Production of the Neurotoxin Salsolinol by a Gut-Associated Bacterium and Its Modulation by Alcohol

Utilizing a simulated gastrointestinal medium which approximates physiological conditions within the mammalian GI tract, experiments aimed at isolating and identifying unique microbial metabolites were conducted. These efforts led to the finding that Escherichia coli, a common member of the gut microbiota, is capable of producing significant quantities of salsolinol. Salsolinol is a neuroactive compound which has been investigated as a potential contributor to the development of neurodegenerative diseases such as Parkinson’s disease (PD). However the origin of salsolinol within the body has remained highly contested. We herein report the first demonstration that salsolinol can be made in vitro in response to microbial activity. We detail the isolation and identification of salsolinol produced by E. coli, which is capable of producing salsolinol in the presence of dopamine with production enhanced in the presence of alcohol. That this discovery was found in a medium that approximates gut conditions suggests that microbial salsolinol production could exist in the gut. This discovery lays the ground work for follow up in vivo investigations to explore whether salsolinol production is a mechanism by which the microbiota may influence the host. As salsolinol has been implicated in the pathogenesis of PD, this work may be relevant, for example, to investigators who have suggested that the development of PD may have a gut origin. This report suggests, but does not establish, an alternative microbiota-based mechanism to explain how the gut may play a critical role in the development of PD as well other conditions involving altered neuronal function due to salsolinol-induced neurotoxicity

The Inherited Intestinal Microbiota from Myeloid-Specific ZIP8KO Mice Impairs Pulmonary Host Defense against Pneumococcal Pneumonia

Intestinal dysbiosis increases susceptibility to infection through the alteration of metabolic profiles, which increases morbidity. Zinc (Zn) homeostasis in mammals is tightly regulated by 24 Zn transporters. ZIP8 is unique in that it is required by myeloid cells to maintain proper host defense against bacterial pneumonia. In addition, a frequently occurring ZIP8 defective variant (SLC39A8 rs13107325) is strongly associated with inflammation-based disorders and bacterial infection. In this study, we developed a novel model to study the effects of ZIP8-mediated intestinal dysbiosis on pulmonary host defense independent of the genetic effects. Cecal microbial communities from a myeloid-specific Zip8 knockout mouse model were transplanted into germ-free mice. Conventionalized ZIP8KO-microbiota mice were then bred to produce F1 and F2 generations of ZIP8KO-microbiota mice. F1 ZIP8KO-microbiota mice were also infected with S. pneumoniae, and pulmonary host defense was assessed. Strikingly, the instillation of pneumococcus into the lung of F1 ZIP8KO-microbiota mice resulted in a significant increase in weight loss, inflammation, and mortality when compared to F1 wild-type (WT)-microbiota recipients. Similar defects in pulmonary host defense were observed in both genders, although consistently greater in females. From these results, we conclude that myeloid Zn homeostasis is not only critical for myeloid function but also plays a significant role in the maintenance and control of gut microbiota composition. Further, these data demonstrate that the intestinal microbiota, independent of host genetics, play a critical role in governing host defense in the lung against infection. Finally, these data strongly support future microbiome-based interventional studies, given the high incidence of zinc deficiency and the rs13107325 allele in humans

Human Alcohol-Microbiota Mice have Increased Susceptibility to Bacterial Pneumonia

Preclinical studies have shown that chronic alcohol abuse leads to alterations in the gastrointestinal microbiota that are associated with behavior changes, physiological alterations, and immunological effects. However, such studies have been limited in their ability to evaluate the direct effects of alcohol-associated dysbiosis. To address this, we developed a humanized alcoholmicrobiota mouse model to systematically evaluate the immunological effects of chronic alcohol abuse mediated by intestinal dysbiosis. Germ-free mice were colonized with human fecal microbiota from individuals with high and low Alcohol Use Disorders Identification Test (AUDIT) scores and bred to produce human alcohol-associated microbiota or human control-microbiota F1 progenies. F1 offspring colonized with fecal microbiota from individuals with high AUDIT scores had increased susceptibility to Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, as determined by increased mortality rates, pulmonary bacterial burden, and post-infection lung damage. These findings highlight the importance of considering both the direct effects of alcohol and alcohol-induced dysbiosis when investigating the mechanisms behind alcohol-related disorders and treatment strategies

Dopamine production in Enterococcus faecium: A microbial endocrinology-based mechanism for the selection of probiotics based on neurochemical-producing potential.

The mechanisms by which probiotics may influence host physiology are still incompletely understood. Microbial endocrinology, a field representing the union of microbiology, endocrinology and neurobiology, has theorized that microorganisms have the capacity to serve as neurochemical delivery vehicles [1]. According to microbial endocrinology, neurochemicals can serve as a common language between host and bacterium, enabling bidirectional communication. We report herein the first demonstration that Enterococcus sp. has the capacity to produce dopamine in a gastrointestinal-like environment when supplied with the dopamine precursor L-3,4 dihydroxyphenylalanine (L-dopa). The results presented herein provide a means to select probiotics based on neurochemical-producing potential and suggest the possibility that probiotics containing E. faecium may serve to influence the host through dopaminergic pathways

Human Alcohol-Microbiota Mice have Increased Susceptibility to Bacterial Pneumonia

Preclinical studies have shown that chronic alcohol abuse leads to alterations in the gastrointestinal microbiota that are associated with behavior changes, physiological alterations, and immunological effects. However, such studies have been limited in their ability to evaluate the direct effects of alcohol-associated dysbiosis. To address this, we developed a humanized alcohol-microbiota mouse model to systematically evaluate the immunological effects of chronic alcohol abuse mediated by intestinal dysbiosis. Germ-free mice were colonized with human fecal microbiota from individuals with high and low Alcohol Use Disorders Identification Test (AUDIT) scores and bred to produce human alcohol-associated microbiota or human control-microbiota F1 progenies. F1 offspring colonized with fecal microbiota from individuals with high AUDIT scores had increased susceptibility to Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, as determined by increased mortality rates, pulmonary bacterial burden, and post-infection lung damage. These findings highlight the importance of considering both the direct effects of alcohol and alcohol-induced dysbiosis when investigating the mechanisms behind alcohol-related disorders and treatment strategies