The brain–gut axis More than a GUTFEELING

It is common human experience that stress or anxiety may modulate gastrointestinal (GI) tract function culminating in symptoms such as diarrhea, nausea, and discomfort. Indeed, the influence that anxiety may exert on the GI tract is often reflected in common phrases such as “butterflies in my stomach” and “gut wrenching.” It was not until the beginning of the 19th century that such observations began to be objectively examined. An early pioneer of GI physiology was the American physician William Beaumont (1785–1853) who linked emotion to GI tract function. In 1833, he published a classic monograph concerning his patient Alexis St Martin, a man who had sustained an abdominal gunshot wound leaving him with a permanent gastrocutaneous fistula. Beaumont recorded in excess of 200 observations of Alexis St Martin over an 8-year period. Beaumont commented that: . . .In febrile diathesis, or predisposition from whatever cause . . .fear, anger or whatever disturbs the nervous system. . .the villous coat becomes sometimes red and dry, and at other times pale and moist, and looses its smooth and healthy appearance.

the most unequivocal evidence of the brain’s influence on human GI function derives from reports of alterations of this function caused by lesions within the central nervous system (CNS). The most frequently encountered clinical example is dysphagia following a cerebrovascular accident

A further example is gastric emptying delay occurring as a sequelae of spinal cord transection or constipation related to Parkinson disease

increased understanding has led to the development of the concept of the brain–gut axis, a bidirectional communication between the gut and the brain, which has gained widespread acceptance as the construct providing an explanation of normal function, and acute and chronic perturbations, of GI function.

Emotional motor system 

Stress, which can be defined as an acute threat to an organism’s homeostasis, may be interoceptive or exteroceptive. For example, interoceptive stress may be caused by infection or inflammation whereas exteroceptive stress usually refers to a real or perceived external threat. Both types of stressor activate a complex and elaborate neurobiological response that serves to ensure allostasis, the process of achieving homeostasis either through physiological or behavioral change, and ultimately ensure the organism’s survival. This neurobiological response is rapidly engaged and similarly rapidly disengaged, thereby limiting the organism’s exposure to the stressor. However, when the stressor is prolonged, it can lead to a maladaptive response culminating in chronic over- or underactivity of downstream physiological systems, which can result in, or indeed exacerbate pre-existing, pathological states. Furthermore, the duration and type of stressor in combination with genetic factors, early life events, concomitant pathology, and social support influence an individual’s outcome

Accumulating evidence from animal studies has also indicated that endogenous CRH plays a role in mediating stress-induced alteration of GI motor function

The primary neural substrate of the parasympathetic nervous system is the vagus nerve . Stress inhibits the parasympathetic nervous system to slow gastric emptying, increase distal colonic motility with an overall acceleration of intestinal transit. Moreover, the efferent vagus nerve is increasingly considered integral in the neuroendocrine–immune axis within the gut through what is termed the cholinergic antiinflammatory pathway. Centrally, this pathway has an antiinflammatory effect through distal vagal release of acetylcholine acting within the spleen on lymphocytes, and subsequently macrophages, and ultimately producing an anticytokine effect

In a key study, Pavlov et al. demonstrated that, in man, acetylcholine, released from the distal portion of vagal nerve efferents, dose dependently inhibited the production of proinflammatory cytokines, such as tumor necrosis factor-α, in macrophage

Brain hypothalamic–pituitary–adrenal gut axis 

Due to the classical way things developed in  investigating  the  various systems  of body we have compartmentalized the  various  organ systems  and  have  developed a compartmentalized thinking  but  it is time  for us to start thinking of the  whole human body as  a single entity with the various  interactions between the  various  biological systems in and  integrated  fashion to  glean new  insight in to the working and develop new methods to treat the various diseases in novel ways.

Glucocorticoids maintain a basal level of activity in order to “calibrate” the individual’s response to stress and promote coordination of the circadian rhythm. In response to stress, cortisol is released from the zona fasciculata of the adrenal gland in response to ACTH, whose action is mediated by two types of intracellular receptors: the glucocorticoid receptors and mineralocorticoid receptors. The latter is most concentrated in the hippocampus where it displays high-affinity binding of cortisol during the basal state when cortisol levels are at relatively low concentrations. In contrast, the hippocampus and other areas such as the amygdala have a relative paucity of glucocorticoid receptors, which bind with low affinity, and are activated during stress. In general terms, during basal conditions the mineralocorticoid receptor activation results in γ-amino-butyric acid mediated inhibition of the HPA axis while glucocorticoid activation during acute stress reduces hippocampal output and increases the activity of the HPA axis. Stress-induced activation of the HPA axis culminates in two opposing steroid actions at the level of the paraventricular nucleus.

