Vagus nerve regulates inflammation and metabolism

Vagus and inflammation, metabolismVagus nerve (cranial nerve X) function, a key regulator of inflammation and metabolism, is under assault in the modern environment. An excellent paper published in Nature Reviews Endocrinology presents a lucid review of the clinically important vagal inflammatory reflex, the role of impaired vagal function in type 2 diabetes and obesity, with therapeutic implications for reducing inflammation and regulating appetite. The authors state:

“The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus.”

The vagus inflammatory reflex

Functional anatomy of the vagal inflammatory reflexThe vagal inflammatory reflex is a crucial factor in the brain’s regulation of inflammation…

Communication between the immune system and the brain is vital for controlling inflammation. The inflammatory reflex is a centrally integrated physiological mechanism in which afferent vagus nerve signaling, activated by cytokines or pathogen-derived products, is functionally associated with efferent vagus nerve-mediated output to regulate proinflammatory cytokine production and inflammation. The absence of this inflammatory reflex…results in excessive innate immune responses and cytokine toxicity.”

Vagal cholinergic control of inflammationWhen cytokines or pathogen-derived products activate the vagus nerve, it acts to regulate proinflammatory cytokine production and inflammation. When function of the inflammatory reflex is diminished there is excessive innate immune inflammatory activity. Disrupted immune regulation results in persistent pro-inflammatory cytokine activity and chronic inflammation.

“This state underlies the pathogenesis of a range of disease syndromes, including sepsis, rheumatoid arthritis, inflammatory bowel disease and other inflammatory and autoimmune disorders.”

Vagal output is a crucial mechanism for calming inflammation in the digestive tract and throughout the body.

Association with metabolism and obesity

Metabolic and immune dysregulation both contribute to chronic inflammation, and vagal stimulation can help remediate both.

“Chronic inflammation as a result of immune and metabolic dysregulation is a characteristic feature in patients with obesity and is causally linked with insulin resistance and other metabolic complications. Decreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.

Importantly, the vagus nerve also acts to control appetite and feeding.

“Vagus nerve afferent and efferent signalling has an important role in the regulation of feeding behaviour and metabolic homeostasis. This finely tuned regulation is aimed at preserving energy balance and preventing fluctuations in body weight and metabolism that can be detrimental to the individual.”

It sends functional and metabolic information from the digestive and hepatic systems to the brain, and instructions from brain in return:

“Vagus nerve afferents innervating the gastrointestinal tract and liver are major constituents of a sensory system that detects changes in micronutrient and metabolic molecules. These nerve fibres transmit information detected by associated mechanoreceptors, chemoreceptors and specific metabolite receptors in the gut and hepatic portal system concerning levels of lipids, cholecystokinin, leptin, peptide YY, insulin and glucose to the brain…Vagus nerve efferents, on the other hand, provide brain-derived output to the gastrointestinal tract, liver and pancreas.”

Morever, vagal stimulation is necessary to maintain the gut barrier:

“…truncal vagotomy is associated with increased bacterial trans location across the intestinal mucosa, which suggests a tonic vagus nerve control of intestinal permeability and postprandial endotoxaemia.”

Vagal dysregulation in the inflammation of obesity

Inflammation is characteristic of obesity, associated with impaired vagal function…

“Disruption in metabolic and immune homeostasis in obesity is associated with hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. This cluster of conditions characterizes the metabolic syndrome. Moreover, levels of proinflammatory cytokines and acute-phase proteins such as CRP are increased in individuals with obesity, indicating chronic inflammation. This inflammatory state is considered to be an essential pathophysiological constituent in obesity, underlying its adverse consequences and linking it to the other components of the metabolic syndrome. Several lines of evidence indicate that vagus nerve activity could be impaired in obesity, and enhancing cholinergic signaling within the inflammatory reflex can suppress obesity-associated inflammation and its adverse implications.”

There are numerous mechanisms by which obesity promotes systemic inflammation i association with disturbed vagal function.

Autonomic dysfunction and diminished vagus nerve activity occur frequently in individuals with obesity and type 2 diabetes mellitus. A 15-year follow-up study has revealed a strong relationship between autonomic dysfunction and insufficient vagus nerve activity (revealed by impaired heart rate recovery following exercise cessation), impaired glucose homeostasis and development of type 2 diabetes mellitus. Together, these preclinical and clinical findings support the hypothesis that diminished vagus nerve signaling in obesity could lead to enhanced inflammation and metabolic complications.”

