Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive dementia and brain accumulation of Aβ-peptide-containing plaques, gliosis, neuroimmune changes, and neurofibrillary tangles. Mushroom polysaccharides have been previously reported to have anti-neuroinflammation activity through the gut–brain axis. This study aimed to evaluate whether a dietary intervention with Phallus atrovolvatus, a recently identified edible mushroom in Thailand, could have a benefit on gut health and alleviate AD-related changes. Methods: Male and female 6–8-month-old littermate wild-type control (C57BL/6J) and App^NL−G−F mice were randomly assigned to either a control diet or a diet supplemented with mushroom aqueous extract (MAE) for 8 weeks to quantify changes in body weight, intestine, immune cells, short chain fatty acids, brain cytokines, amyloid-β (Aβ) levels, gliosis, and memory. Results: MAE had no adverse effects on gut leakiness and increased pyruvate levels in serum. Splenocyte immune profiling revealed a significant increase in the frequency of IgM⁺, IA_IE⁺, and CD14⁺ cells in MAE-administered App^NL−G−Ffemale mice compared to their vehicle controls. App^NL−G−Fmale mice that received MAE showed a significant increase in the frequency of cytotoxic CD8 T cells within the cervical lymph nodes compared to their wild-type counterparts. Aβ deposition and gliosis were significantly reduced in the hippocampi of the MAE-supplemented App^NL−G−F groups. However, MAE feeding did not alter spatial recognition memory in either sex or genotype compared to their vehicle groups. Conclusions: Our findings demonstrated that the administration of P. atrovolvatus aqueous extract showed neuroprotective potential against AD-related changes in the brain with no adverse impact on gut health and memory.

Phallus atrovolvatus, a wild edible mushroom, has attracted increasing interest for consumption due to its unique taste and beneficial health benefits. This study determined the chemical components in the so-called fruiting body during the egg and mature stages and investigated its gut microbiota-modulating activities. The egg stage contained higher total carbohydrates, dietary fiber, glucans, ash, and fat, while the total protein content was lower than in the mature stage. Two consumption forms, including cooked mushrooms and a mushroom aqueous extract from both stages, were used in this study. An in vitro gut fermentation was performed for 24 h to assess gut microbiota regulation. All mushroom-supplemented fermentations increased short-chain fatty acid (SCFA) production compared to the blank control. Furthermore, all mushroom supplementations promoted the growth of Bifidobacterium and Streptococcus. Samples from the mature stage increased the relative abundance of Clostridium sensu stricto 1, while those from the egg stage increased the Bacteroides group. The inhibition of harmful bacteria, including Escherichia-Shigella, Klebsiella, and Veillonella, was only observed for the mature body. Our findings demonstrate that P. atrovolvatus exhibits potential benefits on gut health by promoting SCFA production and the growth of beneficial bacteria, with the mature stage demonstrating superior effects compared to the egg stage.