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Berberine is an isoquinoline alkaloid found in plants. It presents a wide range of pharmacological activities, including anti-inflammatory and antioxidant properties, despite a low oral bioavailability. Growing evidence suggests that the gut microbiota is the target of berberine, and that the microbiota metabolizes berberine to active metabolites, although little evidence exists in the specific species involved in its therapeutic effects. This study was performed to detail the bidirectional interactions of berberine with the broiler chicken gut microbiota, including the regulation of gut microbiota composition and metabolism by berberine and metabolization of berberine by the gut microbiota, and how they contribute to berberine-mediated effects on gut health. As previous evidence showed that high concentrations of berberine may induce dysbiosis, low (0.1 g/kg feed), middle (0.5 g/kg feed) and high (1 g/kg feed) doses were here investigated. Low and middle doses of in-feed berberine stimulated potent beneficial bacteria from the Lachnospiraceae family in the large intestine of chickens, while middle and high doses tended to increase villus length in the small intestine. Plasma levels of the berberine-derived metabolites berberrubine, thalifendine and demethyleneberberine were positively correlated with the villus length of chickens. Berberrubine and thalifendine were the main metabolites of berberine in the caecum, and they were produced in vitro by the caecal microbiota, confirming their microbial origin. We show that members of the genus Blautia could demethylate berberine into mainly thalifendine, and that this reaction may stimulate the production of short-chain fatty acids (SCFAs) acetate and butyrate, via acetogenesis and cross-feeding respectively. We hypothesize that acetogens such as Blautia spp. are key bacteria in the metabolization of berberine, and that berberrubine, thalifendine and SCFAs play a significant role in the biological effect of berberine.

ABSTRACT Phytogenic products are embraced as alternatives to antimicrobials, and some are known to mitigate intestinal inflammation and ensure optimal gut health and performance in broiler chickens. Dietary inclusion of berberine, a benzylisoquinoline alkaloid found in plants, is believed to exert gut health-promoting effects through modulation of the gut microbiota; however, there are only a few studies investigating its effects in chickens. The aim of this study was to investigate the interplay between dietary supplementation of a high concentration of berberine, the gastrointestinal microbiota, and histomorphological parameters in the gut. Berberine was shown to increase villus length and decrease crypt depth and CD3+ T-lymphocyte infiltration in the gut tissue of chickens at different ages. Berberine affected the diversity of the gut microbiota from the jejunum to the colon, both at a compositional and functional level, with larger effects observed in the large intestine. A high concentration of berberine enriched members of the Enterobacteriaceae family and depleted members of the Ruminococcaceae, Lachnospiraceae, and Peptostreptococcaceae families, as well as tended to reduce butyrate production in the cecum. In vivo results were confirmed by in vitro growth experiments, where increasing concentrations of berberine inhibited the growth of several butyrate-producing strains while not affecting that of Enterobacteriaceae strains. Positive correlations were found between berberine levels in plasma and villus length or villus-to-crypt ratio in the jejunum. Our study showed that berberine supplementation at a high concentration improves chicken gut morphology toward decreased inflammation, which is likely not mediated by the induced gut microbiota shifts. IMPORTANCE Dietary additives are widely used to reduce intestinal inflammation and enteritis, a growing problem in the broiler industry. Berberine, with anti-inflammatory, antioxidant, and antimicrobial activity, would be an interesting feed additive in this regard. This study investigates for the first time the impact of berberine supplementation on the chicken gastrointestinal microbiota, as a potential mechanism to improve gut health, together with histological effects in the small intestine. This study identified a dose-effect of berberine on the gut microbiota, indicating the importance of finding an optimal dose to be used as a dietary additive.

Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations.Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure.Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p

In order to improve the efficacy of penicillin injection during caesarean section, we aimed to identify the optimal timing of its preoperative administration. A study was conducted in 12 adult, non-pregnant Belgian Blue cows. To evaluate the plasma penicillin concentrations, blood samples were taken from the jugular vein at −5, 15, 30, 45, 60, 120, 240, 480 min relative to the intramuscular (IM) injection of 21,000 IU/kg of body weight of penicillin G. Results showed that plasma concentrations at 15 min after IM injection (668.3 ± 73.7 ng/mL) largely exceeded the minimal inhibitory concentration (MIC) of penicillin-sensitive bacteria (MIC < 125 ng/mL). With increasing time, plasma concentrations continued to rise, attaining an increasing proportion of moderately sensitive bacteria (250 ng/mL > MIC < 2000 ng/mL). The maximal concentration was reached between 1 and 4 h (average: 1.495.1 ± 181.7 ng/mL) after IM injection in the majority of cows, and decreased non-significantly to 1002.1 ± 93.2 ng/mL at 8 h. In conclusion, plasma penicillin concentrations at 15 min after an IM injection inhibit penicillin-sensitive bacteria. However, in order to obtain the maximal protective effect of the antibiotherapy, surgery should be started at 1 to 2 h after IM penicillin injection.