Clostridioides difficile , previously Clostrdium difficile , is a major cause of antibiotic-associated enteric disease in humans in hospital settings. Increased incidence of C. difficile infection (CDI) in community settings raises concerns over an alternative source of CDI for humans. The detection of genetically similar and toxigenic C. difficile isolates in companion animals, including asymptomatic pets, suggests the potential role of household pets as a source of community-associated CDI. The close association between companion animals and humans, in addition to the use of similar antibiotics in both species, could provide a selective advantage for the emergence of new C. difficile strains and thus increase the incidental transmission of CDI to humans. Therefore, screening household pets for C. difficile is becoming increasingly important from a public health standpoint and may become a part of routine testing in the future, for the benefit of susceptible or infected individuals within a household. In this review, we analyze available information on prevalence, pathophysiology, epidemiology, and molecular genetics of C. difficile infection, focusing on companion animals and evaluate the risk of pet-borne transmission of CDI as an emerging public health concern. Molecular epidemiological characterization of companion animal C. difficile strains could provide further insights into the interspecies transmission of CDI. The mosaic nature of C. difficile genomes and their susceptibility to horizontal gene transfer may facilitate the inter-mixing of genetic material, which could increase the possibility of the emergence of new community-associated CDI strains. However, detailed genome-wide characterization and comparative genome analysis are warranted to confirm this hypothesis.

The gut-brain axis is thought to play a significant role in the development and manifestation of neurologic diseases. This study reports significant alterations in the brain dopamine metabolism in mice infected with C. difficile , an important pathogen that overgrows in the gut after prolonged antibiotic therapy. Such alterations in specific brain regions may have an effect on the precipitation or manifestation of neurodevelopmental disorders in humans.

Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation, urination, defecation, gastrointestinal distress, respiratory distress, and seizures. Although the OPNAs have been studied in the past few decades, little is known about the impact on the gut microbiome which has become of increasing interest across fields. In this study, we challenged animals with the OPNA, diisopropylfluorophosphate (DFP, 4mg/kg, s.c.) followed immediately by 2mg/kg atropine sulfate (i.m.) and 25mg/kg 2-pralidoxime (i.m.) and 30 minutes later by 3mg/kg midazolam (i.m.). One hour after midazolam, animals were treated with a dosing regimen of saracatinib (SAR, 20mg/kg, oral), a src family kinase inhibitor, to mitigate DFP-induced neurotoxicity. We collected fecal samples 48 hours, 7 days, and 5 weeks post DFP intoxication. 16S rRNA genes (V4) were amplified to identify the bacterial composition. At 48 hours, a significant increase in the abundance of Proteobacteria and decrease in the abundance of Firmicutes were observed in DFP treated animals. At 7 days there was a significant reduction in Firmicutes and Actinobacteria, but a significant increase in Bacteroidetes in the DFP groups compared to controls. The taxonomic changes at 5 weeks were negligible. There was no impact of SAR administration on microbial composition. There was a significant DFP-induced reduction in alpha diversity at 48 hours but not at 7 days and 5 weeks. There appeared to be an impact of DFP on beta diversity at 48 hours and 7 days but not at 5 weeks. In conclusion, acute doses of DFP lead to short-term gut dysbiosis and SAR had no effect. Understanding the role of gut dysbiosis in long-term toxicity may reveal therapeutic targets.

Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile in the gut, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism in the brain by increasing p-cresol levels in the gut and circulation and by inhibiting DBH, ultimately leading to elevated DA in the brain. For testing this hypothesis, we induced antibiotic-associated C. difficile in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes significant alterations in the dopaminergic axis in mice (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity was observed in C. difficile infected animals (p < 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.