Reducing obesity-associated inflammation with vagal support

Vagal cholinergic stimulation can alleviate the inflammation and metabolic complications of obesity:

“Targeting cholinergic mechanisms in the inflammatory reflex using α7nAChR agonists or a centrally-acting acetylcholinesterase inhibitor could alleviate inflammation and metabolic complications in obesity.”

Type 2 diabetes and cardiovascular risk can both be ameliorated by reducing inflammation through vagal support.

“The chronic inflammatory state associated with obesity is one such common step that could be targeted. Some anti-inflammatory approaches have already been explored in the treatment of obesity-linked disorders in preclinical and clinical scenarios. For example, patients with type 2 diabetes mellitus who were treated with a recombinant human IL-1 receptor antagonist (anakinra) experienced reductions in levels of IL-6 and CRP. Additionally, HbA1c levels in these patients were reduced and their pancreatic β-cell secretory function improved. Administration of salicylate—a known IKK inhibitor in rodents, which propagates proinflammatory signals—significantly improved glucose homeostasis, reduced free fatty acid levels and increased adiponectin levels in patients with type 2 diabetes mellitus.”

Therapeutic Considerations

In addition to stimulation of the vagus by devices and pharmacotherapy, there are numerous ‘hands-on’ therapies that stimulate the CNS from the periphery (chiropractic, cranial therapy, auriculotherapy, acupuncture, etc.) that, when properly rendered, increase parasympathetic (vagal) activity. The authors conclude:

“The inflammatory reflex mediated by the vagus nerve has been successfully exploited therapeutically in preclinical models of diseases with aetiologies characterized by excessive inflammatory responses. Insufficient efferent vagus nerve cholinergic output might have a causative role in the dysfunctional immune and metabolic regulation observed in obesity, as selective activation of the efferent cholinergic arm of the inflammatory reflex attenuates both inflammation and metabolic derangements. Although cholinergic suppression of inflammation can contribute specifically to alleviating metabolic complications, direct cholinergic effects on metabolic pathways could also have a role in alleviating symptoms associated with the metabolic syndrome and type 2 diabetes mellitus. These complex interactions and the contribution of central and peripheral mechanisms in this regulation are topics of ongoing study. Additionally, intracellular mechanisms by which cholinergic signals control obesity-associated inflammation and modulate insulin signaling are under investigation…The use of cholinergic modalities in combination with existing or new therapeutic approaches to target neural, endocrine and immune functions for therapeutic benefit in patients with obesity-related disorders should also be considered.”

They offer a summary by way of these key points:

  • The inflammatory reflex is a physiological mechanism through which the vagus nerve regulates immune function and inhibits excessive proinflammatory cytokine production
  • Vagus nerve signaling has an important role in the regulation of feeding behaviour and metabolic homeostasis
  • Disruption of metabolic and immune regulation in obesity results in inflammation, which mediates insulin resistance and the development of type 2 diabetes mellitus as well as other debilitating and life-threatening conditions
  • Activation of cholinergic signaling in the efferent arm of the inflammatory reflex alleviates obesity-associated inflammation and metabolic derangements
  • The inflammatory reflex can potentially be exploited for treatment of the metabolic syndrome, type 2 diabetes mellitus and other obesity-driven disorders

Readers may also be interested in how vagal activity regulates the brain-immune relationship.

Skipping breakfast worsens blood glucose and insulin later

Diabetes CareBreakfast is a cornerstone of healthy metabolism. A study just published in the journal Diabetes Care now shows that skipping breakfast damages the blood glucose and insulin response to meals later in the day. The authors note:

Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner. “

They compared postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) for subjects randomly assigned to one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Their data show that skipping the morning meal messed up metabolism for the rest of the day:

“Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day. “

In other words, it worsened hyperglycemia and insulin resistance after both lunch and dinner. The authors conclude:

“Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.”

It’s also clearly important for prevention of type 2 diabetes and all the depredations of insulin resistance and dysregulated blood sugar.

