Polysaccharide Engineered Nanozymes Target Inflammation for Alleviating Colitis-Associated Mental Disorders via Microbiome-Gut-Brain Axis.

Bioinformatic approaches predicted inflammation and metabolism as potential targets for Fucoidan in colitis-associated mental disorders.

• Bioinformatic analysis was employed to guide the therapeutic design of the nanozyme system.
• Fucoidan was identified as having dual potential targets: inflammatory pathways and metabolic pathways.
• This prediction guided the development of Fucoidan-cerium nanocomplexes (FucCeNCs) as an oral therapeutic.

FucCeNCs were engineered to target the inflamed colon through electrostatic interactions and exert anti-inflammatory effects.

• FucCeNCs are oral polysaccharide engineered nanozymes composed of fucoidan and cerium.
• Targeting of inflamed colon tissue was achieved through electrostatic interactions between the nanocomplex and inflamed tissue.
• The nanozymes concurrently exerted anti-inflammatory effects and regulated gut microbiota-derived metabolism.
• The system was designed to address multiple pathways simultaneously to overcome limitations of single-pathway molecular therapies.

FucCeNCs demonstrated anti-inflammatory and gut barrier-protective effects in a murine model of ulcerative colitis-associated mental disorders.

• The study used a murine model of ulcerative colitis-associated mental disorders.
• FucCeNCs suppressed microglial and astrocytic overactivation.
• Neuronal integrity was preserved through the transmission of anti-inflammatory cytokines via the gut-brain axis.
• Gut barrier protection was identified as a key mechanism through which neuroinflammation was reduced.

FucCeNCs restored gut microbial homeostasis by increasing probiotic abundance and reducing pathogen proportions.

• Treatment with FucCeNCs increased the relative abundance of probiotics in gut microbiota.
• Proportions of pathogens were reduced following FucCeNCs treatment.
• This shift in microbial composition contributed to downstream metabolic and neurological effects.
• Gut microbial homeostasis restoration was identified as a pivotal mechanism of action.

FucCeNCs markedly attenuated abnormal amino acid biosynthesis and metabolism in fecal metabolites.

• The shift in gut microbial composition resulted in attenuation of abnormal amino acid biosynthesis and metabolism.
• Changes were detected in fecal metabolites.
• Elevated levels of bioactive metabolites including homovanillic acid and γ-aminobutyric acid (GABA) were observed.
• These metabolite changes were linked to downstream effects on neuroinflammation.

Elevated homovanillic acid and γ-aminobutyric acid levels following FucCeNCs treatment attenuated neuroinflammation and ameliorated depression- and anxiety-like behaviors.

• Homovanillic acid and γ-aminobutyric acid (GABA) were identified as key bioactive metabolites elevated by FucCeNCs treatment.
• These metabolites acted via the microbiome-gut-brain axis to attenuate neuroinflammation.
• Treatment resulted in amelioration of both depression-like and anxiety-like behaviors in the murine model.
• The microbiome-gut-brain axis was identified as a pivotal therapeutic target for colitis-associated mental disorders.

The microbiome-gut-brain axis was identified as a pivotal therapeutic target for colitis-associated mental disorders that can be addressed by polysaccharide engineered nanozymes.

• Results from the murine model support the microbiome-gut-brain axis as a central mechanistic pathway.
• Polysaccharide engineered nanozymes (FucCeNCs) were able to engage this axis therapeutically.
• The study argues that targeting a single pathway shows limited efficacy, whereas FucCeNCs address multiple interconnected pathways.
• Off-target toxicity toward healthy tissues was a stated limitation of existing molecular therapies that this approach sought to overcome.