Siobhain M. O’Mahony

The microbiome‐gut‐brain axis: from bowel to behavior

The ability of gut microbiota to communicate with the brain and thus modulate behavior is emerging as an exciting concept in health and disease. The enteric microbiota interacts with the host to form essential relationships that govern homeostasis. Despite the unique enteric bacterial fingerprint of each individual, there appears to be a certain balance that confers health benefits. It is, therefore, reasonable to note that a decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease. Therefore, studies focusing on the impact of enteric microbiota on the host and in particular on the central nervous system are essential to our understanding of the influence of this system. Recent studies published in this Journal demonstrate that germ‐free mice display alterations in stress‐responsivity, central neurochemistry and behavior indicative of a reduction in anxiety in comparison to conventional mice. Such data offer the enticing proposition that specific modulation of the enteric microbiota may be a useful strategy for stress‐related disorders and for modulating the co‐morbid aspects of gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease.

Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.

The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.

Maternal separation as a model of brain–gut axis dysfunction

RationaleEarly life stress has been implicated in many psychiatric disorders ranging from depression to anxiety. Maternal separation in rodents is a well-studied model of early life stress. However, stress during this critical period also induces alterations in many systems throughout the body. Thus, a variety of other disorders that are associated with adverse early life events are often comorbid with psychiatric illnesses, suggesting a common underlying aetiology. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is thought to involve a dysfunctional interaction between the brain and the gut. Essential aspects of the brain–gut axis include spinal pathways, the hypothalamic pituitary adrenal axis, the immune system, as well as the enteric microbiota. Accumulating evidence suggest that stress, especially in early life, is a predisposing factor to IBS.ObjectiveThe objective of this review was to assess and compile the most relevant data on early life stress and alterations at all levels of the brain gut axis.ResultsIn this review, we describe the components of the brain–gut axis individually and how they are altered by maternal separation. The separated phenotype is characterised by alterations of the intestinal barrier function, altered balance in enteric microflora, exaggerated stress response and visceral hypersensitivity, which are all evident in IBS.ConclusionThus, maternally separated animals are an excellent model of brain–gut axis dysfunction for the study of disorders such as IBS and for the development of novel therapeutic interventions.

An isocratic high performance liquid chromatography method for the determination of GABA and glutamate in discrete regions of the rodent brain

The amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been implicated in mood disorders and high performance liquid chromatography (HPLC) is an important method in their quantitation. This paper describes a method which employs either electrochemical or fluorescent detection of the amino acid derivatives formed by a reaction with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide ions. Elution is based on an isocratic protocol and is achieved in 20 min or less. The method is reproducible, shows excellent linearity and generates derivatives which are stable for up to 16 h. Successful application of the method to a maternal deprivation study has identified the hippocampus and the brainstem as possible sites of long-term alteration in this paradigm.

Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle?

The prenatal and postnatal early-life periods are both dynamic and vulnerable windows for brain development. During these important neurodevelopmental phases, essential processes and structures are established. Exposure to adverse events that interfere with this critical sequence of events confers a high risk for the subsequent emergence of mental illness later in life. It is increasingly accepted that the gastrointestinal microbiota contributes substantially to shaping the development of the central nervous system. Conversely, several studies have shown that early-life events can also impact on this gut community. Due to the bidirectional communication between the gut and the brain, it is possible that aberrant situations affecting either organ in early life can impact on the other. Studies have now shown that deviations from the gold standard trajectory of gut microbiota establishment and development in early life can lead not only to disorders of the gastrointestinal tract but also complex metabolic and immune disorders. These are being extended to disorders of the central nervous system and understanding how the gut microbiome shapes brain and behavior during early life is an important new frontier in neuroscience.

Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities

Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.

