Preoperative Microbiomes and Intestinal Barrier Function Can Differentiate Prodromal Alzheimer’s Disease From Normal Neurocognition in Elderly Patients Scheduled to Undergo Orthopedic Surgery

Abstract

ObjectiveEmerging evidence links perturbations in the microbiome to neurodegeneration in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) and to surgical stress. In this study, we attempted to identify preoperative differences intestinal microbiota (IM) and barrier function between pAD [prodromal AD: Subjective cognitive decline (SCD) and aMCI] patients and normal neurocognition (NC) patients. Additionally, the potential associations between IM and barrier function, inflammation, and the clinical characteristics of pAD were evaluated.DesignEighty elderly patients scheduled to undergo orthopedic surgery were consecutively enrolled and grouped as NC, SCD, and aMCI following neuropsychological assessment. IM was determined by 16S rRNA MiSeq sequencing, and PICRUSt was used to predict functional shifts in IM. Furthermore, we investigated the association between IM and plasma claudin-1, occludin, LPS, systemic inflammatory cytokines, neuropsychological assessment, and clinical characteristics.ResultsThere was a lower Chao1 index in the SCD group (P = 0.004) and differences in beta diversity among the three groups (PCA: P = 0.026, PCoA: P= 0.004). The relative abundance of Bacteroidetes was higher in the SCD group (P = 0.016, P = 0.008), and Firmicutes were more enriched in the aMCI group than in the SCD group (P= 0.026). At the family level, the total abundance of Gram-negative bacteria was higher in the SCD group than in the aMCI group (P = 0.047), and the Christensenellaceae family was detected at lower levels in the SCD and aMCI groups than in the NC group (P= 0.039). At the genus level, the eleven short-chain fatty acid (SCFA)-producing bacteria exhibited differences among the three groups. PICRUSt analysis showed that the pathways involved in SCFA catabolism, biosynthesis, and adherent junctions were reduced in SCD patients, and lipid synthesis proteins were reduced in pAD patients. Meanwhile, elevated plasma LPS and CRP were observed in SCD patients, and higher plasma occludin in aMCI patients. The IM was correlated with plasma claudin-1, LPS, inflammatory factors, neuropsychological assessment, and clinical characteristics.ConclusionThe intestines of SCD and aMCI patients preoperatively exhibited IM dysbiosis and barrier dysfunction, and elevated plasma LPS and CRP were observed in SCD patients.

Gut Microbiota and Depressive Symptoms at the End of CRT for Rectal Cancer: A Cross-Sectional Pilot Study

“…Park et al [ 65 ] proposed that a reduction in the abundances of fermentation-related bacteria may suggest a decay in SCFA production, which in turn may be associated with intestinal barrier dysfunction and an inflammatory response that can cause depression [ 67 ]. In another study, decreased levels of butyrate-producing bacteria (Ruminococcaceae_UG-013 and Lacknospiraceae_NK4A136_ group) were found to be associated with high levels of inflammatory factors such as CRP and TNF-alpha [ 68 ]. There is also clinical evidence of a positive association between stool acetate levels with depressive symptoms, as well as negative associations between butyrate and propionate levels with depressive symptoms [ 69 ].…”

The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging

“…This hypothesis is further supported by studies performed in old mice suffering from memory defects and impaired cognition due to acute inflammations, as well as in mouse models of neurodegeneration [ 168 , 169 ]. Old patients with prodromal Alzheimer’s disease suffer from increased LPS levels [ 170 ] and altered microbiota compositions [ 171 , 172 ]. Targeting the intestinal microbiota composition with probiotics or single bacterial species, e.g., Akkermansia muciniphila , in mice with cognitive deficits has been found to protect the intestinal barrier and improve cognitive functions [ 164 , 173 ].…”

The mechanism of the gut microbiota affecting the development of Alzheimer's disease and expectations on therapeutic methods

“…SCD is the earliest stage in the pathogenesis of AD, and during this stage, changes in the gut microbiota such as significant reduction in the abundance of anti-inflammatory bacteria Faecalibacterium [8], reduction in the number of bacteria producing short-chain fatty acids (SCFAs), decline in the number of butyric acid-producing flora and SCFA-producing flora compared with normal people and patients in MCI stage [9] have taken place in the intestines of patients. Species of the reduced number of SCFAproducing flora include the Class Clostrida, Clostridiales, and Ruminococcaceae.…”

“…Besides, the abundance of the microflora also correlates with other indicators. The level of anti-inflammatory cytokine IL-10 in plasma is negatively correlated with the total abundance of pro-inflammatory Gram-negative bacteria, and the total level of Gram-negative bacteria is negatively correlated with auditory verbal learning test (AVLT) [9].…”

“…The second is the increased abundance of Gramnegative bacteria, which may lead to an increase in lipopolysaccharide (LPS), a characteristic component of the outer leaflet of the Gram-negative bacterial outer membranes within the plasma. In turn, when the intestinal barrier is compromised, the potential for LPS to flow into the extracellular space, blood, or directly into the brain is increased, which in turn causes systemic inflammation, neuroinflammation, and AD pathological processes associated with amyloidosis and impaired neurocognitive function [9,15]. Patients with SCD have elevated levels of C-reactive protein and elevated LPS levels compared to the cognitive normal population, suggesting that LPS is indeed associated with inflammation and may cause inflammation.…”