Associations Between Microbiota, Mitochondrial Function, and Cognition in Chronic Marijuana Users

Abstract

Marijuana (MJ) use is associated with cognitive deficits. Both mitochondrial (mt) dysfunction and gut dysbiosis also affect cognition. We examined whether cognition is related to peripheral blood mononuclear cells' (PBMCs) mt function and fecal microbiota in chronic MJ users. Nineteen chronic MJ users and 20 non-users were evaluated using the Cognition Battery in NIH Toolbox, their mt function for ATP production, and basal and maximal respirations were measured in PBMCs using the Seahorse XFe96 Analyzer, and the abundances of Prevotella and Bacteroides (associated with plant-based and animal product-based diet, respectively) were calculated from stool microbiota analysis. Average Prevotella:Bacteroides ratio was ~13-fold higher in nonusers than users. Lifetime MJ use correlated inversely with Prevotella:Bacteroides ratio (p = 0.05), mt function (p = 0.0027-0.0057), and Flanker Inhibitory Control and Attention (p = 0.041). Prevotella abundance correlated positively, while Bacteroides abundance correlated inversely, with mt function across all participants (p = 0.0004-0.06). Prevotella abundance also correlated positively with scores of Fluid Cognition, Flanker Inhibitory Control and Attention, List Sorting, and Dimension Change Card Sort in MJ users, but not in non-users (interaction-p = 0.018-0.05). Similarly, mt function correlated positively with scores of Fluid Cognition and Flanker Inhibitory Control and Attention in MJ users, but not in non-users (interaction-p = 0.0018-0.08). These preliminary findings suggest that MJ use is associated with alterations of gut microbiota and mt function, which may further contribute to cognitive deficits. We posited that MJ-associated low vegetable/fruit intake may contribute to these changes. Future studies are needed to delineate the relationships among diet, microbiota, mt function, and cognition in MJ users.

Keywords: Bacteroides; Cognition; Diet; Marijuana; Microbiota; Mitochondria; Prevotella.

Figures

Figure 1. Correlations between gut microbiota, lifetime MJ use, and cognitive function

(A) Inverse correlation between Prevotella abundance and Bacteroides abundance in fecal microbiota in all participants. (B) Lower Prevotella:Bacteroides ratio was associated with greater lifetime MJ use among MJ users. (C–F) Lower Prevotella abundance was associated with poorer Fluid Cognition Composite score, Flanker Inhibitory Control and Attention score, List Sorting working memory score, and Dimensional Change Card Sort score in MJ users, but not in nonusers. Statistical significance is noted in bold font.

Figure 2. Mitochondrial oxygen consumption in PBMCs correlated positively with the abundance of Prevotella, and inversely with the abundance of Bacteroides, and with lifetime marijuana use

(A–D) Mt ATP production and basal respiration rate correlated positively with Prevotella abundance (A & C; since the main effect of “group” was significant, trend lines were drawn for each group (red dashed line for user group, and blue dashed line for nonuser group); but since group-by-Prevotella interaction was not significant, all subjects were combined for correlation analyses), but correlated inversely with Bacteroides abundance (B & D) across all participants. (E) Mt ATP production inversely correlated with lifetime MJ use. (F) A representative figure demonstrating strong correlations among mt ATP production and basal (shown) or maximal (not shown) respiration rates. OCR, oxygen consumption rate. Statistical significance is noted in bold font.

Figure 3. PBMCs’ mitochondrial oxygen consumption correlated positively with cognitive function and inversely with lifetime marijuana use among marijuana users

Fluid cognition composite score (A–C) and flanker inhibitory control and attention score (D–F) correlated positively with mt ATP production and basal and maximal respiration rates only in MJ users, but not in nonusers. Flanker inhibitory control and attention score correlated inversely with lifetime MJ use (G). OCR, oxygen consumption rate. Statistical significance is noted in bold font.

Figure 4

Hypothetical network among chronic MJ use, dietary pattern, gut microbiota, mt respiration, and cognitive function.