Elucidating gut microbiota-hippocampus interactions in emerging psychosis: A new perspective for the development of early interventions for memory impairments

Abstract

Hippocampal dysregulation might be a key pathophysiological factor for memory impairments in psychosis. Contemporary models particularly postulate that an imbalance of hippocampal glutamate and GABA leads to impaired memory and may thus serve as a therapeutic target to improve memory deficits. However, currently available interventions in early stages of psychosis do not explicitly target hippocampal pathology. A novel approach for manipulating hippocampus-dependent memory processes is provided via the gut microbiota. In this perspective article, we first recapitulate compelling evidence for emerging hippocampus pathology during the development of psychosis. The following sections emphasize the critical role of the gut microbiota in hippocampus plasticity and memory, and summarize existing evidence of gut microbiota alterations in different stages of psychosis. Finally, we propose a novel conceptual roadmap for future studies deciphering gut microbiota-hippocampus synergisms in emerging psychosis and argue that specific microbial supplementation might be promising for improving hippocampus-dependent memory deficits in early stages of psychosis.

Keywords: brain-gut interactions; early detection and interventions; gut microbiota; hippocampus; memory; psychosis; schizophrenia.

FIGURE 1

(A) SCFAs produced by bacterial commensals in the gut signal the brain via vagus nerve or neurotransmission influencing glutamate and GABA synthesis (54). Vagal sensory signaling enhances memory (49), facilitates neurogenesis, and increases the expression of BDNF (50, 51). A decrease in the BDNF, which regulates hippocampal neuroplasticity (46), decreases learning and memory functioning (47). GABAergic and glutamatergic neurotransmission drives elevated striatal dopamine (–22). Hippocampal hyperperfusion predicts hippocampal volume loss (26). Hippocampal hyperactivity results in excitation/inhibition (glutamate/GABA) imbalance which contributes to hippocampal volume loss (39, 40) leading to memory impairment. (B) Discovery of gut microbiome markers: (1) curve of psychosis progression adapted from Fusar-Poli et al. (118) and Schultze-Lutter et al. (119), (2) peripheral signals such as stress (e.g., cortisol, sirtuins), inflammation (e.g., CRP, IL, TNF-α), plasticity (BDNF), and vagal signaling (e.g., ghrelin), and (3) first psychotic episode. Figure 1 was created with BioRender.com.