05.08.24
Researchers from Tokyo University of Science have discovered a potential mechanism of action by which gut bacteria may be able to positively influence inflammatory bowel disease (IBD) in a new animal study published in Frontiers in Immunology.
The gut microbiome plays a key role in digestive and overall health, and disturbances in the gut, known as dysbiosis, could have far-reaching impacts. Intestinal microbes metabolize dietary components into beneficial fatty acids, supporting metabolism and body homeostasis.
Metabolites originating from polyunsaturated fatty acids (PUFAs), influenced by gut microbes such as Lactobacillus plantarum, exhibit potent effects on inflammation and immune response, and manipulating gut bacteria and metabolites shows promise in treating metabolic and inflammatory disorders.
The team of researchers in the present study, led by Chiharu Nishiyama, a professor at Tokyo University of Science, sought to find a mechanism of action with both in vitro and in vivo mouse models by which gut microbiome metabolites could potentially benefit immune responses.
“PUFAs undergo metabolic transformations such as hydroxylation and saturation by enzymes possessed by intestinal bacteria,” said Nishiyama. “In recent years, a variety of beneficial physiological effects have been discovered for these intestinal bacterial metabolites. In this study, we have investigated the activity of multiple FA metabolites using mouse-derived immune cells.”
In Vitro
The specific cells used were antigen-derived spleen cells, to elicit an enhanced immune response and subsequent inflammation. They then looked at the effects of different PUFA derivatives, focused on metabolites of linoleic acid. They found that KetoC, alpha-KetoC, and gamma-KetoC, all enon derivatives of linoleic acid, markedly reduced levels of interleukin 2, a key protein that triggers the expansion of immune cells and inflammation.
The original PUFAs in their unconverted form didn’t’ demonstrate the same effects, emphasizing the role of bacterial conversion in activating their immunomodulatory properties. The enon fatty acids suppressed prolonged T-cell proliferation and dendritic cell activation, which can lead to inflammation and autoimmune diseases. The anti-inflammatory effect as most pronounced with gamma-KetoC.
Previous studies have shown the involvement of G protein-coupled receptors and the transcription factor NFR2 in antioxidant responses, which are mediated by several fatty acid metabolites. Researchers assessed levels of inflammatory cytokines released from antigen-stimulated and gamma-KetoC treated dendritic cells. They found that that gamma-KetoC stimulated the NRF2 signaling pathway, which suppressed the production of inflammatory cytokines. GPCR-signaling also inhibited inflammatory cytokine production in dendritic cells in an NRF2-dependent manner. Together, these results suggest a mechanism of action by which gamma-KetoC modulates immune response.
In Vivo
These in vitro findings were further validated using a mouse model of inflammatory bowel disease. The researchers found that gamma-KetoC treatment significantly reduced fibrosis-induced tissue damage in the colon, reduced colitis-induced weight loss, and improved stool scores.
The treated mice showed decreased epithelial cell disruption and ulcers, along with reduced infiltration of immune cells and lower serum levels of inflammatory factors. The models that were deficient in NRF2 showed significant restoration after colitis-induced tissue damage following gamma-KetoC treatment.
The present study sheds light on the potential mechanism by which gamma-KetoC alleviates antigen-induced intestinal inflammation. Further studies are needed to understand the complex interplay between gamma-KetoC, GPCR-signaling, and the NRF2 pathway, and uncover other potential targets of this metabolite.
“Our findings demonstrate that the compounds of dietary oils are converted into useful metabolites with anti-inflammatory effects by gut bacteria,” said Nishiyama. “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.”
In the long run, this study may help to develop functional foods and supplements based on these microbial metabolites for patients suffering from inflammatory diseases, the authors concluded.
The gut microbiome plays a key role in digestive and overall health, and disturbances in the gut, known as dysbiosis, could have far-reaching impacts. Intestinal microbes metabolize dietary components into beneficial fatty acids, supporting metabolism and body homeostasis.
Metabolites originating from polyunsaturated fatty acids (PUFAs), influenced by gut microbes such as Lactobacillus plantarum, exhibit potent effects on inflammation and immune response, and manipulating gut bacteria and metabolites shows promise in treating metabolic and inflammatory disorders.
The team of researchers in the present study, led by Chiharu Nishiyama, a professor at Tokyo University of Science, sought to find a mechanism of action with both in vitro and in vivo mouse models by which gut microbiome metabolites could potentially benefit immune responses.
“PUFAs undergo metabolic transformations such as hydroxylation and saturation by enzymes possessed by intestinal bacteria,” said Nishiyama. “In recent years, a variety of beneficial physiological effects have been discovered for these intestinal bacterial metabolites. In this study, we have investigated the activity of multiple FA metabolites using mouse-derived immune cells.”
In Vitro
The specific cells used were antigen-derived spleen cells, to elicit an enhanced immune response and subsequent inflammation. They then looked at the effects of different PUFA derivatives, focused on metabolites of linoleic acid. They found that KetoC, alpha-KetoC, and gamma-KetoC, all enon derivatives of linoleic acid, markedly reduced levels of interleukin 2, a key protein that triggers the expansion of immune cells and inflammation.
The original PUFAs in their unconverted form didn’t’ demonstrate the same effects, emphasizing the role of bacterial conversion in activating their immunomodulatory properties. The enon fatty acids suppressed prolonged T-cell proliferation and dendritic cell activation, which can lead to inflammation and autoimmune diseases. The anti-inflammatory effect as most pronounced with gamma-KetoC.
Previous studies have shown the involvement of G protein-coupled receptors and the transcription factor NFR2 in antioxidant responses, which are mediated by several fatty acid metabolites. Researchers assessed levels of inflammatory cytokines released from antigen-stimulated and gamma-KetoC treated dendritic cells. They found that that gamma-KetoC stimulated the NRF2 signaling pathway, which suppressed the production of inflammatory cytokines. GPCR-signaling also inhibited inflammatory cytokine production in dendritic cells in an NRF2-dependent manner. Together, these results suggest a mechanism of action by which gamma-KetoC modulates immune response.
In Vivo
These in vitro findings were further validated using a mouse model of inflammatory bowel disease. The researchers found that gamma-KetoC treatment significantly reduced fibrosis-induced tissue damage in the colon, reduced colitis-induced weight loss, and improved stool scores.
The treated mice showed decreased epithelial cell disruption and ulcers, along with reduced infiltration of immune cells and lower serum levels of inflammatory factors. The models that were deficient in NRF2 showed significant restoration after colitis-induced tissue damage following gamma-KetoC treatment.
The present study sheds light on the potential mechanism by which gamma-KetoC alleviates antigen-induced intestinal inflammation. Further studies are needed to understand the complex interplay between gamma-KetoC, GPCR-signaling, and the NRF2 pathway, and uncover other potential targets of this metabolite.
“Our findings demonstrate that the compounds of dietary oils are converted into useful metabolites with anti-inflammatory effects by gut bacteria,” said Nishiyama. “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.”
In the long run, this study may help to develop functional foods and supplements based on these microbial metabolites for patients suffering from inflammatory diseases, the authors concluded.
