The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time
It is clear that inflammation participates in the link between obesity and disease
Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells
adipose tissue macrophage (ATM)
well-known regulators of lipid metabolism and mitochondrial activity
increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).
The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ
Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).
Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).
inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)
Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass
JNK, TLR4, ER stress)
NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells
Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)
DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)
saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)
Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity
Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)
Placental inflammation is a characteristic of maternal obesity
a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74
Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB
Nod-like receptor (NLR) family of PRRs
ceramides and sphingolipids
The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.
adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate
Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)
NF-κB, obesity also activates JNK in insulin-responsive tissues
The gut microbiota participates in the body’s metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders
Firmicutes and Bacteroidetes represent the two largest phyla in the human and mouse microbiota and a shift in the ratio of these phyla has been associated with many disease conditions, including obesity
In obese humans, there is decreased abundance of Bacteroidetes compared to lean individuals
weight loss in obese individuals results in an increase in the abundance of Bacteroidetes
there is conflicting evidence on the composition of the obese microbiota phenotype with regards to Bacteroidetes and Firmicutes ratios
Bifidobacteria spp. from the phyla Actinobacteria, has been shown to be depleted in both obese mice and human subjects
While it is not yet clear which specific microbes are inducing or preventing obesity, evidence suggests that the microbiota is a factor.
targeted manipulation of the microbiota results in divergent metabolic outcomes depending on the composition of the diet
The microbiota has been linked to insulin resistance or type 2 diabetes (T2D) via metabolic syndrome and indeed the microbiota of individuals with T2D is also characterized by an increased Bacteroidetes/Firmicutes ratio, as well as an increase in Bacillus and Lactobacillus spp
It was also observed that the ratio of Bacteriodes-Prevotella to C. coccoides-E. rectale positively correlated with glucose levels but did not correlate with body mass index [80]. This suggests that the microbiota may influence T2D in conjunction with or independently of obesity
In humans, high-fat Western-style diets fed to individuals over one month can induce a 71% increase in plasma levels of endotoxins, suggesting that endotoxemia may develop in individuals with GI barrier dyfunction connected to dysbiosis
LPS increases macrophage infiltration essential for systemic inflammation preceding insulin resistance, LPS alone does not impair glucose metabolism
early treatment of dysbiosis may slow down or prevent the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences
increased Firmicutes and decreased Bacteroidetes, which is the microbial profile found in lean phenotypes, along with an increase in Bifidobacteria spp. and Lactobacillus spp
mouse and rat models of T1D have been shown to have microbiota marked by decreased diversity and decreased Lactobacillus spp., as well as a decrease in the Firmicutes/Bacteroidetes ratio
microbial antigens through the innate immune system are involved in T1D progression
The microbiota appears to be essential in maintaining the Th17/Treg cell balance in intestinal tissues, mesenteric and pancreatic lymph nodes, and in developing insulitis, although progression to overt diabetes has not been shown to be controlled by the microbiota
There is evidence that dietary and microbial antigens independently influence T1D
Lactobacillus johnsonii N6.2 protects BB-rats from T1D by mediating intestinal barrier function and inflammation [101,102] and a combination probiotic VSL#3 has been shown to attenuate insulitis and diabetes in NOD mice
breast fed infants have higher levels of Bifidobacteria spp. while formula fed infants have higher levels of Bacteroides spp., as well as increased Clostridium coccoides and Lactobacillus spp
the composition of the gut microbiota strongly correlates with diet
In mice fed a diet high in fat, there are many key gut population changes, such as the absence of gut barrier-protecting Bifidobacteria spp
diet has a dominating role in shaping gut microbiota and changing key populations may transform healthy gut microbiota into a disease-inducing entity
“Western” diet, which is high in sugar and fat, causes dysbiosis which affects both host GI tract metabolism and immune homeostasis
The gut microbial composition is altered during pregnancy
probiotic supplements may contribute to the maintenance of bacterial diversity and glucose homeostasis in individuals with metabolic disturbances
Assessment of four randomized controlled trials in this review involving 288 pregnant women with GDM found that a 6–8 week probiotic intervention did not improve FBG or LDL-cholesterol levels
probiotic supplementation in women with GDM was associated with significant reductions in insulin resistance
One proposed method is by the production of short chain fatty acids (SCFAs), generated as a by-product of bacterial fermentation of dietary fibers. SCFAs act as an energy source for intestinal cells and have been found to regulate the production of hormones effecting energy intake and expenditure such as leptin and grehlin
Another hypothesized mechanism of SCFA action includes reducing gastrointestinal permeability by upregulating transcription of tight junction proteins, enhancing production of Glucagon-like peptide-2 (GLP-2) which promotes crypt cell proliferation, and reducing inflammation in colonic epithelial cells by increasing PPAR-gamma activation
Maintenance of the integrity of the gut barrier minimizes the concentration of lipopolysaccharide (LPS) in circulation
LPS is a structural component of gram negative bacterial cell walls, which induces an immune-cell response upon absorption into the human bloodstream, stimulating proinflammatory cytokine production and the onset of insulin resistance and hyperglycemia
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surgery per se can promote cancer metastasis through a series of local and systemic events
surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers
Key point; add to presentation on surgery and metastasis
After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear
infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients
Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis
Surgery-induced cancer metastasis has been well established in animal models
tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis
the surgical resection of primary tumors is beneficial is controversial
CTCs abruptly increase just after surgery
Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer
immune surveillance against tumors is considered to be impaired by surgical stress
In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla
NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids
In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases
primary tumors may secrete angiogenic inhibitors as well as angiogenic activators
second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.
HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity
neutrophils play various roles in the initiation and progression of cancer
NETosis
many inflammatory and neoplastic diseases
formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1
NETosis has been highlighted as an inflammatory event that promotes cancer metastasis
Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves
Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells
two types of NEToses, suicidal (or lytic) NETosis and vital NETosis
Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)
Since neutrophils die during this process, it is called suicidal NETosis.
vital NETosis
vital NETosis occurs independently of ROS production
Vital NETosis can be induced by Gram-negative bacteria. LPS
NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia
neutrophils actively undergo NETosis in the tumor microenvironment
Hypoxia
NETosis plays a pivotal role in noninfectious autoimmune diseases,
cytokines
tumor-derived proteases
tumor exosomes
NETosis generally actively progresses in the tumor microenvironment.
the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
NETosis is a defense system to protect the body from invading pathogens
when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences
plasma levels of NETosis markers are elevated after major surgeries
local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases
NETs promote metastasis at multiple steps
NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells
NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow
NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)
neutrophil elastase, matrix metalloproteinase 9, and cathepsin G
NETs also promote the intravasation of cancer cells
millions of tumor cells are released into the circulation every day,
NETs can wrap up CTCs with platelets
β1-integrin plays an important role in the interaction between CTCs and NETs
NET-platelet-CTC aggregates.
After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late
NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions
NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells
A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
saturated fatty acids are the most potent inducers of this inflammatory response
Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
C-reactive protein (CRP)
these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
γ-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-γ.
these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by γ-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.
Bronchial asthma is a typical helper T cell type 2 (Th2) disease
Through the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, orchestrate the recruitment and activation of the primary effector cells of the allergic response: the mast cells and the eosinophils
Glutathione is the most abundant nonprotein sulfhydryl compound in almost all cells. This tripeptide plays a significant role in many biological processes. It also constitutes the first line of the cellular defense mechanism against oxidative injury along with SOD, ascorbate, vitamin E, and catalase, and is the major intracellular redox buffer in ubiquitous cell types
We have shown that glutathione redox status, namely the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in murine antigen-presenting cells (APC) plays a central role in determining which of the reductive and oxidative APC predominate during immune status, and the balance between reductive and oxidative APC regulates Th1/Th2 balance through production of IL-12
we have also shown that exposure of human alveolar macrophages to the Th1 cytokine IFN-γ or the Th2 cytokine IL-4 either increases or decreases the GSH/GSSG ratio, respectively, which regulates Th1/Th2 balance through IL-12 production
the ability to generate a Th1 or Th2 type response has turned out to depend not only on T cells but also on the intracellular glutathione redox status of APC
Th1 cytokine IFN-γ and Th2 cytokine IL-4 increases and decreases the GSH/GSSG ratio, respectively, and that this ratio influences LPS-induced IL-12 production from alveolar macrophages
the ability to generate a Th1 or Th2 response is dependent on glutathione redox status of APC
administration of γ-GCE elevates GSH level and GSH/GSSG ratio in the lung, and ameliorates AHR and eosinophilic airway inflammation by altering the Th1/Th2 balance and suppressing chemokine production and eosinophil migration in a mouse asthma model
DF are highly complex substances that can be described as any nondigestible carbohydrates and lignins not degraded in the
upper gut
Commonly, DF are classified according to their solubility in water, even though grading according to viscosity, gel-forming
capabilities, or fermentation rate by the gut microbiota might be physiologically more relevant
Main sources of soluble
DF are fruits and vegetables
n increased intake of total DF was inversely associated with markers of insulin resistance in several studies
consumption of insoluble DF increased whole
body glucose disposal independent of changes in body weight in both short-term and more prolonged studies
Short-chain fatty acids (SCFA) such as acetate, propionate, and butyrate are produced by bacterial fermentation of indigestible
DF polysaccharides in the colon
increased production of SCFA is assumed to be beneficial by reducing hepatic glucose output and improving lipid
homeostasis
a high DF diet (oligofructose) reduced gram-negative bacterial content and body weight, whereas a high fat
diet increased the proportion of a gram-negative bacterial lipopolysaccharides (LPS) containing microbiota in humans
Prospective cohort studies indicate that diets high in insoluble cereal DF and whole grains might reduce diabetes risk
prebiotics found to increase leptin sensitivity, improved glucose metabolism, lipid metabolism, reduced inflammation and improved leaky gut. The probiotics increased the bifidobacterium species versus a decrease in the Firmicutes phyla.
Must read and a great read at that, of the GI's contribution to health or disease. The article reviews the current understanding of the GALT layer and it's contribution to health or metabolic endotoxemia and how this then leads to disease. The article reviews the effects of disrupted GI bacteria in the gut as well as in other organ systems.
Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.
Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models