Weight gain-mediated recovery of metabolic and gut microbiome impairments in a TDP-43 mouse model of ALS

There is increasing interest in the use of hypercaloric diets in patients with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), as gaining weight, and subsequently fat mass, has been associated with better survival in patients with ALS. However, the precise mechanisms by which nutritional state modifies the onset or progression of ALS remain unclear. We therefore investigated the effects of a short-term high fat (HF) diet treatment (8 weeks) in male NEFH-tTA/tetO-hTDP-43ΔNLS (rNLS mice). This hypercaloric nutritional intervention mitigated motor decline and increased weight in rNLS mice without influencing age of disease onset. HF diet did not alter the disease-associated atrophy of hindlimb tibialis anterior muscle in rNLS mice, and did not correct hippocampal long-term potentiation impairment. However, HF diet did alter glial cell population changes in the hippocampus and cortex of rNLS mice. HF diet also improved glucose homeostasis and reduced plasma metabolic disturbances present in rNLS mice. In addition, we present the first evidence of a significant shift in the gut microbiome of rNLS mice in response to the nutritional intervention. Together, we demonstrate specific improvements in metabolic disturbances of ALS in male rNLS mice, providing, to our knowledge, the first insights to the benefit of this approach to mitigate metabolic alterations in ALS.