Keller, Lena. Inflammatory dynamics in the gut: exploring diet-immune interplay in obesity. 2024, Doctoral Thesis, University of Basel, Faculty of Science.
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Abstract
"The dose makes the poison: A high-fat diet based on extra virgin olive oil
leads to glucose intolerance and increased total liver lipids in mice"
1.Obesity is associated with the development of glucose intolerance and systemic low-grade
inflammation. Extra virgin olive oil (EVOO) has been identified as a promising candidate
in dietary interventions due to its anti-oxidative and anti-inflammatory effects. However,
the effect on metabolic health remains inconclusive. In parallel, this study aimed to
investigate the metabolic and immunological outcomes of an EVOO high-fat diet (E-HFD)
compared to another plant-based high-fat diet (coconut oil HFD, C-HFD).
Male mice aged 5-8 weeks were fed an E-HFD, C-HFD, or control diet for up to 6 months
and metabolically characterized by glucose, insulin, pyruvate tolerance tests, and glucosestimulated
insulin secretion. Immune cell phenotyping was performed using flow
cytometry in the gut, adipose, and liver tissues. Both HFDs induced hyperinsulinemia, but
the E-HFD led to more pronounced glucose intolerance and insulin resistance. Mice fed an
E-HFD had significantly elevated total liver lipids and increased expression of lipogenesis
genes, particularly Srebp1c, after only one week of HFD, consistent with increased
lipogenesis
Additionally, mice fed E-HFD exhibited increased glycogenic capacity as a measure of
glycogenesis. There were no differences in gut microbiota, systemic inflammation, and
cholesterol between both HFDs, but plasma triglycerides were elevated in C-HFD.
Supporting anti-inflammatory effects, mice on E-HFD showed partial protection from
inflammation in the adipose tissue and colon. In conclusion, our study highlights tissuespecific
metabolic and immune responses induced by different dietary fat sources.
Importantly, although E-HFD has less pro-inflammatory properties than C-HFD, it results
in more pronounced glucose intolerance/insulin resistance, potentially driven by
increased hepatic lipogenesis.
"scRNA-seq analysis of intestinal immune cells reveals dynamic changes upon
high-fat diet feeding in mice"
2.Obesity represents a significant global health concern and is linked to chronic low-grade
inflammation, glucose intolerance, and diabetes. The gastrointestinal tract and its
immune system play a pivotal role in developing and progressing metabolic diseases.
High-fat diets (HFDs), commonly employed to model obesity in mice, have been
demonstrated to significantly alter the composition and function of intestinal immune
cells. These immune cells are sensors of the environment and likely play a crucial role in
the pathogenesis of obesity-induced inflammation and glucose intolerance. Our study,
therefore, investigates how intestinal immune cells, in particular monocytes and
macrophages, evolve over the course of HFD exposure, to elucidate their role in metabolic
disease.
Here, we show that short-term HFD exposure significantly increased pro-inflammatory
macrophage subpopulations (P1 and P2) and upregulated interferon (IFN)γ and IFNα
pathways in monocytes and macrophages. This early innate immune response occured
before significant weight gain and was lost upon prolonged HFD exposure. At this stage,
adaptive immune responses became active, pro-inflammatory macrophages decreased,
and oxidative phosphorylation pathways were downregulated, resembling endotoxin
tolerance. Several genes of the cGAS-STING pathway were upregulated in monocytes and
macrophages after short-term HFD exposure, which might represent the onset of the
chronic gut inflammation. Local and short-term inhibition of the cGAS-STING pathway
resulted in a slight improvement in glucose tolerance. Our study emphasizes the timedependent
changes in intestinal immunity, highlighting an upregulated cGAS-STING
pathway and interferon response that initiates the disease process. At the chronic stage
of the disease, there is an exhaustion of innate immunity, while the adaptive immune
response takes over.
This dynamic nature of intestinal immune cell responses upon HFD provides new
insights into the role of the gut-immune axis in obesity-induced inflammation and metabolic dysfunction. Understanding these mechanisms offers potential avenues for
therapeutic strategies targeting early immune responses to prevent or mitigate obesity-related
metabolic diseases.
