Recent studies conducted by the Tokyo University of Science have highlighted that KetoC, αKetoC, γKetoA, and γKetoC — metabolites of bacteria present in the gut microbiota — can assist in reducing the symptoms of inflammatory bowel disease (IBD), as well as the body’s inflammatory response through a reduction in interleukin 2.
The series of experiments using both in vitro and in vivo mouse models were developed to understand how bacteria-generated fatty acids (FAs) regulate immune responses, which have been published in Frontiers in Nutrition.
PUFAs reduce intestinal inflammation
After investigating the impacts of different polyunsaturated fatty acid (PUFA) derivatives, focusing on metabolites of linoleic acid, findings revealed that (enon derivatives of LA) markedly reduced the levels of interleukin 2 — a key protein that triggers the expansion of immune cells and inflammation.
Intestinal microbes metabolise dietary components into beneficial fatty acids (FAs), supporting metabolism and maintaining host body homeostasis. Metabolites originating from polyunsaturated fatty acids (PUFAs), influenced by gut microbes such as Lactobacillus plantarum, exhibit potent effects on inflammation and immune responses.
However, it’s interesting to note that the original PUFAs in their unconverted form did not demonstrate the same immunosuppressive effects, emphasising the critical role of bacterial conversion in activating their immunomodulatory properties.
enon FAs suppressed prolonged T-cell proliferation and dendritic cell activation
Suppressing T-cell proliferation
They also observed that the enon FAs also suppressed prolonged T-cell proliferation and dendritic cell activation, which can lead to inflammation and autoimmune disease pathology.
This anti-inflammatory effect was most pronounced with γKetoC. Hence, the researchers aimed to unravel the molecular mechanisms through which γKetoC exerted its immunosuppressive effects.
GPCR and NRF2 activation
In addition, previous studies have shown the involvement of G protein-coupled receptors (GPCRs) and the transcription factor, NRF2, in anti-oxidant responses, which are mediated by several FA metabolites, whereas the involvement of GPCRs and NRF2 in the effects of γKetoC in dendritic cells was largely unknown.
To clarify the role of these proteins in γKetoC-mediated immune responses, the researchers assessed the levels of inflammatory cytokines released from antigen-stimulated and γKetoC-treated dendritic cells. Their results suggested that γKetoC stimulated the NRF2 signalling pathway, which suppressed the production of inflammatory cytokines.
γKetoC treatment significantly reduced fibrosis-induced tissue damage in the colon, reduced colitis-induced weight loss and improved stool scores
Reducing the symptom burden of IBD
To further validate their findings in vivo, the researchers used a mouse model of inflammatory bowel disease and examined immune and inflammatory responses by involving γKetoC treatment. They found that γKetoC treatment significantly reduced fibrosis-induced tissue damage in the colon, reduced colitis-induced weight loss and improved stool scores.
Furthermore, the treated mice showed decreased epithelial cell disruption and ulcers, along with reduced infiltration of immune cells and lower serum levels of inflammatory factors. Notably, the models that were deficient in NRF2 showed significant restoration of colitis-induced tissue damage following γKetoC treatment.
γKetoC as an inflammatory reduction agent
Overall, the present study sheds light on the potential mechanism by which γKetoC alleviates antigen-induced intestinal inflammation.
Further studies are needed to understand the complex interplay between γKetoC, GPCR-signaling, and the NRF2 pathway, and uncover other potential targets of γKetoC which mediate its anti-inflammatory effects.
Nevertheless, anti-inflammatory FA metabolites hold therapeutic promise in the treatment of intestinal inflammatory diseases and maintenance of gut health, as prebiotic or probiotic formulations. Sharing her concluding thoughts,
Prof. Nishiyama, the principal investigator in the studies, commented: "Our findings demonstrate that the compounds of dietary oils are converted into useful metabolites with anti-inflammatory effects by gut bacteria. By conducting detailed analyses at the individual, cellular, and genetic levels, we hope to understand how the food we eat daily influences the function of immune cells, and how these effects can be targeted for the prevention and mitigation of inflammatory diseases."
