Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve

Abstract

Background: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotictreated microbiota depletion. Methods: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. Results: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression-and anhedonialike phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotictreated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. Conclusions: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Abnormal composition of microbiota in the gut and skin of imiquimod-treated mice

“…At the species level, the three Lactobacillus microbes such as Lactobacillus intestinalis , Lactobacillus reuteri , and Lactobacillus taiwanensis were significantly higher in the intestine of IMQ-treated mice compared to control mice. A recent study showed that Lactobacillus intestinalis and Lactobacillus reuteri may be responsible for the depression-like behavior in mice after transplantation of “depression-related microbes” 40 . The increased abundance of Lactobacillus intestinalis, Lactobacillus reuteri and Lactobacillus taiwanensis by IMQ treatment may contribute to the increased levels of lactic acid in the IMQ-treated mice since Lactobacilli ferment lactose into lactic acid 41 .…”

“…The DNA extractions from the fecal and skin samples and 16S rRNA sequencing analyses were performed by MyMetagenome Co., Ltd. (Tokyo, Japan), as reported previously 40 , 50 – 52 . DNA extraction from mouse samples and purification were performed according to the method of the previous report 53 , 54 .…”

Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection

“…Among those bacteria, Bacteroides uniformis and Lactobacillus johnsonii, which were abundant in malaria-resistant mice, are well known for probiotic potential (Morita et al, 2020). Conversely, the Alistipes genus and Lactobacillus reuteri, which are abundant in malaria-susceptible mice, are associated with detrimental health effects like depression, anhedonia-like phenotypes, inflammation of spinal cords, cancer, and mental health (Miyauchi et al, 2020;Parker et al, 2020;Wang et al, 2020). In addition, L. reuteri is associated with higher plasma interleukin-6 (IL-6) levels in mice, and circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mice (Wang et al, 2020;Wunderlich et al, 2012).…”

Gut Microbiota Comparison Between Intestinal Contents and Mucosa in Mice With Repeated Stress-Related Diarrhea Provides Novel Insight

“…In the intestinal contents, the abundance of the pathogenic bacterium Helicobacter ganmani , a relative of Helicobacter pylori ( Nagamine et al, 2015 ), was significantly increased. The results show an increase in the relative abundance of Lactobacillus intestinalis in the intestinal contents in repeated stress-related diarrhea mice, and it has been reported that L. intestinalis can aggravate the emotional disorder of diarrhea mice via the vagus nerve ( Wang S. etal., 2020 ), which indicates that the imbalance of microbiota in this study may aggravate the psychological stress of repeated stress-related diarrhea mice.…”