"scRNA-seq analysis of human intestinal myeloid cells suggests immunedampened
phenotype in obesity"
3.Obesity is associated with chronic low-grade inflammation and metabolic dysfunction.
Previous studies have shown that obesity is linked to significant changes in the immune
landscape of the gastrointestinal tract, impacting both metabolic and immune
responses. However, the differential transcriptional changes, in particular in myeloid
cells comprising most cells of the innate immune system within the gut of obese
individuals, remain unclear. This study aimed to elucidate the impact of obesity on
intestinal myeloid cells, specifically monocytes, macrophages, and dendritic cells using
single-cell RNA sequencing (scRNA-seq). Obese and non-obese participants were
recruited for colonoscopies, during which colon biopsies were collected from four
individuals in each group. Flow cytometry and scRNA-seq were employed to analyze the
immune cell populations and their gene expression profiles. The study identified
eight distinct clusters of myeloid cells, including monocytes, inflammatory macrophages,
resident macrophages, conventional dendritic cells (cDC1 and cDC2 subtypes), and a
transitional dendritic cell cluster. Our findings revealed that obesity causes only minor
transcriptional changes within identified cell clusters. Utilizing gene set enrichment
analysis, we found a general downregulation of genes involved in innate immune
activation and metabolic processes. Specifically, oxidative phosphorylation and other
mitochondrial-related pathways were downregulated in several myeloid cell clusters,
suggesting altered energy metabolism. These changes imply a shift towards a state
resembling endotoxin tolerance, characterized by reduced immune responsiveness. Our
results demonstrate that intestinal myeloid cells adapt during the chronic state of obesity
towards an immune-dampened phenotype.
This study highlights the complex nature of intestinal immunity in the context of obesity,
emphasizing the importance of understanding the dynamic immune cell changes. The
downregulation of critical metabolic and immune pathways in myeloid cells suggests
potential targets for interventions aimed at restoring immune function and metabolic
balance in obese individuals.
leads to glucose intolerance and increased total liver lipids in mice"
1.Obesity is associated with the development of glucose intolerance and systemic low-grade
inflammation. Extra virgin olive oil (EVOO) has been identified as a promising candidate
in dietary interventions due to its anti-oxidative and anti-inflammatory effects. However,
the effect on metabolic health remains inconclusive. In parallel, this study aimed to
investigate the metabolic and immunological outcomes of an EVOO high-fat diet (E-HFD)
compared to another plant-based high-fat diet (coconut oil HFD, C-HFD).
Male mice aged 5-8 weeks were fed an E-HFD, C-HFD, or control diet for up to 6 months
and metabolically characterized by glucose, insulin, pyruvate tolerance tests, and glucosestimulated
insulin secretion. Immune cell phenotyping was performed using flow
cytometry in the gut, adipose, and liver tissues. Both HFDs induced hyperinsulinemia, but
the E-HFD led to more pronounced glucose intolerance and insulin resistance. Mice fed an
E-HFD had significantly elevated total liver lipids and increased expression of lipogenesis
genes, particularly Srebp1c, after only one week of HFD, consistent with increased
lipogenesis
Additionally, mice fed E-HFD exhibited increased glycogenic capacity as a measure of
glycogenesis. There were no differences in gut microbiota, systemic inflammation, and
cholesterol between both HFDs, but plasma triglycerides were elevated in C-HFD.
Supporting anti-inflammatory effects, mice on E-HFD showed partial protection from
inflammation in the adipose tissue and colon. In conclusion, our study highlights tissuespecific
metabolic and immune responses induced by different dietary fat sources.
Importantly, although E-HFD has less pro-inflammatory properties than C-HFD, it results
in more pronounced glucose intolerance/insulin resistance, potentially driven by
increased hepatic lipogenesis.
"scRNA-seq analysis of intestinal immune cells reveals dynamic changes upon
high-fat diet feeding in mice"
2.Obesity represents a significant global health concern and is linked to chronic low-grade
inflammation, glucose intolerance, and diabetes. The gastrointestinal tract and its
immune system play a pivotal role in developing and progressing metabolic diseases.
