The gut microbiota and inflammatory non-communicable diseases: Associations and potentials for gut microbiota therapies

The health of our modern society is being threatened by a plethora of chronic inflammatory non-communicable diseases (NCDs) which share in common, an underlying low-grade inflammation. These include early onset NCDs such as allergy, asthma and some autoimmune diseases and later onset NCDs including cardiovascular disease (CVD), metabolic disease and neurodegenerative disorders. While inflammation and the pathways to disease are multifactorial, the altered gut colonization patterns associated with declining microbial diversity is a central theme, and increasingly implicated in the physiological, immunological and metabolic dysregulation seen in many NCDs. Upon review of the current literature, West et al discuss the relationships between gut colonization and inflammatory NCDs, and gut microbiota modulation strategies for their treatment and prevention (J Allergy Clin Immunol 2015; 135: 3-13).

The critical role of the gut microbiota in immune development has been well documented in germ free animal models, demonstrating the failure of normal maturation and, in particular, failure of the systemic immune regulatory networks that result in both allergic and autoimmune phenomena. Data from several animal models have formed a basis to further explore the role of gut microbiota in early programming of host responses in humans. Collectively, recent literature suggests that the imprinting of human gut microbiota may commence already in utero and is then further shaped by postnatal exposures such as cesarean or vaginal delivery, antibiotics to the mother or infant, breastfeeding, and introduction to solid foods.

Culture independent DNA-based studies have demonstrated associations between reduced gut microbiota diversity and early onset NCDs including atopy, eczema, and asthma. Furthermore, inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes have been shown to be associated with dysbiosis. It is also suggested that the early microbial environment drives more sustained predisposition to low-grade inflammation into adulthood and the propensity for later onset NCDs. Aberrations in the gut microbiota may also have implications for obesity-associated NCDs.

The most widely used approach for treatment and prevention of NCDs has been to administer probiotics. For example, specific probiotics promote favorable intestinal colonization and their fermented products have anti-inflammatory, immunomodulatory, and metabolic effects, although the effects are variable when evaluated in clinical trials. Fecal microbiota transplantation (FMT) is an emerging therapy that has been successful in the treatment of Clostridium difficile infection and possibly IBD. While much remains unknown, multidisciplinary and integrative approaches may ultimately lead to improved strategies to overcome the disease epidemic of modern civilizations. 

Question for the authors:

 

Most treatment and prevention research focuses on early development and manipulation of the gut microbiota. What is known about treatment of allergic and autoimmune diseases in adults through diet and lifestyle modifications that directly alter the gut microbiota composition?

Most treatment and prevention research focuses on early development and manipulation of the gut microbiota. What is known about treatment of allergic and autoimmune diseases in adults through diet and lifestyle modifications that directly alter the gut microbiota composition?

There is clear evidence that diet impacts gut microbiota composition, however intervention studies aiming at modulating the gut microbiota in adults with allergic or autoimmune disease are scarce.  Dietary patterns such as the Mediterranean diet have been associated with increased asthma control in cross-sectional studies although the effect on gut microbiota composition was not studied. However, there is some support that a Mediterranean-style diet may influence gut microbiota.  In a small pilot study, Marlow et al 2013, examined the effects of a Mediterranean-influenced dietary intervention on inflammatory biomarkers and gut microbiota in eight Crohn’s disease patients. This 6-week dietary intervention resulted in a trend for reduced inflammation and ”normalised” gut microbiota with an increase in Bacteroidetes and the Clostridium clusters, and a decrease in Proteobacteria and Bacillaceae.

Even though most probiotic prevention and treatment studies have targeted a pediatric population, there are also randomized controlled trials with probiotics (although most commonly given as supplements and not incorporated in the diet) for treatment of allergic disease also in adults. The results have been variable, although meta-analyses generally show no benefit of probiotics for treatment of allergic disease.

The impact of lifestyle modifications other than diet in this context is even less studied. Benjamin et al 2012, reported smoking to be associated with an increase in Bacteroides-Prevotella both in patients with active Crohn’s disease and in healthy controls suggesting that smoking may at least partially contribute to the dysbiotic state. Stress is another lifestyle  factor with potential to impact gut microbiota composition via the gut-brain axis, however there is a paucity of studies in the context of allergic and autoimmune disease.

Clearly, there is need for well-designed dietary and life-style intervention studies targeting gut microbiota in both allergic and autoimmune disease.

The Microbiome in Asthma

Newly developed culture-independent methods for microbial detection are deepening the understanding of their role in lung disease. A persuasive body of evidence suggests that the microbiome of the lower airways differs distinctly in the obstructive lung disease, including asthma. Huang and Boushey provide their perspective on the findings of studies of differences in the airway microbiome in patients with asthma vs. healthy subjects, and of studies of relationships between environmental microbiota, gut microbiota, immune function, and the development of asthma (J Allergy Clin Immunol 2015; 135: 25-30). Additionally, they provide a rationale for approaches involving directed manipulation of the gut and airway microbiome for treatment and prevention of allergic asthma.

