###### Abstract  
There is a global and increasing demand for natural ingredients that support the human immune response. In this study, the immunomodulatory effect and mechanism of action of rice bran extract fermented by _Lentinus edodes_ was investigated. The potential immunomodulatory effect of fermented rice bran (FRB) and processed rice bran (RB) was evaluated using male BALB/c mice whose immunity was lowered by Cyclophosphamide (CY). The changes in the weight of the thymus and the spleen, immunoglobulins, and cytokine expressions were measured as biomarkers of immunomodulating potential after 14 days of oral administration of FRB and RB (0.5 g/kg-body weight (b.w. ), respectively). The FRB and RB groups treated with CY resulted in increased weight of the thymus (1.73 \(\pm\) 0.40 and 1.45 \(\pm\) 0.43 mg/g-b.w., respectively) compared to the CY-treated control group (1.05 \(\pm\) 0.36 mg/g-b.w.). The levels of the immunoglobulin (Ig) G in the group treated with FRB (21.98 \(\pm\) 2.17, \(p\)\(<\) 0.01) were significantly increased when compared to the RB group (18.48 \(\pm\) 1.52 mg/mL, \(p\)\(<\) 0.01). The expression of serum cytokines, including IL-1\(\alpha\) (\(p\)\(<\) 0.05), IL-2 (\(p\)\(<\) 0.05), IL-6 (\(p\)\(<\) 0.001), IL-12 p70 (\(p\)\(<\) 0.01), IFN-\(\gamma\) (\(p\)\(<\) 0.01), and TNF-\(\alpha\) (\(p\)\(<\) 0.01) were also significantly increased by the administration of FRB (0.5 g/kg-b.w.). Similarly, the expression of spleen cytokines, including IL-1\(\alpha\) (\(p\)\(<\) 0.05), IL-2 (\(p\)\(<\) 0.05), IFN-\(\gamma\) (\(p\)\(<\) 0.01), and TNF-\(\alpha\) (\(p\)\(<\) 0.05), was also significantly increased in the group receiving the FRB (0.5 g/kg-b.w.). The natural killer cell (NK) cell activities at a 1:25 ratio of YAC-1 cells to splenocytes were significantly increased in positive control red ginseng extract 0.5 g/kg (38.64 \(\pm\) 2.13%, \(p\)\(<\) 0.05), FRB (34.85 \(\pm\) 3.45%, \(p\)\(<\) 0.05), and RB (25.00 \(\pm\) 4.18%), compared to that of negative control CY group (12.67 \(\pm\) 3.23%). These results suggest that FRB administration could stimulate the innate immune system by increasing the expression of cytokines in splenocytes and serum, especially IFN-\(\gamma\), IL-2, and IL-12 (p70), which are associated with TNF-\(\alpha\) and NK cell activities. The above results could provide the biochemical rationale to further evaluate the use of FRB for immunomodulatory applications. f  
###### Abstract  
The human immune system is the first line of protection of the body that identifies, eliminates, and fights numerous xenobiotics (such as toxins) and living organisms (such as viruses and microorganisms). In addition to fighting foreign invaders, the immune system can potentially cause damage through the initiation of non-specific inflammatory re-sponses [1]. Natural immunostimulants, such as echinacea and spirulina, can stimulate autoimmune responses [2]. Evidence suggests that autoimmune disorders are increasing globally due to exposure to xenobiotics, infections, stress, pollution, and climate change [3]. In addition, immune-metabolic disorders, such as asthma and bowel diseases, are increasing dramatically over the years [4] and the influence of gut microbiome alternations has been indicated as a possible cause for this observation [4]. With the above in mind, immunomododulation is the desired response as opposed to immunostimulation. Immunity can be divided into innate immunity and adaptive immunity. Innate immunity consists of cellular and biochemical defense mechanisms that exist prior to infection and immediately respond to infection. This mechanism primarily responds only to microorganisms and the products of cells damaged by them and responds in essentially the same way to repeated infections. Interestingly, the innate immune system functions as the first line of our body's protection against microbial and viral threats [5]. In addition, innate immunity stimulates and controls adaptive immune responses.