation of T4-like coliphages from the stool of diarrhea patients, their pilot plant amplification and purification, and the constitution and testing of a cocktail of T4-like phages in mice. A series of phase I clinical trials has demonstrated the safety of PT. Oral phage given without protection survived gastric passage and was recovered in the feces. Oral T4 phage cocktail was then tested in parallel to a commercial phage product in a phase II randomized, placebo-controlled single-center trial in Bangladeshi children hospitalized with acute E. coli diarrhea. It was found that oral phage did not perform better than the current standard of care by oral rehydration/zinc treatment. Furthermore, fecal E. coli pathogen titers were low and mixed infections were found to be frequent. Microbiota analysis showed a correlation between diarrhea and increased levels of Streptococcus, which raises fundamental questions on the causative agent of diarrhea that may explain PT clinical failure.

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E. coli Lipopolysaccharide: Acute oral toxicity study in mice

Cited by 9 publications

References 26 publications

Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice

Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice

Amplification and Purification of T4-Like Escherichia coli Phages for Phage Therapy: from Laboratory to Pilot Scale

From bench to bed and back again: phage therapy of childhood Escherichia coli diarrhea

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