Brain–gut microbiota axis 

The human microbiota is a diverse and dynamic ecosystem, which has evolved to form a symbiotic relationship with the host. The host is vertically inoculated from the mother during birth and the ecosystem becomes established during the first year of life and evolves over the course of the host’s life [59]. The microbiota helps safeguard the host from external pathogens, aids in the metabolism of polysaccharides and lipids, modulates intestinal motility, in addition to modulating visceral perception [60]. The human GI microbiota in the oral cavity contains approximately 102–3 colony-forming units of bacteria per gram of saliva. The density of the microbiota rises to 1010–12 colony-forming units per gram of feces in the colon comprising of between 400 and 1000 different species [61]. Bacteroides and Firmicutes are the two predominant bacterial phylotypes, with Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia phyla present in relatively low concentrations
the CNS can alter the GI microbiota composition directly or indirectly. Direct alterations are exerted by the intraluminal action of neurotransmitters, such as 5-HT (released by enterochromaffin cells), neurones, and immune cells located in the lamina propria. Enterochromaffin cells are particularly important in these interactions given their location on the luminal aspect of the mucosa; they can be readily accessed and stimulated by the GI microbiota. Enterochromaffin cells are also in close proximity to the afferent and efferent vagal nerve terminals in the lamina propria and are therefore well positioned to act as a bidirectional communication pathway influencing nociceptive and immune signaling

There is accumulating evidence that the microbiota can influence behavior via the CNS; the mechanisms by which communication occurs is incompletely understood. For example, emotional factors, such as stress or depression, influence the course of a number of GI disease states such as inflammatory bowel disease. Furthermore, stress can alter the integrity of the GI epithelium, modulates GI motility and can also induce the release of catecholamines and cortisol which impacts on intestinal immunity and cytokine production

Study of germ-free animals has facilitated the evaluation of the role of the microbiota in GI physiology. Germ-free animals maintained in a sterile environment permit comparison with conventionally reared animals to assess the influence of the microbiome at both neuronal and behavioral levels

at the neuronal level, germ-free animals had a relative paucity of brain-derived neurotrophic factor (BDNF), a critical neurotrophic protein involved in neuronal survival and growth and survival, and reduced expression of the N-methyl-D-aspartate receptor subunit 2A in the cortex and hippocampus compared with controls [69]. Interestingly, alterations of BDNF have been implicated in anxiety states although further work is needed to clarify the absolute contribution to behavioral change
( Is it possible that the  increased levels of depression and  anxiety in developed  germ free world  compared to the  happier people in  less developed  countries  a reflection of this ?

Brain–gut axis in the regulation of appetite and satiety 

 Eating habits are not solely governed by metabolic needs but also by psychosocial environment and epicurean factors. Particularly within Western societies, obesity and anorexia nervosa, the sequelae of excessive and pathologically limited eating behaviors respectively, are increasingly prevalent, the former is amongst the great public health burdens of the 21st century  While preclinical models have enhanced our basic understanding of the homoeostatic mechanisms of energy balance, translation into humans has been limited by the inability to investigate the influence of psychological influences on eating behavior. However, functional neuroimaging techniques are beginning to identify the brain areas that are activated in response to the ingestion of nutrient, and define the effects of anorexigenic and orexigenic gut peptides and factors that regulate satiety

Although a relationship between emotional state and feeding behavior exists, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood.

vagal-mediated activation of the hypothalamus and limbic brain regions following hepatic release of proinflammatory cytokines which may culminate in “sickness behavior” that includes, fever, depression, and withdrawal from usual activity . A diverse array of inflammatory mediators may be released by mucosal immune and glial cells within the brain–gut axis, resulting in the recruitment of hitherto silent nociceptors. These nociceptors sensitize ascending spinal pathways resulting in a reduction of thresholds to visceral pain.

chronic dysfunction within the brain–gut axis has been proposed in a number of chronic disease states characterized by abnormal GI function, this has been particularly relevant for the functional GI disorders (FGID)

 FGIDs are characterized by chronic GI symptoms including discomfort and pain emanating from the viscera without any demonstrable physical, biological or anatomical abnormalities

Psychological comorbidity such as depression, anxiety, and hypochondriasis is common in FGIDs and it has been estimated that over half of patients with IBS suffer from these disorders to one degree or another
accumulating knowledge gathered through a variety of approaches is making it increasingly clear that there is dynamic interaction between physiological and psychological factors that influence GI function and health. Alteration or disruption in these interactions appears to contribute to the pathogenesis and clinical manifestation of a multitude of disorders of the GI tract.