Chain reactions: Early-life stress alters the metabolic profile of plasma polyunsaturated fatty acids in adulthood

The rat maternal separation paradigm can be used to examine the biological consequences of early-life stress. Immunomodulatory polyunsaturated fatty acids (PUFAs) have recently attracted attention in the study of stress-related disorders. We established the plasma PUFA profile of maternally separated rodents compared to controls. Our results identify a proinflammatory PUFA profile as a persistent consequence of early-life stress and suggest new avenues of investigation in stress-related disorders.

Differential activation of the prefrontal cortex and amygdala following psychological stress and colorectal distension in the maternally separated rat

Visceral hypersensitivity is a hallmark of many clinical conditions and remains an ongoing medical challenge. Although the central neural mechanisms that regulate visceral hypersensitivity are incompletely understood, it has been suggested that stress and anxiety often act as initiating or exacerbating factors. Dysfunctional corticolimbic structures have been implicated in disorders of visceral hypersensitivity such as irritable bowel syndrome (IBS). Moreover, the pattern of altered physiological responses to psychological and visceral stressors reported in IBS patients is also observed in the maternally separated (MS) rat model of IBS. However, the relative contribution of various divisions within the cortex to the altered stress responsivity of MS rats remains unknown. The aim of this study was to analyze the cellular activation pattern of the prefrontal cortex and amygdala in response to an acute psychological stressor (open field) and colorectal distension (CRD) using c-fos immunohistochemistry. Several corticoamygdalar structures were analyzed for the presence of c-fos-positive immunoreactivity including the prelimbic cortex, infralimbic cortex, the anterior cingulate cortex (both rostral and caudal) and the amygdala. Our data demonstrate distinct activation patterns within these corticoamygdalar regions including differential activation in basolateral versus central amygdala following exposure to CRD but not the open field stress. The identification of this neuronal activation pattern may provide further insight into the neurochemical pathways through which therapeutic strategies for IBS could be derived.

The microbiome and childhood diseases: Focus on brain‐gut axis

Many childhood diseases such as autism spectrum disorders, allergic disease, and obesity are on the increase. Although environmental factors are thought to play a role in this increase. The mechanisms at play are unclear but increasing evidence points to an interaction with the gastrointestinal microbiota as being potentially important. Recently this community of bacteria and perturbation of its colonization in early life has been linked to a number of diseases. Many factors are capable of influencing this colonization and ultimately leading to an altered gut microbiota which is known to affect key systems within the body. The impact of the microbial composition of our gastrointestinal tract on systems outside the gut is also becoming apparent. Here we highlight the factors that are capable of impacting on microbiota colonization in early-life and the developing systems that are affected and finally how this may be involved in the manifestation of childhood diseases.

The effects of gabapentin in two animal models of co-morbid anxiety and visceral hypersensitivity.

Visceral hypersensitivity and an increased response to stress are two of the main symptoms of irritable bowel syndrome. Thus efforts to develop animal models of irritable bowel syndrome have centred on both of these parameters. The anticonvulsant gabapentin, which is widely used as an analgesic agent, also reduces anxiety. No data exists to our knowledge of the effects of gabapentin in animal models of co-morbid exaggerated stress response and visceral pain. Our aim was to assess the effect of gabapentin on stress and visceral hypersensitivity in two different animal models of irritable bowel syndrome. The animal models employed were the genetically susceptible Wistar Kyoto rat and the neonatally stressed maternal separation model. These animals were subjected to the open field paradigm to assess stress-induced defecation rates and colorectal distension to assess the level of visceral sensitivity. Gabapentin (30 mg/kg) prevented the stress-induced increase in faecal pellet output in the maternally separated rat, but not the Wistar Kyoto animals. On the other hand gabapentin (30 mg/kg) reduced the number of pain behaviours in response to colorectal distension in both models. These results show that whilst both models have similar responses to gabapentin in terms of visceral pain they differ in terms of their physiological response to stress. This indicates that the origin of anxiety and perhaps then visceral hypersensitivity differs in these models. Overall, these data suggest that gabapentin may be a useful treatment in disorders of co-morbid pain and an overactive stress system such as irritable bowel syndrome.