While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet. C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks. HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice. HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.

The major commercial ginsengs are Panax ginseng Meyer (Korean ginseng), P. quinquifolium L. (American ginseng), and P. notoginseng (Burk.) FH Chen (Notoginseng). P. ginseng is the most commonly used as an adaptogenic agent and has been shown to enhance physical performance, promote vitality, increase resistance to stress and aging, and have immunomodulatory activity. These ginsengs contain saponins, which can be classified as dammarane-type, ocotillol-type and oleanane-type oligoglycosides, and polysaccharides as main constituents. Dammarane ginsenosides are transformed into compounds such as the ginsenosides Rg3, Rg5, and Rk1 by steaming and heating and are metabolized into metabolites such as compound K, ginsenoside Rh1, protoand panaxatriol by intestinal microflora. These metabolites are nonpolar, pharmacologically active and easily absorbed from the gastrointestinal tract. However, the activities metabolizing these constituents into bioactive compounds differ significantly among individuals because all individuals possess characteristic indigenous strains of intestinal bacteria. To overcome this difference, ginsengs fermented with enzymes or microbes have been developed.

Early intervention using dietary supplements may be effective in alleviating cognitive impairment among individuals with mild cognitive impairment (MCI). This study investigated the efficacy and safety of Lactobacillus plantarum C29-fermented soybean (DW2009) as a nutritional supplement for cognitive enhancement. One hundred individuals with MCI were randomly assigned to take DW2009 (800 mg/day, n = 50) or placebo (800 mg/day, n = 50) for 12 weeks. The primary outcome measure was change in the composite score of cognitive functions related to memory and attention, measured by computerized neurocognitive function tests. Associations between changes in serum brain-derived neurotrophic factor (BDNF) levels and cognitive performance for each treatment group were evaluated. Compared to the placebo group, the DW2009 group showed greater improvements in the combined cognitive functions (z = 2.36, p for interaction = 0.02), especially in the attention domain (z = 2.34, p for interaction = 0.02). Cognitive improvement was associated with increased serum BDNF levels after consumption of DW2009 (t = 2.83, p = 0.007). The results of this clinical trial suggest that DW2009 can be safely administered to enhance cognitive function in individuals with MCI. Increased serum BDNF levels after administering DW2009 may provide preliminary insight into the underlying effects of cognitive improvement, which suggests the importance of the gut-brain axis in ameliorating cognitive deficits in MCI.

Orally administered ginsengs come in contact with the gut microbiota, and their hydrophilic constituents, such as ginsenosides, are metabolized to hydrophobic compounds by gastric juice and gut microbiota: protopanxadiol-type ginsenosides are mainly transformed into compound K and ginsenoside Rh2; protopanaxatriol-type ginsenosides to ginsenoside Rh1 and protopanaxatriol, and ocotillol-type ginsenosides to ocotillol. Although this metabolizing activity varies between individuals, the metabolism of ginsenosides to compound K by gut microbiota in individuals treated with ginseng is proportional to the area under the blood concentration curve for compound K in their blood samples. These metabolites such as compound K exhibit potent pharmacological effects, such as antitumor, anti-inflammatory, antidiabetic, antiallergic, and neuroprotective effects compared with the parent ginsenosides, such as Rb1, Rb2, and Re. Therefore, to monitor the potent pharmacological effects of ginseng, a novel probiotic fermentation technology has been developed to produce absorbable and bioactive metabolites. Based on these findings, it is concluded that gut microbiota play an important role in the pharmacological action of orally administered ginseng, and probiotics that can replace gut microbiota can be used in the development of beneficial and bioactive ginsengs.

The gut dysbiosis by stressors such as immobilization deteriorates psychiatric disorders through microbiota-gut-brain axis activation. To understand whether probiotics could simultaneously alleviate anxiety/depression and colitis, we examined their effects on immobilization stress (IS)-induced anxiety/depression and colitis in mice. The probiotics Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 were isolated from healthy human feces. Mice with anxiety/depression and colitis were prepared by IS treatment. NK33 and NK98 potently suppressed NF-κB activation in lipopolysaccharide (LPS)-induced BV-2 cells. Treatment with NK33 and/or NK98, which were orally gavaged in mice before or after IS treatment, significantly suppressed the occurrence and development of anxiety/depression, infiltration of Iba1⁺ and LPS⁺/CD11b⁺ cells (activated microglia) into the hippocampus, and corticosterone, IL-6, and LPS levels in the blood. Furthermore, they induced hippocampal BDNF expression while NF-κB activation was suppressed. NK33 and/or NK98 treatments suppressed IS-induced colon shortening, myeloperoxidase activity, infiltration of CD11b⁺/CD11c⁺ cells, and IL-6 expression in the colon. Their treatments also suppressed the IS-induced fecal Proteobacteria population and excessive LPS production. They also induced BDNF expression in LPS-induced SH-SY5Y cells in vitro. In conclusion, NK33 and NK98 synergistically alleviated the occurrence and development of anxiety/depression and colitis through the regulation of gut immune responses and microbiota composition.