As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“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…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen.  The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

1. B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
2. BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
3. A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

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A study just published in the prestigious medical journal The Lancet finds a clear relationship between diet and behavior in ADHD when investigated by a supervised elimination diet but not by IgG (immunoglobulin G antibody) blood tests. The authors state:

“The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children.”

They conducted a randomised controlled trial in which children aged 4-8 years who were diagnosed with ADHD were randomly assigned to either a 5 week restricted elimination diet or instructions for a healthy diet in the first phase.

“Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child’s individual IgG blood test results) were added to the diet.”

Pediatricians and others involved were masked to group and challenge allocation. Changes in the ARS score in both phases and correlations between food-specific IgG levels related and behavior were the endpoints. What did their data show?

“Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23·7 according to the masked ratings… The ARS total score increased in clinical responders after the challenge by 20·8… In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels.“

This significant study offers three very important points here for clinicians and parents:

1. Foods can trigger ADHD behavior.
2. Supervised elimination diets can identify the offending foods.
3. IgG blood tests do not identify them.

Parents and practitioners should appreciate the authors’ conclusion:

“A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged.“

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Ménière’s disease is an autoimmune condition with vertigo, tinnitus and hearing loss caused by an inflammatory attack on the sensorineural structures of hearing and balance in the inner ear. It’s surprising how often food and inhalant allergies are overlooked as a contributing cause. A paper just published in Otolaryngologic Clinics of North America reminds us of their importance.

“Ménière’s disease (MD), which by definition is idiopathic, has been ascribed to various causes, including inhalant and food allergies. Patients with MD report higher rates of allergy history and positive skin or in vitro tests compared with a control group of patients with other otologic diseases and to the general public.”

The authors review immunologic research and clinical trials involving allergy avoidance and immunotherapy and report:

“Recent immunologic studies have shown higher rates of circulating immune complexes, CD4, and other immunologic components in patients with MD compared with normal controls. Published treatment results have shown benefit from immunotherapy and/or dietary restriction for symptoms of MD in patients who present with allergy and MD.”

A very interesting paper published in the Journal of Laryngology & Otology delves deep into the matter by evaluating…

“…the role of allergy in the pathogenesis of Ménière’s disease by means of cytokine profiles, allergic parameters and lymphocyte subgroups.”

The authors measured lymphocyte subgroups in the peripheral blood, IFN-γ, IL4, total IgE levels, and specific IgE levels pertaining to tree, fungus, fruit, egg-white, cow’s milk, wheat flour, corn flour, beef, and rice allergens, and compared them in the patient and control groups. What did the data show?

“This study found that the prevalence of allergy was higher in patients with Ménière’s disease than in the control group. Thus the authors suggest that allergy should be taken into account when patients with this disease are treated.”

Hormonal factors promoting inflammation can exacerbate the symptoms, as discussed by another paper in Otolaryngologic Clinics of North America recognizes how premenstrual hormonal dysregulation can be an exacerbating factor:

“Some women with Meniere disease demonstrate exacerbation of symptoms during the premenstrual period. It is believed that the hormonal stress of the premenstrual period acts on the volatile inner ear with Meniere disease to result in dysfunction. Migraine, Meniere disease, and the premenstrual period may be a complex interaction leading to exacerbation of symptoms.”

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This becomes an important question when someone realizes how much they benefit from avoiding gluten due to celiac disease or non-celiac gluten sensitivity. The evidence suggests that corn (maize) has to be considered on an individual basis. It is possible, but not certain, that you may react to corn when you are sensitive to wheat gluten.

Consider this study that was published in the journal GUT, An International Journal of Gastroenterology and Hepatology. The authors investigated how nitric oxide is part of the intestinal inflammatory reaction reaction to gluten, and how it relates to the white blood cell response. They noted this in their conclusion:

“Mucosal activation of neutrophils and eosinophils [white blood cells] precedes pronounced enhancement of mucosal NO [nitric oxide] production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.”