Nuts reduce inflammation and all-cause mortality

Asia Pacific Journal of Clinical NutritionNuts have been shown to confer multiple health benefits, so it’s disconcerting to see  some apparently popular paleo diet plans that forbid them. In the absence of a nut allergy it’s a shame to forgo the benefit of such a healthful and convenient food. The intent of the paleo diet is to reduce inflammation, so it’s worth considering a paper published in the Asia Pacific Journal of Clinical Nutrition offering evidence that nuts reduce inflammation. The authors note:

“Several large epidemiological studies have associated the frequency of nut consumption with reduced risk of coronary heart disease (CHD), CVD, myocardial infarction, sudden death, and all causes of mortality, Type 2 diabetes (T2D) and other chronic disease.

Nuts are anti-inflammatory

Key inflammatory markers including CRP and IL-6 are reduced by nut consumption:

“Epidemiological and clinical studies suggest that some dietary factors, such as n–3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.”

Nuts also benefit cholesterol and lipids

“In the last two decades, a considerable number of clinical trials have consistently demonstrated beneficial effects on blood lipids and lipoproteins, primarily a decrease in Low-density lipoprotein (LDL) cholesterol, a classical CHD risk factor. This effect has been demonstrated consistently in different population groups, using different types of nuts (walnuts, hazelnuts, almonds, pecan, pistachio and macadamia nuts) and study designs. The favourable effects of tree nuts or tree nut oils on plasma lipid and lipoprotein profiles is a mechanism that appears to account for some of the cardio protective effects observed in the epidemiological studies.”

Nuts and olive oil are a great combination for cardiovascular risk:

“…in a cross-sectional study we evaluated the association between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects with high risk of cardiovascular disease. Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; although this difference was statistically significant for ICAM-1 only in the case of nuts and for VCAM-1 in the case of olive oil.”

After reviewing several other studies documenting improvements in inflammation and endothelial function the authors conclude:

“In conclusion, nuts are complex food matrices containing diverse nutrients and other chemical constituents that may favourably influence human physiology. These sub- stances may inhibit the activation of the innate immune system, probably by decreasing the production of proinflammatory cytokines such as CRP, IL-6, TNF-α or IL-18, and increase the production of antiinflammatory cytokines such as adiponectin. This may improve the proinflammatory milieu, which in turn ameliorates endothelial dysfunction at the vascular level, and ultimately decreases the risk of insulin resistance, type 2 diabetes and coronary heart disease. The capacity of nuts to modulate inflammation may explain at least in part why frequent nut consumption is associated with reduced risk of diabetes and cardiovascular disease in epidemiological studies.”

Nut consumption reduces total and cause-specific mortality

New England Journal of MedicineA paper published earlier this year in The New England Journal of Medicine add more extensive data presenting evidence that eating nuts reduces death from cancer, heart disease, respiratory disease and ‘all causes’.

“Observational and intervention studies of nut consumption have also shown reductions in various mediators of chronic diseases, including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. In prospective cohort studies, increased nut intake has been associated with reduced risks of type 2 diabetes mellitus, the metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and death from inflammatory diseases.”

To extend the data to encompass the effects of eating nuts and all causes of death the authors:

“…examined the association of nut consumption with total and cause-specific mortality in two large, independent cohort studies of nurses and other health professionals. These studies provide repeated measures of diet (including separate data on peanuts and tree nuts), extensive data on known or suspected confounding variables, 30 years of follow-up, and data on more than 27,000 deaths for analysis.”

Their data suggest that nuts are among the healthiest foods to eat:

“In two large prospective U.S. cohorts, we found a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. As compared with participants who did not eat nuts, those who consumed nuts seven or more times per week had a 20% lower death rate. Inverse associations were observed for most major causes of death, including heart disease, cancer, and respiratory diseases. Results were similar for peanuts and tree nuts, and the inverse association persisted across all subgroups.”

Some nuts every day was the best:

“Our results are consistent with the findings in previous, smaller studies. The Adventist Health Study showed that, as compared with nut consumption less than once per week, consumption five or more times per week was associated with reduced total mortality among whites, blacks, and elderly persons, with hazard ratios ranging from 0.56 to 0.82. Similarly, a study of a U.K. cohort, the Iowa Women’s Health Study, the Netherlands Cohort Study, and an earlier analysis of the NHS all showed significant inverse associations between nut intake and total mortality. Finally, in a recent secondary analysis within the PREDIMED (Prevención con Dieta Mediterránea) trial, a hazard ratio for death of 0.61 (95% CI, 0.45 to 0.83) was found for consumption of more than three servings of nuts per week, as compared with no nut consumption.”

