Effects of gut-derived endotoxin on anxiety-like and repetitive behaviors in male and female mice

Abstract

BackgroundGut dysbiosis is observed in several neuropsychiatric disorders exhibiting increases in anxiety behavior, and recent work suggests links between gut inflammation and such disorders. One source of this inflammation may be lipopolysaccharide (LPS), a toxic component of gram-negative bacteria. Here, we (1) determine whether oral gavage of LPS, as a model of gut-derived endotoxemia, affects anxiety-like and/or repetitive behaviors; (2) test whether these changes depend on TLR4 signaling; and (3) test the extent to which gut-derived endotoxin and TLR4 antagonism affects males and females differently.MethodsIn experiment 1, male wild-type (WT) and Tlr4−/− mice were tested for locomotor, anxiety-like, and repetitive behaviors in an automated open field test apparatus, 2 h after oral gavage of LPS or saline. In experiment 2, male and female WT mice received an oral gavage of LPS and an injection of one or two TLR4 antagonists that target different TLR4 signaling pathways ((+)-naloxone and LPS derived from R. sphaeroides (LPS-RS)). Univariate and multivariate analyses were used to identify effects of treatment, sex, and genotype and their interaction.ResultsIn experiment 1, oral gavage of LPS increased anxiety-like behavior in male WT mice but not in Tlr4−/− mice. In experiment 2, oral gavage of LPS increased anxiety-like and decreased repetitive behaviors in WT mice of both sexes. Neither antagonist directly blocked the effects of orally administered LPS. However, treatment with (+)-naloxone, which blocks the TRIF pathway of TLR4, had opposing behavioral effects in males and females (independent of LPS treatment). We also identified sex differences in the expression of interleukin-6, a pro-inflammatory cytokine, in the gut both in basal conditions and in response to LPS.ConclusionIn spite of the ubiquitous nature of LPS in the gut lumen, this is the first study to demonstrate that intestinally derived LPS can initiate behavioral aspects of the sickness response. While an increased enteric load of LPS increases anxiety-like behavior in both sexes, it likely does so via sex-specific mechanisms. Similarly, TLR4 signaling may promote baseline expression of repetitive behavior differently in males and females. This study lays the groundwork for future interrogations into connections between gut-derived endotoxin and behavioral pathology in males and females.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0166-x) contains supplementary material, which is available to authorized users.

Effects of Hypothalamic Arcuate Nucleus NPY5 Receptor Signaling Pathway on Feeding Regulation in Normal Rats and Obesity Rats

“…Central injection of NPY can result in excessive feeding and reduced energy expenditure in rats [19,20] . In addition, a large number of studies have shown that NPY mainly participates in the regulation of energy balance through NPY1 receptor, NPY2 receptor, and NPY5 receptor [21][22][23][24] . Therefore, in this study we observed the expression levels of NPY5 receptor in ARC in normal rats and obese rats.…”

Effect of Food Endotoxin on Infant Health

“…This is equivalent to 0.067-91.67 µg/kg endotoxin per day (calculated according to an infant weight of 6 kg and 100 g of milk powder per day, for example). The endotoxin level in milk and milk products is still far from the dose that can cause a severe immune reaction (250 µg/kg) [38][39][40], which suggests that the endotoxin content in milk powder cannot cause disease in infants and young children. However, heat tolerance leads to endotoxin remaining in dairy products.…”

“…The oral intake of endotoxin can increase the content of endotoxin in the blood, which leads to an immune response (Table 2). It was found that the concentration of endotoxin in the serum of mice increased by 1.5 times after treatment with 300 µg/kg endotoxin by oral gavage for 2 hours, which also caused the mice to exhibit anxious behavior [40]. The intestine, liver, and lung cytokine-induced neutrophil chemoattractant 1(CINC-1) concentrations in mice fed 250-500 µg of endotoxin orally increased by about four times (equivalent to human IL-8); plasma and lung TNF-α concentrations also increased significantly.…”

Microbiome meets microglia in neuroinflammation and neurological disorders

“…The Gram-negative bacterial membrane component LPS is an endotoxin commonly utilized to study the effects of inflammation on behavior in rodent models, including voluntary ethanol intake, anxiety-like behaviors, and blood-brain barrier integrity [46][47][48][49] . Studies have demonstrated the direct effects of LPS on microglial activation and subsequent neurological pathologies and behaviors.…”