Invited ReviewMood and gut feelings
Introduction
Psychiatric disorders which are on the increase globally, already rank among the leading causes of disability, and are expected to take over first place within the next few years. Indeed, the World Health Report 2001 cites depression as causing the largest amount of disability worldwide (disability adjusted life years-DALYs) and in 2004 Ustun et al. stated that depression was the fourth leading cause of disease burden but represents the largest amount of non-fatal burden globally (WHO, 2001, Ustun et al., 2004). In addition, there is extensive epidemiological evidence to support the view that significant co-morbidity exists between many chronic medical and psychiatric diseases, especially mood disorders (Moussavi et al., 2007, Van Lieshout et al., 2008). The severity and prognosis of medical illness are substantially affected by the presence or absence of co-morbid depression. For example, depression is a significant risk factor for myocardial infarction (Rosengren et al., 2004) and its presence at the time of infarction predicts a greater than threefold increase in likely death from cardiac causes within 5 years (Lesperance et al., 2002). Individuals with depression also have higher rates of obesity, hypertension, dyslipidemia, metabolic syndrome and diabetes than the general population (Chengappa et al., 2004, Heiskanen et al., 2006).
Therefore, a better understanding of the biology of mood disorders is critically important not only to provide more effective treatment to patients with these conditions but also to those with chronic co-morbid medical illnesses.
Recent dramatic scientific advances in molecular biology and their application to the study of the human genome have produced much evidence to support the genetic basis of a number of chronic diseases. However, the results are fraught with difficulty of interpretation as well as the knowledge that most of these diseases are polygenic in origin. Indeed the solution to some of the conundra of causation of chronic diseases may lie in greater understanding of the consequences of gene-environment interactions (Cooper, 2003). As a result, the field of epigenetics is expanding explosively and is being applied to psychiatric disorders (Mill and Petronis, 2007, Tsankova et al., 2007).
We believe that one of the most significant areas that need to be investigated in terms of potential environmental factors contributing to both mood disorders and chronic diseases is the external milieu of microbes found in the intestine. In this review we highlight the evidence that is coming together to support the contention that the gut microbiome may be playing a role in neuronal development and plasticity, modulating pain perception and even behavior. This fertile area for exploratory research may shed some light on the causes of, and eventually offer novel therapeutic approaches to, mood disorders and the medical disorders that are often co-morbidly associated with them. (Fig. 1).
Section snippets
The gut microbiome
The human gut is sterile at birth. Immediately after birth, it is colonized by numerous types of microorganisms. In the first weeks of life, tremendous temporal and inter-individual variation is evident in the infant’s microbial populations (microbiome). By 1 year of age, while babies retain their unique bacterial profiles, these converge toward a profile characteristic of the adult individual gastrointestinal tract (Palmer et al., 2007). While significant changes may occur in things such as
Immune system and cytokines
The development of the intestinal immune system is largely dependent upon exposure to microorganisms (Umesaki et al., 1995). In germ free (GF) animals which have scanty lymphoid tissue and constitutively and are almost devoid of immune activity (Talham et al., 1999), association with certain individual selected microorganisms has been shown to be effective in generation of the complete repertoire of immune function. For example, colonization with the segmented filamentous bacterium was able to
Role of gut microbiota in host metabolism
It is widely recognized that gut microbes are responsible for an enormous array of metabolic activities that include effects on the digestion of food and the production of a host of biologically active substances. Recent data suggest that gut microbiota also affect host metabolism, have an impact on energy storage and may therefore be an important environmental factor in the development of obesity and type 2 diabetes (Turnbaugh et al., 2006). These observations are relevant to the
Microbiota and the nervous system
While the role of gut microbiota in influencing brain and nerve function may not be strikingly obvious at first glance, recent research in several different disciplinary fields suggests that intestinal microbiota may be intimately and constitutively involved in modulation of both central and peripheral nerve function. A good example of this influence can be found in clinical medicine in hepatic failure. Hepatic encephalopathyis a commonly encountered medical condition consequent to hepatic
Possible pathways involved in this signaling
The exact mechanisms whereby gut bacteria-induced local changes in gut epithelium and the enteric nervous system communicate with the brain and possibly alter its function and activity, remain to be elucidated. The underlying pathways are highly complex, and it is unlikely that only one common pathway or series of molecules is involved. Two possible pathways we feel may be implicated, however, are reviewed below.
Microbe cell wall constituents
Many different microorganisms may have constitutive and modulatory effects on neuronal function. Commensal microbiota are also being widely consumed by the general public in the form of probiotics. Ingestion of Saccharomyces boulardii, one of these probiotic organisms, has been shown to alter the distribution of the regulatory calcium binding molecule calbindin in the enteric nervous system of conventional pigs (Kamm et al., 2004). The question thus arises as to any common mechanisms of action
Conclusions and perspectives
It is rapidly becoming apparent that the gut microbiome plays a major role in the development and regulation of metabolic systems such as those governing energy production and fat metabolism, neuroendocrine systems such as the HPA axis and the development and function of the immune system. Moreover, evidence is beginning now to accumulate suggesting that intestinal commensals may also be involved in neural development both peripherally in the enteric nervous system and centrally in the brain,
Acknowledgment
We gratefully acknowledge the contribution of the Giovanni and Concetta Guglietti Foundation to some of the research conducted at the Brain-Body Institute.
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