Is the human gut microbiota the critical mediator of health?

In a review this month, Greer and co-authors present interesting information on just how much our health depends on the well-being and communal balance of the microscopic symbionts in our gastrointestinal tract [Journal of Allergy and Clinical Immunology 2013; 132(2): 253-262].  They begin their review noting that, until fairly recently, immunity, metabolic functions and gut physiology had been studied as separate biological systems.  In light of growing evidence that the delineation between these is arbitrary, the authors point out that systems biology has developed new methods for investigating the interactions between the intestinal microbiota and immune and metabolic outcomes.

Greer et al covers two broad categories, small intestine enteropathies and obesity with metabolic syndrome.  They describe current animal models used to study immunodeficiency enteropathies, celiac disease, inflammatory bowel disease, obesity and lipid metabolism dysregulation.

The authors discuss notable findings from mouse models that have been employed to study enteropathies.  For example, B lymphocyte deficient mice are known have fat absorption issues, which correlate to IgA deficiency.  B cell secreted IgA is required for maintaining a proper balance between immunity, fat metabolism and gut microbes.  They note that B cell deficient mice have intestinal gene expression profiles that are very similar to those seen in HIV/CVID patients.

They note that gut microbiota contribute to dyslipidemia and insulin resistance in obese mice and induce intestinal inflammation in response to increased fat intake.  Greer et al discuss also the physical changes in the ileum that cause increased uptake of fats in the diet-induced obese mice.  Interesting, they comment that TLR5 knock-out mice have increased weight gain, pointing to innate immune interactions in fat metabolism.

Greer et al discuss evidence on short chain fatty acid balance and metabolism as critical to maintenance of a “core” microbiota.  Transplantation of microbes from diet-induced obese mice to control mice results in obesity in the control mice without increase in food intake.  The authors suggest that this points to persisting changes in gut microbiota that may be causally related to obesity and altered fat metabolism.  Concluding, Greer et al suggest that the gut microbiota is a cardinal mediator between the immune system and gastrointestinal epithelium. 

In answer to the question, "In your opinion, does manipulation of the gut microbiota present a therapeutic intervention for obesity and/or lipid metabolism disorders?", the authors responded, "Yes, we believe that manipulation of gut microbiota presents great potential for therapeutic interventions in a range of diseases, including obesity and metabolic syndrome, but we need first to understand which taxa or which microbial genes might be most beneficial and in each case."

A novel mode of cell death in active versus resting eosinophils: a potential pathway for treatment of asthma and allergic disease

Apoptosis was previously thought to be the only mode of regulated or programmed cell death in eosinophils, as necrosis was regarded as unregulated cell death.  However, Kano et al., have discovered that the activated eosinophils, found in abundance in asthma and allergic disease, can die by means of a type of regulated necrosis in response to Siglec-8 ligation [J Allergy Clin Immunol 2013; 132(2): 437-445]. Siglec-8 is a cell-surface receptor protein that is highly and selectively expressed by human eosinophils, as well as mast cells and basophils. The authors show that Siglec-8 ligation in the presence of IL-5 triggers necrosis in activated eosinophils in a reactive oxygen species (ROS)–dependent manner. Further, they explain why IL-5 promotes cell death in this system even though it is typically a pro-survival signal.  They demonstrate that ROS switch IL-5’s function from pro-survival to cell death enhancement by augmenting ERK phosphorylation and this serves as a decisive trigger of necrotic cell death. These discoveries indicate that necrotic eosinophil cell death can be regulated by signal transduction, suggesting that potential therapeutics targeting regulation of the mode of cell death could be beneficial in various eosinophilic diseases.

Pattern recognition receptors in obesity and metabolic disturbances

Highlighting the role of innate immunity in the evolution of obesity and associated metabolic disorders, Jin and Flavell deliver a concise review of mechanisms involving pattern recognition receptors that produce pathology in liver, pancreas, brain and intestinal microbiota [J Allergy Clin Immunol 2013; 132(2):287-294]. 

The authors provide a summary of the biology of the major types of pattern recognition receptors [PRR], with emphasis on toll-like receptors [TLR] and NOD-like receptors [NLR].  They discuss briefly their activity in response to pathogen infection and endogenous injury.  Several NLRs can coalesce into multiprotein complexes called inflammasomes which have proven to be importantly involved in the development of insulin resistance. 

Jin and Flavell review PRR mechanisms in five critical physiologic areas: brain, pancreatic islet, and vascular inflammation, induction of peripheral insulin resistance, and disruption of intestinal microbiota homeostasis.  They note that PRRs can directly mediate and sustain inflammation in response to excessive nutrient resulting in abnormal lipid metabolism and insulin resistance in multiple tissues, which accounts for comorbidities such as type 2 diabetes and atherosclerosis.

