Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r −0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

Endotoxaemia has been described in cases of Human African trypanosomiasis (HAT), but it is unclear if this phenomenon influences inflammatory pathology either in the periphery or central nervous system (CNS). We studied endotoxin concentrations in the plasma and cerebrospinal fluid (CSF) of Trypanosoma brucei rhodesiense patients using the chromogenic Limulus Amoebocyte lysate assay. The relationship of endotoxin concentration to the presentation of gross signs of inflammation and the inflammatory/counter-inflammatory cytokine profile of the relevant compartments were analysed. We demonstrate that HAT patients exhibit parasitaemia-independent plasma endotoxaemia, and that this is associated with splenomegaly and lymphadenopathy. Endotoxin concentrations normalize rapidly after treatment. There was no evidence of endotoxin release in the CNS. A rapid normalization of endotoxin levels after treatment and lack of association with parasitaemia suggest that gut leakage is the main source of endotoxin in the circulation. Low CSF endotoxin concentrations and a lack of any association with neuroinflammatory markers or neurological sequelae suggest that endotoxin does not play a role in the pathogenesis of the disease in the CNS.

The optimal dosage of ornithine α-ketoglutarate (OKG) for repleting tissue glutamine (Gln) concentrations and maintaining N homeostasis after injury is unknown. We set out to perform ‘dose-ranging’ of OKG supplementation after an endotoxaemic challenge. Sixty-one male Wistar rats were injected with 3 mg lipopolysaccharide (LPS) from Escherichia coli/kg (n 50) or saline vehicle (9 g NaCl/l; controls n 11). After a 24 h fast, survivors were fed by gavage for 48 h with a polymeric standard diet (879 kJ/kg per d and 1·18 g N/kg per d) supplemented with non-essential amino acids (control, n 11; LPS-OKG-0·0, n 9), or with 0·5 g OKG/kg per d (LPS-OKG-0·5, n 12), 1·5 OKG/kg per d (LPS-OKG-1.5, n 11) or 4·5 g OKG/kg per d (LPS-OKG-4·5, n 10). The diets for all groups were made isonitrogenous with the LPS-OKG-4·5 diet by adding an appropriate amount of non-essential amino acids. Rats were killed on day 3 for blood and tissue sampling (muscle, jejunum mucosa, liver). Urine was collected daily for 3-methylhistidine and total N assays. The OKG dose was correlated with Gln concentrations in every tissue and with cumulative N balance (Spearman test, P<0·01). 3-Methylhistidine excretion was increased in endotoxaemic groups compared with controls (ANOVA, P<0·05) except in the LPS-OKG-4·5 group. Only the LPS-OKG-4·5 group achieved a positive post-injury N balance (t test, P<0·05). In conclusion, OKG exerted a dose-dependent effect on tissue Gln concentration and N balance, but only the highest dosage counteracted myofibrillar hypercatabolism and caused a positive N balance.

Summary

Background and objective: Since the moribund hypodynamic phase of septic shock has primarily been studied in small animal models, the objective of this study was to investigate the usefulness of infusing Salmonella typhosa endotoxin at incrementing doses to establish an ovine model of hypodynamic endotoxaemia.

Methods: In a prospective laboratory experiment, eight adult ewes were instrumented for a chronic study. Following a baseline measurement in the healthy state, a continuous endotoxin infusion was started with 10 ng kg−1 min−1 and was doubled every hour seven times. Haemodynamics, key variables of oxygen transport, and arterial lactate concentrations were determined every hour.

Results: In a dose-dependent manner, endotoxin infusion caused pulmonary hypertension, decreased cardiac output and mean arterial pressure, increased heart rate, and to a certain extent, systemic vascular resistance index. Following 4 h of endotoxaemia, the maximum decrease in cardiac output occurred (4.8 ± 0.2 vs. 7.6 ± 0.3L min−1; P < 0.001). This was accompanied by tissue dysoxia, represented by decreases in oxygen delivery (797 ± 20 vs. 1041 ± 28 mL min−1), oxygen consumption (277 ± 14 vs. 396 ± 15 mL min−1) and oxygen extraction rate (0.35 ± 0.01 vs. 0.38 ± 0.01%; each P < 0.01), as well as an increase in arterial lactate concentration (1.7 ± 0.1 vs. 0.7 ± 0.1 mmol L−1; P < 0.05).

Conclusions: This large animal model may be helpful to study the pathophysiology responsible for cardiovascular failure, and also new therapeutic approaches relevant to management of hypodynamic circulation in the common setting of progressed systemic inflammation.