Alterations in respiratory tract immune function are at least theoretically linked to the immunomodulatory activity of gut microbiota through the concept of a “common mucosal response”. This proposes that antigen presentation at one mucosal site stimulates migration of lymphoid cells to other mucosal sites, shaping immune responsiveness at those sites as well. Studies in mice provide strong support for the concept that bacterial community composition of the gut can shape developing immune function to foster or protect against allergic sensitization.   Similarly, studies focused exclusively on lung microbiota suggest that establishment of a lung microbiome occurs and is a dynamic process after birth. The authors discuss relationships of gut microbiota in response to viral respiratory infection, and provide findings that bacteria regulate immune defense against viral infections in mouse models. For example, interaction between exposure to allergens and microbial exposure has been seen in inner city children. Surprisingly, children with the highest rates of atopic sensitization and recurrent, presumably virus induced wheeze were found in children exposed to the lowest levels of cockroach, mouse and cat allergen and the lowest levels of bacterial diversity in their first year of life. On the contrary, the lowest rates of atopy and wheezing were found in those who had been exposed to the highest levels of these allergens and bacterial diversity. These results suggest that the bacteria served as a tolerance-inducing adjuvant for allergens.

The authors emphasize that dissecting the role of the microbiome in asthma is challenged by the heterogeneity of the disease at multiple levels. These levels include asthma’s clinical and inflammatory heterogeneity, genetic factors that contribute to asthma risk, and the multiplicity of immune pathways involved in asthma. To progress to clinical studies of oral or aerosol administration of microbiota for treatment and especially for prevention of asthma which will necessarily involve enrollment of pregnant women or of newborn infants will likely require overcoming ethical, legal, and cultural hurdles as high as the scientific ones we currently face.

Question for the authors:

 

The studies described in your review focus on the early development of the mucosal microbiota. Is there evidence that manipulating the microbiota in adults with allergic asthma may be a potential therapeutic?

We are a long way from human studies of the effects on allergic or asthmatic symptoms of manipulating the microbiota in adults with the condition. So the evidence available is largely from studies of mice, like Karimi et al’s study showing that dietary supplementation with L. reuteri increased Treg cell number and activity and reduced the allergic inflammation induced by allergen challenge in previously sensitized and challenged BALB/c mice (Am J Respir Crit Care Med Vol 179. pp 186–193, 2009).  Nothing comparable has been done in humans with established allergic asthma.

Update on Epigenetics in allergic disease

Chronic inflammatory diseases, including allergies and asthma, are the result of complex interactions between the genetic predisposition and environmental factors.  Epigenetics comprises the umbrella of such biochemical reactions and mechanisms including DNA methylation and chromatin modifications on histones and other structures. In their review, Harb and Renz review the recent developments in this context with emphasis on allergy and asthma research (J Allergy Clin Immunol 2015; 135: 15-24) .

There are many different epigenetic modifications affecting the status of the transcription of genes. For example, epigenetic modifications of T-cells start very early during the activation/differentiation program with naïve non-committed precursors during fetal immune development. DNA methylation is a biochemical process by the addition of a methyl group to the DNA nucleotides cysteine or adenine. This process leads mainly to gene silencing and subsequently to the inhibition of gene transcription. Histones are highly alkaline proteins found in eukaryotic cells nuclei that package and order the DNA into structural units called nucleosomes. Histone modifications range from gene activation to gene silencing and can have some DNA repair functions as well. The authors have previously shown that allergen sensitization and development of the TH2 immune response is closely linked to epigenetic programming of the previously naïve T-cell during development of the effector status. Moreover, house dust mite can also elucidate epigenetic modifications in asthmatic patients. Furthermore, environmental microbes are also considered to play an important role in shaping the immune response particularly early in life. For example, regulatory T-cell function was shown to be more efficient with farming exposure and was associated with demethylation of the FOXP3 promoter in offspring of mothers with farm milk exposure compared to controls. On the other hand,tobacco smoke has also been shown to impact epigenetic programming of different cell types.

There are many studies suggesting that different diet and nutrients exert their effect through epigenetic mechanisms, such as folic acid and vitamin B12 which are prominent methyl donors and can affect the DNA methylation status universally. In addition to that, fish oil is the main source of Omega-3 fatty acids that are precursors of a large number of anti-inflammatory mediators including defensins and resolvins, and recent data provides mechanisms toward an altered expression of NF-KB affecting important inflammatory regulatory pathways through deacetylation. The authors discuss a variety of examples indicating a role of epigenetic alteration as a mechanism linking obesity and the effect on altered gene expression leading to an asthma phenotype. Moreover, stress represents an additional environmental factor through epigenetic modifications, with evidence of altered gene expression that modifies the allergic phenotype.

The authors emphasize that questions remain on the role of different epigenetic regulator mechanisms in various areas. More clinical studies are needed to unmask the exact mechanism of epigenetic modifications and their role in disease development. Other questions relate to the regulation of gene-specific epigenetic modifications and the control of the events through the underlying enzymatic machinery. Reversibility and stability of these effects also require further attention together with the question about the inheritance of different epigenetic marks.