Chronic stress exposure alters the gut barrier: sex-specific effects on microbiota and jejunum tight junctions

Abstract

Major depressive disorder (MDD) is the leading cause of disability worldwide. However, 30-50% of patients are unresponsive to commonly prescribed antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis, the bidirectional communications between the central nervous system and gastrointestinal tract that are modulated by gut microorganisms, has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity, still, little is known about intestinal barrier function in these conditions particularly for the small intestine where most food and drug absorption takes place. Thus, here we investigate how chronic social or variable stress, two mouse models of depression, impact the jejunum (JEJ) intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Altered microbial populations as well as changes in gene expression of JEJ tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We took advantage of machine learning to characterize in detail morphological tight junction properties identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated if LPS injection recapitulates stress-induced changes in the JEJ and observed profound sex differences. Finally, LPS-binding protein (LBP), a marker of gut barrier leakiness, was associated with stress vulnerability in mice and translational value was confirmed on blood samples from women with MDD. Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and possibly, human depression.

Post-stress changes in the gut microbiome composition in rats with different levels of nervous system excitability

“…However, it is necessary to conduct a study aimed at correcting the intestinal microbiota in highly excitable rats (for example, treatment with probiotics). Despite the recommendations to take into account possible dynamic processes in the microbiota composition of intact animals [ 35 ], in most studies, stool sampling for analysis is done in the control and experimental group once: for illustration [ 36 , 37 ]. At the same time, there is evidence of significant changes in alpha diversity indexes in intact mature rodents kept under standard conditions if biomaterial sampling is carried out every week [ 38 ].…”

Characterizing the blood–brain barrier and gut barrier with super-resolution imaging: opportunities and challenges

“…Finally, the blood–brain and gut barriers are large structures with a high density of vessels and cell types. Super-resolution imaging excels in imaging very small units such as synapses or vesicles and, in the context of barriers, tight junctions, 4 , 19 but it may not be well suited to image networks of barrier-related cells. Still, optical nanoscopy can be powerful for studying cell–cell connections, ligand–receptor interactions, etc.…”

“…There are a lot of advantages to using quantitative super-resolution imaging 13 to study the blood–brain and gut barriers. The detection of subtle visual phenotypes, linked to behavioral profiles, genetic, or pharmacological manipulations, can be easily overseen by the human eye, 15 but quantitative approaches can be designed for such complex analysis tasks 19 . The impressive images produced by super-resolution microscopy have raised the need to develop machine-learning- (ML), and more specifically deep-learning- (DL), based algorithms to improve quantitative analysis by increasing the throughput 20 …”