Ergothioneine, a metabolite of the gut bacteriumLactobacillus reuteri, protects against stress-induced sleep disturbances

Abstract

The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least one month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression.

Ergothioneine in the brain

“…Matsuda et al [20] also reported that oral administration of ERGO prevented depressive behavior and depression-like sleep abnormalities in rats (Table 2). In their studies, preventive administration of ERGO (0.25 mgÁmL À1 ) via drinking water corresponding to ~30 mgÁkg À1 Áday À1 based on water intake and body weight, ameliorated social defeat stress (SDS)-induced social avoidance behaviors against other rats and sleep abnormalities such as an increase in rapid eye movement sleep [20]. Furthermore, they demonstrated that SDS substantially increases the levels of the fecal gut bacterium Lactobacillus reuteri in correlation with fecal ERGO level, implying a protective system against psychosocial stress in the microbiota-gut-brain axis [20].…”

“…In fact, oral ingestion of ERGO (120 mg/100 g diet) for 2 weeks in mice significantly decreased the immobility time, an index of depression-like behavior, in forced swimming and tail suspension tests with a concomitant increase in ERGO concentration in the brain (~20 µgÁg À1 tissue, Table 2) [19], and the ingestion promotes neurogenesis in the hippocampus, indicating that oral ERGO ingestion exerts antidepressant-like activity, possibly via promotion of neurogenesis in mice [19]. Matsuda et al [20] also reported that oral administration of ERGO prevented depressive behavior and depression-like sleep abnormalities in rats (Table 2). In their studies, preventive administration of ERGO (0.25 mgÁmL À1 ) via drinking water corresponding to ~30 mgÁkg À1 Áday À1 based on water intake and body weight, ameliorated social defeat stress (SDS)-induced social avoidance behaviors against other rats and sleep abnormalities such as an increase in rapid eye movement sleep [20].…”

“…In their studies, preventive administration of ERGO (0.25 mgÁmL À1 ) via drinking water corresponding to ~30 mgÁkg À1 Áday À1 based on water intake and body weight, ameliorated social defeat stress (SDS)-induced social avoidance behaviors against other rats and sleep abnormalities such as an increase in rapid eye movement sleep [20]. Furthermore, they demonstrated that SDS substantially increases the levels of the fecal gut bacterium Lactobacillus reuteri in correlation with fecal ERGO level, implying a protective system against psychosocial stress in the microbiota-gut-brain axis [20]. ERGO in the cerebellum and plasma of the sleepstate was significantly reduced compared with that in the awake state, suggesting an association between ERGO and sleep [49].…”

“…Moreover, oral administration of ERGO enhances memory function in humans [17] and mice [18] and exhibits antidepressant activity in mice [19]. Oral administration of ERGO protects against stressinduced sleep disturbance [20] and neuronal injury induced by amyloid b (Ab) in rodents [21]. Many in vitro studies have suggested that the effects of ERGO on brain function may be the result of its antioxidative activity, whereas promotion of neurogenesis and neuronal maturation are also beneficial effects of ERGO in the brain [2,10,18,[21][22][23][24].…”