In this prospective observational cohort study, the gut bacteria Parabacteroides distasonis, was associated with the incidence of postoperative delirium in patients. Pending confirmative studies, these data suggest that gut microbiota dysbiosis, the pathogenesis of several brain dysfunction 22–25, contributes partially to the development of postoperative delirium. Certain gut bacteria may serve as risk biomarkers, pathogenesis, and potential target of intervention(s) of postoperative delirium in patients.
In this study about 12% of participants developed postoperative. These findings are consistent with many other postoperative delirium clinical investigations 47–50, which revealed a 5.1–19.4% incidence of postoperative delirium in patients.
Increases in the abundance of postoperative gut bacteria Parabacteroides distasonis were associated with the increases in the incidence of postoperative delirium in the patients after the adjustment of age and sex. Although generally lower in delirious patients, decreases in the abundance of Prevotella and Collinsella were not significantly associated with delirium. Moreover, patients who developed postoperative delirium had a higher abundance of postoperative gut Parabacteroides distasonis, and lower abundance of postoperative gut Prevotella and Collinsella. These data suggest the contribution of the gut-brain axis to postoperative delirium, and certain gut bacteria can predict postoperative delirium. Future studies will include whether we can target changing the abundance of postoperative gut bacteria, for example, by reducing the abundance of Parabacteroides distasonis, to prevent and/or treat postoperative delirium.
Parabacteroides distasonis is a bacteria implicated in Crohn's Disease and ulcerative colitis 43 and Prevotella is associated with chronic inflammatory disease 51. Therefore, future studies should also determine the potential association between postoperative delirium and Crohn's Disease, ulcerative colitis, and chronic inflammatory disease.
Previous studies have shown that patients who developed postoperative delirium (N = 20) and did not develop postoperative delirium (N = 20) had a different abundance of preoperative gut bacteria 52. Specifically, gut bacteria Proteobacteria, Enterobacteriaceae, Escherichia shigella, Klebsiella, Ruminococcus, Roseburia, Blautia, Holdemanella, Anaerostipes, Burkholderiaceae, Peptococcus, Lactobacillus, and Dorea were abundant in the patients with postoperative delirium, and Streptococcus equinus and Blautia hominis were abundant in the patients without postoperative delirium 52. However, this previous study is different from the current study, as it determined preoperative, not postoperative, gut microbiota; did not establish an association with the incidence of postoperative delirium; and did not assess the severity of delirium with the MDAS. Thus, the previous study did not demonstrate the association between gut microbiota and postoperative delirum in patients. Future studies should include the systematical determination of the association between postoperative delirium and both pre-and postoperative gut microbiota in a larger-scale study.
Interestingly, the present study did not find the associations between the three gut bacteria and the severity of postoperative delirium in patients, as represented by MDAS scores. However, previous studies show that some biomarkers are only associated with the incidence, not severity, of postoperative delirium in patients 53.
Notably, the average MDAS score of the participants in the present study was 6.6 (Table 1). Although Breitbart et al. stated that MDAS Scores ≥ 13 indicate the presence of delirium 38, the participants in the study by Breitbart et al. included psychiatry consult patients 38. Marcantonio et al. showed that the best MDAS cutoff for postoperative delirium was 5 in the participants with surgery for hip fracture repair 35. Therefore, it is reasonable that the average MDAS score was 6.6 in the present study.
A strength of the present study included the use of a Dimension-reduction Algorithm in Small Human-datasets (DASH). This method combined a statistical dimensionality reduction algorithm and domain expertise to perform high-throughput data screening and efficiently extract real signals from the noise background. Because of the small sample size and complicated data structure, data-driven methodology alone was insufficient in finding the relationship between gut microbiota and postoperative delirium in patients. Therefore, by infusing our current research knowledge into the data-driven methodology that allowed us to filter through several hundred variables in a small data set. This method can be particularly powerful for analyzing small but high-dimensional patient-level datasets. However, an important component of this approach requires the manual selection of interesting bacteria, which can introduce bias due to subjective opinions. Nevertheless, in the present study, we identified Parabacteroides distasonis because it is associated with inflammation-related disorders43, and inflammation is associated with postoperative delirium12. Prevotella was selected because of its association with chronic inflammatory disease 44, and Collinsella was selected because of its known association with cumulative inflammatory response 45.
Limitations of this study included a small sample size at a single center. However, similar biomarker studies (N = 11 54 and N = 14 55) used smaller sample sizes to draw a solid conclusion. In the present study, one hundred and thirty-four of 220 enrolled participants were excluded primarily due to insufficient DNA amounts in the swapped samples and others. However, there were no significant differences in the characteristics between the 86 participants included in the final data analysis and the 134 patients excluded from the study after the enrollment except for anesthesia type (Supplemental Table 1). But, previous studies have demonstrated that anesthesia type does not affect postoperative delirium 47, 56. In addition, we did not perform preoperative CAM in the participants since these participants had elective cases and the rate of preoperative delirium would be very low based on the findings from previous studies by Mei et al. (0 of 606 participants) 36 and Shi et al. (3 of 192 participants) 37. Therefore, the presence of postoperative delirium in the study may not be called incident delirium but just postoperative delirium.
In conclusion, in this present proof of concept and system establishment study, patients who developed postoperative delirium had a higher abundance of postoperative gut bacteria Parabacteroides distasonis than those who did not develop postoperative delirium. These findings suggest that gut microbiota dysbiosis significantly contributes to postoperative delirium, and may be used to promote more research to prevent or treat postoperative delirium by restoring gut microbiota dysbiosis.