Cysteine proteases obtained from the stem of pineapple or papaya latex, bromelain and papain, respectively, exhibit a broad spectrum of beneficial effects on human health. However, their effects on gut microbiota composition or dose-manner effects on the intestinal integrity of healthy tissue have not been evaluated. In this study, C57BL/6 young, healthy mice were fed bromelain or papain in a dose of 1 mg per animal/day for three consecutive days, followed by the assessment of digestive protein capacity, intestinal morphology and gut microbiota composition. Furthermore, a human reconstructed 3D tissue model EpiIntestinal (SMI-100) was used to study the effects of 1, 0.1 and 10 mg/mL doses of each enzyme on tissue integrity and mucosal permeability using TEER measurements and passage of Lucifer Yellow marker from the apical to the basolateral side of the mucosa. The results indicated that fruit proteases have the potential to modulate gut microbiota with decreasing abundance of Proteobacteria and increasing beneficial Akkermansia muciniphila. The enhancement of pancreatic trypsin was observed in bromelain and papain supplementation, while bromelain also increased the thickness of the ileal mucosa. Furthermore, an in vitro study showed a dose-dependent interruption in epithelial integrity, which resulted in increased paracellular permeability by the highest doses of enzymes. These findings define bromelain and papain as promising enzymatic supplementation for controlled enhancement of paracellular uptake when needed, together with beneficial effects on the gut microbiota.

High-fat diets are associated with neuronal and memory dysfunction. Berries may be useful in improving age-related memory deficits in humans, as well as in mice receiving high-fat diets. Emerging research has also demonstrated that brain health and cognitive function may be related to the dynamic changes in the gut microbiota. In this study, the impact of Nordic berries on the brain and the gut microbiota was investigated in middle-aged C57BL/6J mice. The mice were fed high-fat diets (60%E fat) supplemented with freeze-dried powder (6% dwb) of bilberry, lingonberry, cloudberry, blueberry, blackcurrant, and sea buckthorn for 4 months. The results suggest that supplementation with bilberry, blackcurrant, blueberry, lingonberry, and (to some extent) cloudberry has beneficial effects on spatial cognition, as seen by the enhanced performance following the T-maze alternation test, as well as a greater proportion of DCX-expressing cells with prolongation in hippocampus. Furthermore, the proportion of the mucosa-associated symbiotic bacteria Akkermansia muciniphila increased by 4–14 times in the cecal microbiota of mice fed diets supplemented with lingonberry, bilberry, sea buckthorn, and blueberry. These findings demonstrate the potential of Nordic berries to preserve memory and cognitive function, and to induce alterations of the gut microbiota composition.

• mTOR and AKG are involved in the regulation of energy homeostasis. • An imbalance of mTOR signaling is correlated with neurological disorders. • AKG metabolism could overlap with mTOR signaling via ATP synthase inhibition. • AKG may activate mTOR by replenishing the TCA-intermediate pool. • Modulation of mTOR activity with AKG may increase the effectiveness of therapeutic strategies in brain disorders treatment.

The gut microbiota modulates various physiological functions in the human body, including digestion, immune regulation, gut barrier maintenance, and even nervous system activity. The bidirectional communication between gut microbes and the brain, known as the microbiota–gut–brain axis, is crucial for balanced metabolism. Recent studies have indicated that gut microbiota metabolites, such as short-chain fatty acids, indole derivatives, neurotransmitters, and other bioactive compounds, can positively impact neurogenesis, myelination, and axonal regeneration, suggesting their potential in therapeutic strategies for neuroprotection and neuroregeneration. Despite the growing number of studies on gut microbiota metabolites, understanding their role in neuroprotective mechanisms remains limited. This article reviews the classification, production, functions and therapeutic potential of the most well-known gut microbiota metabolites, as well as their impact on neurogenesis, synaptogenesis, energy metabolism, immune modulation, and blood–brain barrier integrity, which will provide a foundation for the study of gut microbiota metabolites in the field of biomedical engineering.