So it depends on the individual. The more serious your condition the more important it is to check yourself for corn sensitivity with the immunological ‘gold standard’—a properly managed elimination-provocation protocol.

We are also bereft of a perfectly decisive indication  for oats because rare individuals can react, though this study published in the Scandinavian Journal of Gastroenterology indicates that most celiac patients can tolerate them. First the authors note that…

“We have…identified three adult coeliac disease patients who developed a flare of active coeliac disease after ingestion of oats, which suggests that oats might not be entirely innocent in coeliac disease.”

They set out to compare the immune response to oats and wheat by comparing production of the main intestinal antibody (IgA) that participates in the reaction. Although other immune activity was observed,…

“No significant differences were found in IgA against oats in oats-eating and non-oats-eating coeliac disease patients.”

Their conclusion:

“Ingestion of oats does not cause increased levels of IgA against oats in adult coeliac disease patients on a gluten-free diet. The findings support the notion that most adult coeliac disease patients can tolerate oats.”

Note the “most”. And even if you are not sensitive to oats, it is important to be sure that they are certified gluten-free. Otherwise they can be contaminated with gluten during storage, transport, processing and packaging.

What about blood tests for food allergies? Too many variables influence antibody tests for them to give a reliable indication. If you have a serious condition with an autoimmune basis, it’s best to consult with a functional medicine practitioner who can  help you through an elimination-provocation protocol (eliminating and re-introducing foods), and who knows how to use objective lab tests to profile your immune imbalance.

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It may come as a surprise to you there are many who consider food allergy primarily a pediatric problem, which of course is incorrect. “Epidemiologic studies report an increase in food allergies in industrialized countries, but mainly focus on children and young adults. This leads to the impression that food allergies do not occur in the older population.” This paper published in the journal Gerontology shows why food allergy is a major problem for the older population too. As the authors state, “age-related changes dramatically affect both the innate as well as the adaptive immune system – a phenomenon known as immunosenescence.” They go on to detail why we can acquire food allergies later in life, which include the use of acid-blocking ulcer drugs: “Deficiencies in micronutrients, especially zinc and iron, as well as vitamin D, in the elderly may also contribute to the development of allergies. A further risk factor of the elderly in developing food allergies could also be the decreased digestive ability of the stomach due to atrophic gastritis or anti-ulcer medication. In these settings, undigested proteins may persist and become allergenic. In fact, mouse models indicate that these pharmaceuticals support the induction of Th2 responses not only in young adult, but also in aged animals.” The authors conclude, “Previous reports have already suggested that allergies are underdiagnosed among the elderly. Based on our own recent study conducted in a geriatric nursing home, we also suggest that food allergies may be underestimated.”

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Food allergy and food sensitivity are common aggravating factors for chronic inflammation of many kinds. If you think food allergy or sensitivity may be contributing to your problems, be sure to find a doctor who has the right knowledge and experience. This paper just published in the journal Pediatrics examined 407 primary care physicians for their knowledge and confidence about food allergy. The authors report that “…only 24% knew that oral food challenges may be used in the diagnosis of food allergy, 12% correctly rejected that chronic nasal problems are not symptom of food allergy, and 23% recognized that yogurts/cheeses from milk are unsafe for children with immunoglobulin E–mediated milk allergies.” Their polite conclusion: “Knowledge of food allergy among primary care physicians was fair. Opportunities for improvement exist, as acknowledged by participants’ own perceptions of their clinical abilities in the management of food allergy.”

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Although these two papers, both published in the journal Pediatrics, don’t clarify the distinction between increase in incidence and increase in detection, they give you a sense for how weighty an issue this is:

1. Food Allergy Among Children in the United States
2. The Changing Face of Childhood Celiac Disease in North America

Bear in mind that this the tip of the iceberg. These studies depended on antibody testing. Because of  factors that can cause antibodies to not be detected many diagnoses are missed (the ‘gold standard’ is the elimination-provocation protocol). An assessment of most common childhood disorders is not complete without determining whether food allergy or sensitivity is among the contributing causes.

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