Bottom line: ‘paleo’ and ‘autoimmune’ paleo diets can be fine healing diets for many, but like everything else should not be applied dogmatically or in a ‘rubber stamp’, ‘one-size-fits-all’ manner. In the absence of allergy, the evidence supports the consumption of nuts as wholesome foods with anti-inflammatory and metabolic benefits, exactly what paleo diets intend to accomplish.

Breast cancer and glucose intolerance

PLOS ONEBreast cancer, insulin resistance and blood sugar dysregulation are associated, and more evidence for the breast cancer link with glucose intolerance is presented in a study just published in PLOS ONE (Public Library of Science). The authors used oral glucose tolerance tests (OGTT) to assess breast cancer patients at their initial diagnosis and during chemotherapy and found a persistent association:

“The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5%, 50.6% and 28.1%, and 25.3% and 33.3%, respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT.”

It is fundamentally important to regulate blood glucose and insulin in oncologic case management since high glycation and insulin promote disease progression. The authors conclude:

Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.”

Blood sugar dysregulation damages learning and memory

More evidence for the deleterious effects on the brain of hyperglycemia and hypoglycemia is presented in a study just published in the journal Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. The authors’ research was designed to…

“…evaluate the effects of streptozotocin (STZ)-induced hyperglycemia and insulin-induced hypoglycemia in cortical and hippocampal mitochondria bioenergetics and oxidative status.”

The hippocampus is the seat of short-term memory and a regulatory center for adrenal function. STZ-induced hyperglycemia and insulin-induced hypoglycemia are standard methods employed to examine the physiological repercussions of high and low blood sugar respectively. They analyzed the respiratory chain and phosphorylation system for the capacity to produce energy in the mitochondria (cellular energy ‘factories’), thiobarbituric acid reactive substances (TBARS) levels and the hydrogen peroxide (H2O2) production rate for oxidative stress, and non-enzymatic and enzymatic antioxidant defenses. What did their data show?

“Cortical mitochondria from insulin-induced hypoglycemic rats present a significant decrease in the ADP/O index, a significant increase in the repolarization lag phase and a decrease in GSH/GSSG ratio when compared with STZ and control mitochondria. Both STZ-induced diabetes and insulin-induced hypoglycemia promote a significant increase in TBARS levels and a decrease in glutathione disulfide reductase activity. Diabetic cortical mitochondria present a significant decrease in glutathione peroxidase (GPx) activity compared to control mitochondria. In turn, insulin-induced hypoglycemia induced a significant increase in GPx and manganese superoxide dismutase (MnSOD) activities. In hippocampal mitochondria, insulin-induced hypoglycemia increases the respiratory control ratio whereas both situations, hyper- and hypoglycemia, potentiate H2O2 production and decrease the activity of MnSOD.”

In other words, both hyper- and hypoglycemia impair cortical and hippocampal function deranging energy production, increasing damage due to oxidative stress. In reference to type 1 diabetes, the authors state in conclusion:

“These results suggest that the poor glycemic control that occurs in type 1 diabetic patients undergoing insulin therapy may have detrimental effects in brain areas involved in learning and memory.”

More evidence that coffee helps blood sugar and liver inflammation

Journal of Agricultural and Food ChemistryYet another study on the benefits of coffee was just published in the Journal of Agricultural and Food Chemistry. This ones demonstrates how this salubrious beverage improves insulin function and fatty liver by reducing inflammation. The authors observe:

“Epidemiological surveys have demonstrated that habitual coffee consumption reduces the risk of type 2 diabetes. The aim of this work was to study the antidiabetic effect of coffee and caffeine in spontaneously diabetic KK-Ay mice.”

The mice were not taken to Starbucks for mini espresso shots, but were…

“…given regular drinking water (controls) or 2-fold diluted coffee for 5 weeks.”

The results were pretty amazing:

“Coffee ingestion ameliorated the development of hyperglycemia and improved insulin sensitivity. White adipose tissue mRNA levels of inflammatory cytokines (MCP-1, IL-6, and TNFα), adipose tissue MCP-1 concentration, and serum IL-6 concentration in the coffee group were lower than the control group. Moreover, coffee ingestion improved the fatty liver.”

The authors summed up their findings by stating:

“…coffee exerts a suppressive effect on hyperglycemia by improving insulin sensitivity, partly due to reducing inflammatory cytokine expression and improving fatty liver. Moreover, caffeine may be one of the effective antidiabetic compounds in coffee.”