Colitis-associated intestinal microbiota regulates brain glycine and host behavior in mice

Abstract

Inflammatory bowel diseases (IBD) are chronic and relapsing inflammatory disorders of the gastrointestinal tract with complex etiology and no strategies for complete cure. IBD are often complicated by mental disorders like anxiety and depression, indicating substantial shifts in the microbiota gut-brain axis. However, the mechanisms connecting IBD to mental diseases are still under debate. Here we use Muc2 knockout mouse model of chronic colitis to uncouple the effects of the intestinal microbiota on host behavior from chronic inflammation in the gut. Muc2 knockout male mice exhibit high exploratory activity, reduced anxiety-related behaviors, impaired sensorimotor gating, and altered social preference towards males and females. Microbial transfer to wild-type mice via littermate co-housing shows that colitis-associated microbiota rather than inflammation per se defines behavioral features in Muc2 colitis model. Metagenomic profiling and combination of antibiotic treatments revealed that bacterial species Akkermansia muciniphila is associated with the behavioral phenotype in mutants, and that its intestinal abundance correlates with social preference towards males. Metabolomic analysis together with pharmacological inhibition of Gly and NMDA receptors helped us to determine that brain glycine is responsible for the behavioral phenotype in Muc2 mice. Blood and brain metabolic profiles suggest that microbiota-dependent changes in choline metabolism might be involved in regulation of central glycine neurotransmission. Taken together, our data demonstrates that colitis-associated microbiota controls anxiety, sensorimotor gating and social behavior via metabolic regulation of the brain glycinergic system, providing new venues to combat neurological complications of IBD.

Investigating social communication in mice: a Two-intruders test approach

“…Our results demonstrate that both BALB/c and C57BL/6 mice are suitable for the Two-intruders test as male intruders (Fig. 1,3), which agrees with the results obtained earlier (Morozova et al, 2022). Moreover, BALB/c intruders provoke efficient response in the resident-intruder assay (Amstislavskaya T.G., 2018; Amstislavskaya & Khrapova, 2002; Novikov S.N., 1988).…”

“…The Two-intruders test reported in this study is based on the previously described mating choice assays and our own design published earlier (Amstislavskaya et al, 2013; Koolhaas et al, 2013; Kuznetsova E.G., 2006; Leypold et al, 2002; Liu et al, 2011; Morozova et al, 2022; Norlin et al, 2003). For instance, Leypold and colleagues used the Two-intruders test together with separate resident-intruder aggression and mating tests with either a male or a female intruder alone.…”

“…By recording the frequencies, durations, latencies and temporal and sequential patterns of all the observed behavioral acts, a detailed quantitative picture resident and also intruder behaviors can be obtained. Thus, a number of studies describe interaction with a male and a female in a resident-intruder paradigm in mice in different settings (Belousova I.I., 2009; Kuznetsova E.G., 2006; Leypold et al, 2002; Liu et al, 2011; Morozova et al, 2022; Norlin, Gussing, & Berghard, 2003; Zinck & Lima, 2013). However, given the competitive and mutually repressive nature of male- and female-derived cues in MPOA and VMH, simultaneous interaction with animals of both sexes represents social communication as it occurs in a natural environment.…”

The Effect of Dietary Phospholipids on the Ultrastructure and Function of Intestinal Epithelial Cells

“…The metabolomic composition of the serum sample was analyzed at the Center of Collective Use “Mass spectrometric investigations” SB RAS (Novosibirsk, Russia) by high-resolution 1 H NMR spectroscopy. The extraction of metabolites from serum was performed by using a short sample preparation protocol earlier evaluated for quantitative NMR-based metabolomics [ 75 , 76 , 77 ]. Namely, 100 μL of ice-cold methanol and 100 μL of ice-cold chloroform were added to 100 μL of serum and vortexed for 30 s, kept on ice for 10 min and incubated at −20 °C for 30 min.…”

Quantitative Metabolomic Analysis of Changes in the Rat Blood Serum during Autophagy Modulation: A Focus on Accelerated Senescence

“…At the first stage of the study, the protocol for sample preparation of biological tissues of experimental animals was optimized (separation of blood serum and extraction of water-soluble metabolites). Based on previous experience [ 48 , 49 , 50 ], cold methanol-chloroform extraction was chosen as the most efficient method for extracting metabolites from blood serum. On the basis of preliminary experiments, the optimal ratio of the volumes of serum and extracting solution is the ratio: serum/methanol/chloroform = 1/1/1.…”