In the gut, the authors point out that PRRs are critical to sensing and regulating the microbiota as well as responding to pathogenic insult.  TLR/NLR deficiency-associated microbial imbalance has been associated with obesity risk, insulin resistance, and fatty liver.  Interestingly, transplantation of abnormal microbiota from obese mice into wild-type mice results in reproduction of the obese metabolic phenotype that can be corrected by antibiotic treatment.  This points to a causal relationship between disrupted intestinal microbiota and the development of metabolic syndrome. 

Regarding the recent AMA announcement that obesity is a disease as opposed to lifestyle that results in a disease state, I think this is supported by findings from basic research that the development of obesity is not simply due to a lifestyle exemplified by overeating and inactivity, but also profoundly impacted by intrinsic genetic factors in metabolic system, immune system and intestinal microbial ecosystem. Recognizing obesity as a disease will help the community pay more attention to this emerging health issue and also hopefully stimulate research to understand the complex pathophysiology of obesity.

SLIT immunotherapy in South Africa

In a new series for the Journal, “Allergy and clinical immunology around the world,” Paul Potter, MD, describes sublingual immunotherapy practice in South Africa, which is based on recommendations put forth by the Allergy Society of South Africa [J Allergy Clin Immunol 2013; 132(1): 99-100].  Because of the long grass pollen season, approximately 8 months, seasonal rhinitis in the region is reclassified as persistent rhinitis, for which SLIT is indicated. 

Potter notes that SLIT has been available for 15 years in South Africa.  European vaccines are employed for Bermuda/rye grass pollens and D. pteronyssinus/farinae for mite allergies.  Patients eligible for SLIT must be sensitive to only one allergen per the recommendations, though 80% of the patient population is allergic to multiple allergens. 

The author reports that clinical trials for SLIT in South Africa have had variable outcome agreement, in spite of significant efficacy results.  A retrospective review is discussed by Potter who notes that the drop-out rate is highest in the first year of a 3-year intervention.  Reasons for discontinuing study participation were most commonly financial and logistic.  He discusses additional findings that implementing 6-month follow-up contact with subjects and administering a quality of life questionnaire increases compliance with therapy and completion of the full course of treatment. 

MicroRNAs – the hot new thing in allergic inflammation regulation

While investigations of microRNAs [miRNA] and their role in transcription in disease have been growing for the last decade, more recently they have come under the scrutiny of immunologists searching for signs of miRNA dysregulation in allergic inflammation.  This month, Lu and Rothenberg review the evidence to-date and give us some very interesting news on miRNA in several atopic diseases [J Allergy Clin Immunol 2013; 132(1): 3-13].

Lu and Rothenberg start with a review of the general pathophysiology of miRNAs, which effect gene transcription networks by silencing posttranscriptional gene expression of mRNA.  One miRNA can modulate multiple genes and one gene may be targeted by many miRNAs.  miRNAs are also known to modify DNA methylation and histone acetylation, as well as interact with transcription factors.  The authors comment that miRNAs have been found in exosomes in cell-free body fluids, raising the intriguing possibility of their usefulness as peripheral biomarkers.  

The authors present the current knowledge of miRNA profiles that have been identified in allergic asthma, eosinophilic esophagitis, atopic dermatitis, and allergic rhinitis.  By far the most abundant information is available for allergic asthma.  One particular miRNA – miR-21 – has been well characterized in experimental models of asthma.  Lu and Rothenberg discuss findings that point to miR-21 involvement in T_H1-T_H2 polarization.  In these models, miR-21 is over-expressed in experimental asthma and strongly suppresses expression of IL-12p35 mRNA, permitting T_H2 bias in the immune response.  They note that studies of MiR-21 deficiency in asthma mice report increases in IL-12p35 and IFN-g production and concomitant decreases in eosinophilia and IL-4 in bronchoaveolar fluid.  Lu and Rothenberg discuss other miRNAs that have been identified in allergic inflammatory processes such as miR-126 and the Let miRNA family. Critical miRNAs associated with airway smooth muscle function are also discussed along with the early results of miRNA profiling in human asthma. 