High-fat diets (HFDs), commonly employed to model obesity in mice, have been
demonstrated to significantly alter the composition and function of intestinal immune
cells. These immune cells are sensors of the environment and likely play a crucial role in
the pathogenesis of obesity-induced inflammation and glucose intolerance. Our study,
therefore, investigates how intestinal immune cells, in particular monocytes and
macrophages, evolve over the course of HFD exposure, to elucidate their role in metabolic
disease.
Here, we show that short-term HFD exposure significantly increased pro-inflammatory
macrophage subpopulations (P1 and P2) and upregulated interferon (IFN)γ and IFNα
pathways in monocytes and macrophages. This early innate immune response occured
before significant weight gain and was lost upon prolonged HFD exposure. At this stage,
adaptive immune responses became active, pro-inflammatory macrophages decreased,
and oxidative phosphorylation pathways were downregulated, resembling endotoxin
tolerance. Several genes of the cGAS-STING pathway were upregulated in monocytes and
macrophages after short-term HFD exposure, which might represent the onset of the
chronic gut inflammation. Local and short-term inhibition of the cGAS-STING pathway
resulted in a slight improvement in glucose tolerance. Our study emphasizes the timedependent
changes in intestinal immunity, highlighting an upregulated cGAS-STING
pathway and interferon response that initiates the disease process. At the chronic stage
of the disease, there is an exhaustion of innate immunity, while the adaptive immune
response takes over.
This dynamic nature of intestinal immune cell responses upon HFD provides new
insights into the role of the gut-immune axis in obesity-induced inflammation and metabolic dysfunction. Understanding these mechanisms offers potential avenues for
therapeutic strategies targeting early immune responses to prevent or mitigate obesity-related
metabolic diseases.
"scRNA-seq analysis of human intestinal myeloid cells suggests immunedampened
phenotype in obesity"
3.Obesity is associated with chronic low-grade inflammation and metabolic dysfunction.
Previous studies have shown that obesity is linked to significant changes in the immune
landscape of the gastrointestinal tract, impacting both metabolic and immune
responses. However, the differential transcriptional changes, in particular in myeloid
cells comprising most cells of the innate immune system within the gut of obese
individuals, remain unclear. This study aimed to elucidate the impact of obesity on
intestinal myeloid cells, specifically monocytes, macrophages, and dendritic cells using
single-cell RNA sequencing (scRNA-seq). Obese and non-obese participants were
recruited for colonoscopies, during which colon biopsies were collected from four
individuals in each group. Flow cytometry and scRNA-seq were employed to analyze the
immune cell populations and their gene expression profiles. The study identified
eight distinct clusters of myeloid cells, including monocytes, inflammatory macrophages,
resident macrophages, conventional dendritic cells (cDC1 and cDC2 subtypes), and a
transitional dendritic cell cluster. Our findings revealed that obesity causes only minor
transcriptional changes within identified cell clusters. Utilizing gene set enrichment
analysis, we found a general downregulation of genes involved in innate immune
activation and metabolic processes. Specifically, oxidative phosphorylation and other
mitochondrial-related pathways were downregulated in several myeloid cell clusters,
suggesting altered energy metabolism. These changes imply a shift towards a state
resembling endotoxin tolerance, characterized by reduced immune responsiveness. Our
results demonstrate that intestinal myeloid cells adapt during the chronic state of obesity
towards an immune-dampened phenotype.
This study highlights the complex nature of intestinal immunity in the context of obesity,
emphasizing the importance of understanding the dynamic immune cell changes. The
downregulation of critical metabolic and immune pathways in myeloid cells suggests
potential targets for interventions aimed at restoring immune function and metabolic
balance in obese individuals.
Advisors: | Cavelti-Weder, Claudia |
---|---|
Committee Members: | Schär, Primo Leo and von Meyenn, Ferdinand |
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Translational Diabetes (Cavelti-Weder) 03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär) |
UniBasel Contributors: | Cavelti-Weder, Claudia and Schär, Primo Leo |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15455 |
Thesis status: | Complete |
Number of Pages: | IX, 139 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 13 Sep 2024 04:30 |
Deposited On: | 12 Sep 2024 09:53 |
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