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Linking the Microbiota, Chronic Disease, and the Immune System

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Chronic inflammatory disease is associated with shifts in the microbiota, often toward reduced diversity and increased inflammatory character.

The immune system can identify shifts in the microbiota by direct interaction with bacteria in addition to ‘sensing’ of microbiota-derived metabolites.

Immune activation associated with shifts in the microbiota can have far-reaching systemic effects and contribute to disease.

The incidence of chronic disease is on the rise and has been linked to a number of environmental factors, including antibiotic use, diet, and infection. There is evidence that these factors act on the host via shifting the microbiota.

Chronic inflammatory diseases (CIDs) are the most important causes of mortality in the world today and are on the rise. We now know that immune-driven inflammation is critical in the etiology of these diseases, though the environmental triggers and cellular mechanisms that lead to their development are still mysterious. Many CIDs are associated with significant shifts in the microbiota toward inflammatory configurations, which can affect the host both by inducing local and systemic inflammation and by alterations in microbiota-derived metabolites. This review discusses recent findings suggesting that shifts in the microbiota may contribute to chronic disease via effects on the immune system.

Section snippets

Immunity, the Microbiota, and Chronic Inflammatory Disease

In the past decade, our knowledge of chronic inflammatory disease (CID) has been transformed by a new understanding of the central role of the immune system in driving pathology. The immune system functions as a ‘rheostat for the entire body’, seeking out physiological disturbances (infectious or otherwise) and rectifying them via both inflammatory immune responses and by critical repair/regulatory processes such as the clearance of dead cells and the restoration of the physical barrier 1, 2.

Immune–Microbiota Interaction

Humans exist as metaorganisms consisting of host cells in addition to a vast consortium of microbial organisms that live on all of our barrier tissues. The highest density of organisms lives in the intestine, and these organisms provide a tremendous benefit to the host via the enzymatic processing of complex dietary constituents, such as fiber, into metabolites digestible by the host, in addition to many other enzymatic functions. Often, these enzymatic pathways can involve multiple genes

The Microbiota and Chronic Diseases of the Mucosa

The intestine is home to the largest and most metabolically active microbial community in the human body. Therefore, it is perhaps unsurprising that the predominant inflammatory diseases of the gut, Crohn's disease (CD) and ulcerative colitis, are intertwined with shifts in the microbiota. In both diseases, inflammatory immune responses in the intestine against the microbiota induce shifts toward more aggressive members of the population. The most salient example of this effect is the outgrowth

The Microbiota, Obesity, and Metabolic Syndrome

Obesity and associated pathologies, including type II diabetes (T2D) and dyslipidemia, are a worldwide epidemic and affect an increasing number of people each year. The mechanism of T2D is now believed to be a block in insulin signaling driven by inflammatory cytokines [53]. In lean individuals, the fat is dominated by M2 macrophages, eosinophils, group 2 innate lymphoid cells, and Tregs, all of which contribute in their own way to adipose tissue homeostasis [34]. In obese individuals, the

The Microbiota and Cardiovascular Disease

CVD, and in particular atherosclerosis, is the most common cause of death in high-income countries. The root cause of atherosclerosis is blockages in coronary arteries, which is caused by plaques formed of fat deposits and the development of fat-laden macrophages called foam cells. Development of atherosclerosis has long been associated with diets high in animal fats, cholesterol, and red meat. Recently, Hazen and colleagues 80, 81 have identified that a chemical derivative of red meat,

Modern Life and Changing Host–Microbiota Relationships

As discussed, a multitude of evidence now suggests that shifts in the microbiota toward inflammatory and low diversity states can contribute to chronic disease. One of the primary ways that modern life has changed our relationship with our resident bacteria is the advent of antibiotics. The invention of antibiotics sparked a revolution that fundamentally changed morbidity and mortality associated with bacterial infections. However, it can be argued that antibiotics have been overused as

Concluding Remarks and Future Perspectives

It is now clear that the microbiota acts as a genetically distinct organ that is critical for the enzymatic digestion of food, promotion of immune homeostasis, and prevention of enteric infection. Just like the host-derived organs of the body, the microbiota can be damaged, or, as commonly described, become dysbiotic, leading to a negative impact on dependent host systems. Alterations to the microbiota can certainly contribute to pathology and in cases where these changes include the outgrowth

Acknowledgments

The authors would like to apologize that due to length requirements not all work in this burgeoning field could be discussed and properly cited. This work was supported by NIAID K22 AI108719 (T.W.H.) and the NIH intramural program (V.K.R., I.V-C., and Y.B.). The authors would like to thank K. Gopalakrishna and J. Tometich for critical reading of the manuscript.

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