Important findings on critical miRNAs identified in eosinophilic esophagitis are reviewed.  The authors discuss miR-21 mechanisms in eosinophilic esophagitis that are consistent with those reported for allergic asthma.  One miRNA, miR-146a, has been characterized in eosinophilic esophagitis as a repressor of T_H1 responses through dysregulation of T_reg suppression in a STAT1 dependent manner. Peripherally circulating miR-146a and miR-223 in patients with eosinophilic esophagitis are discussed as promising non-invasive biomarkers for diagnosis and therapy response. 

Lu and Rothenberg further review miRNA profiles that have been characterized in atopic dermatitis and allergic rhinitis, noting that miRNA data in AR is currently sparse.  Also discussed is the role of miRNA in eosinophil development in light of the collaborative interaction between miR-21 and miR-223 in eosinophil viability, proliferation, and maturation. 

The authors provide an excellent table that summarizes miRNAs common to allergic asthma, eosinophilic esophagitis, and atopic dermatitis.  Concluding, Lu and Rothenberg offer a number of topics for future research focus.  

Restoring health

The rise in non-communicable, inflammatory diseases (NCD), and in particular allergic and atopic illnesses, has begun to redirect the efforts of the clinical research community toward early prevention in addition to supportive intervention.   This is in light of the significant burden on healthcare created by NCD as well as the realization of the limitations of pharmacotherapies to affect underlying causes. 

This month’s review article by Pfefferle, Prescott and Kopp (J Allergy Clin Immunol 2013; 131(6): 1453-1463) assesses the practical application of findings that commensal gut microbes are critical partners in the evolution of environmental tolerance.   They focus on the accumulating evidence supporting a disrupted human microbiome that has led researchers to propose the use of pro- and pre-biotic therapies as means to prevent inflammatory immune processes that create chronic allergic and atopic diseases.

Pfefferle et al. review briefly the current knowledge on the collaboration of the gut and the immune system in developing tolerance, pointing out the importance of maternal exposure to both pathogenic and non-pathogenic microbes in directing fetal immunity.  They note that high prenatal exposure has been shown to have an independent protective effect on allergic outcomes and that these effects are epigenetic.  Citing a study that compared the immune status and responsiveness of urban Australian children with native Papua New Guinea children, Pfefferle discuss the higher immune activation but lower reactivity of the Papua New Guinea children compared to their urban counterparts, an observation that points to highly divergent microbial exposure of the mothers and their children.

The authors go on to cover the research on maternal pro- and prebiotic interventions for eczema and food allergies.  At least half of the maternal probiotic intervention studies for eczema and food allergy showed positive results, but conflicting results were presented in the remainder.  Maternal prebiotic studies also showed positive effects in both animal models and human subjects, with offspring having greatly diminished expression of eczema.  The observed variability of trial results is analyzed with respect to study design, dosing, population and environmental region. 

Mechanically prepared bacterial lysates (BL) for protection against respiratory illness is also discussed in Pfefferle et al.  Observations that BL push upper airway responses toward Th1 maturation were the basis for studies that examined the effect of BL in reducing the incidence of acute respiratory tract infections (ARTI).  Results showed a protective effect of BL, especially in high risk children.  The authors comment that ARTI and recurrent wheeze in childhood is associated with the development of asthma and suggest that BL may be a future focus of asthma prevention research. 

Pfefferle et al. concludes noting that both the intrinsic and extrinsic microbial environment are implicated in almost all inflammatory NCD and suggest that methods of microbial manipulation are an important focus of future research aimed at prevention strategies. 

Early life BMI progression and asthma incidence

Results from an interesting epidemiological investigation based on data from eight birth cohorts collected under the Global Allergy and Asthma European Network [GA²LEN] research initiatives are presented this month in Rzehak et al (J Allergy Clin Immunol 2013; 131(6): 1528-1536).  Risk of “incident asthma,” defined as first reported physician diagnosis, for 3 age brackets up to 6 years old is analyzed.

Using a novel growth curve analysis method to identify classes of BMI trajectories normalized according to WHO standards [BMI-SDS], the authors identify three classes, a normative class [Class 1], an early rapid growth only up to 2 years class [Class 2], and a persistent rapid growth to 6 years class [Class 3].  Survival analysis of the three BMI-SDS trajectories assessed the hazard ratio [HR] for incident asthma in each. 

Rzehak et al. report that children in the Class 2 trajectory had a significant increased risk of incident asthma within their first 6 years.  Class 3 children had similar risk that did not achieve significance.  Hazard ratios were similar between Class 2 and 3, the latter class having a greater prevalence of excess weight and obesity, suggesting that there is an association of early rapid weight gain with incident asthma, independent of overweight or obesity.

Rzehak et al. conclude that rapid weight gain during the first two years of life increases the risk of incident asthma by the age of 6 years.