Contributed by Flavia Barreto Garcez MD, PhD and Thiago Junqueira Avelino-Silva, MD, PhD
Laboratorio de Investigacao Medica em Envelhecimento (LIM 66), Servico de Geriatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Brazil
The gut microbiota, the collection of microorganisms in our gastrointestinal tract,1 has gained increasing attention in recent years. It has been associated with various conditions, including obesity, insulin resistance, and inflammatory bowel disease.2 Moreover, gut dysbiosis (i.e., disturbances in the gut microbiota) has been linked to chronic neuropsychiatric diseases like depression and Alzheimer’s disease.3-4 However, data on gut dysbiosis in acute conditions like delirium are scarce.5 In this blog, we discuss a recent study6 we conducted to explore the association between gut microbiota diversity and delirium occurrence in acutely ill older adults.
We conducted the study at Hospital das Clinicas, a tertiary university hospital in Sao Paulo, Brazil, between September 2019 and March 2020. We included participants older than ≥ 65 years admitted to the emergency department. Patients were excluded if they had recently received antibiotics or enteral/parenteral nutrition, were recently hospitalized, or were discharged before 48 hours of hospitalization.
We collected sociodemographic, clinical, and laboratory data on admission and throughout the hospital stay. For gut microbiota sampling, we obtained rectal swabs at admission and 72 hours after admission; a third sample was collected whenever delirium newly occurred or first resolved. Trained researchers used the Confusion Assessment Method (CAM) to assess for delirium twice daily throughout the hospital stay. We measured cytokine plasma levels using the Milliplex© immunoassay.
We reported the alpha diversity (microbial abundance or richness within each community or sample), beta diversity (microbial differences between two communities or samples), and core microbiota (taxa detected in the totality or majority of samples per group). Also, we used linear discriminant analysis effect sizes to compare microbial differences between participants with and without delirium.
We applied various statistical analyses, including GEE, generalized linear models, logistic regression models, Wilcoxon’s rank-sum or Kruskal-Wallis tests, and Spearman’s correlation coefficients, to compare microbiota data and delirium occurrence, delirium severity, and impaired consciousness. Additionally, we used directed acyclic graphs to select covariables and the Benjamin-Hochberg method to adjust p-values for multiple comparisons.
Delirium occurred in 38 (29%) of the 133 enrolled patients. A total of 257 rectal swabs were collected and analyzed. After adjusting for potential confounders, we found that higher fecal alpha diversity was significantly associated with lower delirium occurrence [Shannon diversity index: odds ratio (OR)=0.77; 95% confidence interval (CI)=0.60-0.99; Pielou diversity index: OR=0.69; 95% CI=0.51=0.87). Beta diversity analyses revealed gut microbiota differences between the delirium and non-delirium groups and patients with and without impaired consciousness.
Gut microbiota was found to be different between the delirium (vs. no delirium) group. For example, the delirium group was more likely to have bacterial taxa related to pro-inflammatory pathways, such as Enterobacteriaceae, and those involved in neurotransmitter modulation (Serratia for dopamine, Bacteroides and Parabacteroides for GABA). These associations between gut microbiota and delirium persisted regardless of patients’ baseline nutritional status.
Our study indicates that gut microbiota diversity and composition may play a significant role in the development of delirium in acutely ill hospitalized older adults. Our observation that inflammatory biomarkers (e.g., IL-6 and IL-10) were higher in the delirium group suggests that gut dysbiosis and inflammation may have a potential role in delirium’s mechanistic pathway.
We hypothesize this potential relationship between gut microbiota and delirium may be bidirectional. The factors that precipitate delirium or the underlying pathophysiology of delirium may impact gut microbiota composition. Conversely, gut bacteria may influence delirium by producing cytokines and neurotransmitters that modulate inflammation and alter brain function. Our results suggest the interplay between gut microbiota, inflammation, and delirium in acutely ill older adults is complex.
By exploring the association between gut microbiota and delirium, we have uncovered a new avenue of research for understanding the complex relationship between the gut and brain health. As we continue to learn more about the intricate workings of the gut microbiome, it is crucial to investigate its potential impact on acute conditions like delirium. Identifying new biomarkers and therapeutic targets could inform new approaches for delirium prevention and treatment.
We are grateful to the Network for Investigation of Delirium: Unifying Scientists (NIDUS) for their leadership and collaborative spirit, encouraging scientists like ourselves to embrace new challenges in delirium research worldwide. We also thank Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) for supporting this work.
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- Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369–2379. doi:10.1056/NEJMra1600266
- O’Toole PW, Jeffery IB. Gut microbiota and aging. Science.2015;350(6265):1214-1215. doi:10.1126/science.aac8469.
- Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016; 21(6):738-748. doi:10.1038/mp.2016.50.
- Zhang Y, Baldyga K, Dong Y, et al. The association between gut microbiota and postoperative delirium in patients. Transl Psychiatry. 2023;13(1):156
- Garcez FB, Garcia de Alencar JC, Fernandez SSM, et al. Association between gut microbiota and delirium in acutely ill older adults [published online ahead of print, 2023 Mar 3]. J Gerontol A Biol Sci Med Sci. 2023;glad074. doi:10.1093/gerona/glad074