Abstract The Neuronal Ceroid Lipofuscinoses (NCLs) are fatal inherited lysosomal storage diseases, with pronounced neuron loss in the central nervous system (CNS). Gastrointestinal issues are frequently reported by people with NCLs, although mechanisms underlying these symptoms are poorly understood. We recently demonstrated degeneration occurs within the enteric nervous system (ENS) in several NCLs. Given that the gut microbiome has been shown to be altered a CLN2 mouse model ( Tpp1 R207X/R207X ) and may potentially influence both CNS and ENS pathology, we investigated the long-term impact of modulating the gut microbiome in these mice. This was done by administering a VNAM antibiotic cocktail (vancomycin, neomycin, ampicillin, and metronidazole) for 1-week post-weaning, examining its effects at disease endstage. While VNAM treatment markedly altered the gut microbiome and caused significant loss of enteric neurons in wildtype mice, it did not exacerbate key pathological parameters in either bowel or brain of Tpp1 R207X/R207X mice. These included histomorphometric changes in the small intestine and neurodegeneration of enteric neurons, or CNS neuropathology. However, we did find evidence for moderate protective effects of VNAM upon enteric neurons in the ileum, and upon CNS microglia, but all other pathologies were unaltered in Tpp1 R207X/R207X mice. These findings suggest that intestinal and ENS pathology is primarily driven by TPP1-deficiency rather than changes in the gut microbiome. Indeed, these alterations to the gut microbiome may occur secondary to the impact of CLN2 disease upon the bowel.
Ziólkowska et al. (Sat,) studied this question.