Long‐term molecular differences between resilient and susceptible mice after a single traumatic exposure

Abstract

Background and Purpose: Post-traumatic stress disorder (PTSD) is a heterogeneous disorder induced by trauma, resulting in severe long-term impairments of an individual's mental health. PTSD does not develop in every individual and, thus, some individuals are more resilient. However, the underlying molecular mechanisms are poorly understood. Here, we aimed to elucidate these processes. Experimental Approach: We used a single-trauma PTSD model in mice to induce long-term maladaptive behaviours and profiled the mice 4 weeks after trauma into resilient or susceptible individuals. The classification of phenotype was based on individual responses in different behavioural experiments. We analysed microbiome, circulating endocannabinoids, and long-term changes in brain phospholipid and transcript levels.Key Results: We found many molecular differences between resilient and susceptible individuals across multiple molecular domains, including lipidome, transcriptome and gut microbiome. Some differences were stable even several weeks after the trauma, indicating the long-term impact of traumatic stimuli on the organism's physiology.Furthermore, the integration of these multilayered molecular data revealed that resilient and susceptible individuals have very distinct molecular signatures across various physiological systems. Conclusion and Implications: Trauma induced individual-specific behaviouralresponses that, in combination with a longitudinal characterisation of mice, could be used to identify distinct sub-phenotypes within the trauma-exposed group. These groups differed significantly not only in their behaviour but also in specific molecular aspects across a variety of tissues and brain regions. This approach may reveal new targets and predictive biomarkers for the pharmacological treatment and prognosis of stress-related disorders.

The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism

“…Moreover, using animal models of stress, it was described that stress can affect gut microbial composition ( Gareau et al, 2007 ; Bharwani et al, 2016 ; Burokas et al, 2017 ; Pascual Cuadrado et al, 2021 ; Figure 2 ). Clinical studies also found changes in microbial composition in patients with a diagnosis of depression or anxiety disorder ( Bastiaanssen et al, 2019 ).…”

“…Indeed, the idea that diet might influence emotional responses has been established many years ago. Some studies found that certain species of bacteria are more abundant in resilient mice in comparison to control or susceptible mice ( Marin et al, 2017 ; Yang et al, 2017 ; Bassett et al, 2019 ; Pascual Cuadrado et al, 2021 ). Recently, we have demonstrated differences in gut microbial composition associated with a resilience outcome to a single trauma in mice ( Pascual Cuadrado et al, 2021 ).…”

“…Some studies found that certain species of bacteria are more abundant in resilient mice in comparison to control or susceptible mice ( Marin et al, 2017 ; Yang et al, 2017 ; Bassett et al, 2019 ; Pascual Cuadrado et al, 2021 ). Recently, we have demonstrated differences in gut microbial composition associated with a resilience outcome to a single trauma in mice ( Pascual Cuadrado et al, 2021 ). Interestingly, we found an increased abundance of A. municiphila in resilient mice as compared to susceptible littermates.…”

“…The social stress in rodents produce the most striking changes in the relative abundance of microbiota in the genus Lactobacillus , Akkermansia , Oscillospira, Coriobacteriaceae , and Anaeroplasma ( Bharwani et al, 2016 ; Gautam et al, 2018 ). In a PTSD mouse model, we recently identified an increased abundance of Akkermansia muciniphila in resilient mice in the analysis of different taxa inhabiting the gut ( Pascual Cuadrado et al, 2021 ). The prenatal stress and the disruption of mother-infant bond lead to stress related behavioral disorders as well as changes in the gut microbiota.…”

We're living much longer, but are we healthier?

“…In this Themed Issue, through a series of reviews and research articles focused on the aetiology of specific diseases, their symptomatology and new treatment strategies, how these disorders might be prevented is discussed. Cuadrado et al (2022) address molecular fingerprints of resilient and susceptible phenotypes after a single traumatic exposure in mice.…”