A crosstalk between gut and brain in sepsis-induced cognitive decline

Abstract

Background Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors. Methods To test our hypothesis, adult Wistar rats were subjected to cecal–ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory. Results Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group. Conclusions Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.

The central role of the gut in intensive care

“…While no human studies are available, a recent preclinical study has shown how the GM plays a part in sepsis-associated encephalopathy by improving neurological outcomes when indole-3-propionic acid, a microbial neuroprotective metabolite, is produced, leading to the inhibition of NLRP3 inflammasome activation and IL-1β secretion in the microglia [ 26 ]. Similar preclinical results have been found in model of sepsis-induced cognitive decline [ 25 ], emphasizing the link between GM dysbiosis and the brain.…”

“…These molecules affect memory, learning, behavior, and locomotion. Unbalanced molecular communication contributes to neurodegenerative and neuropsychiatric diseases [ 23 ], traumatic brain injury (TBI) [ 24 ], and sepsis-correlated brain impairment [ 25 , 26 ]. The gut–brain axis (GBA) bidirectionally connects the central nervous system with the enteric one.…”

“…Indeed, the inflammasome binds pathogenassociated and/or danger-associated molecular patterns, specific molecular motifs carried by gut microorganisms. Thus, a perturbation of the GM composition could overstimulate the inflammasome and compromise the GBA homeostasis, promoting neuroinflammation as seen in multiple sclerosis [36], Alzheimer's disease [37], Parkinson's disease [38], neuropsychiatric disorders [39], and sepsis [25,26]. While no human studies are available, a recent preclinical study has shown how the GM plays a part in sepsis-associated encephalopathy by improving neurological outcomes when indole-3-propionic acid, a microbial neuroprotective metabolite, is produced, leading to the inhibition of NLRP3 inflammasome activation and IL-1β secretion in the microglia [26].…”

Disrupted metabolic and spontaneous neuronal activity of hippocampus in sepsis associated encephalopathy rats: A study combining magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging

“…The hippocampus is well known for its role in long-term memory and MWM-associated spatial learning and memory in rodents has been linked to the hippocampus ( Liu et al, 2021 ). As CLP surgery has been shown to cause sustained cognitive impairment 5–15 days post-surgery and a previous study performed the MWM test at 1–2 weeks post CLP surgery to assess cognitive function in SAE rats ( Shen et al, 2020 ; Giridharan et al, 2022 ), we further analyzed the ALFF values and metabolism changes during the same time period. In our results, the increased ALFF values in the hippocampus supported the deteriorated behavioral results in the MWM test, which was consistent with a previous studies using the MWM test to evaluate hippocampal function ( Barnhart et al, 2015 ).…”

Gut microbiota may be involved in Alzheimer’s disease pathology by dysregulating pyrimidine metabolism in APP/PS1 mice

“…Fresh fecal samples ( n = 8/group) were collected into individual sterile EP tubes on two consecutive mornings ( Wang et al, 2019 ) after the MWM test and immediately frozen at −80°C until analysis ( Giridharan et al, 2022 ).…”