Persistent gastrointestinal symptoms demand a look at the brain-gut axis
Assuming that gross pathologies, infections and dietary imprudence have been ruled out, persistent gastrointestinal symptoms require an assessment of the brain-gut axis. More than ever before, research is revealing the profound degree to which gastrointestinal function and even tissue integrity depend on brain output. A spate of earlier reports emphasized the abnormal brain response to sensory signals received from the gut, as in a paper published in Gastroenterology Clinics of North America. The author states:
"Functional neuroimaging studies have demonstrated evidence of altered regional brain activation responses during visceral and somatic stimuli in IBS [irritable bowel syndrome]...Altered brain responses in IBS, particularly to visceral stimuli, include activation of regions concerned with attentional processes and response selection, corticolimbic regions concerned with emotional and autonomic responses to stimuli, and subcortical regions receiving cortical projections from the latter and afferent input from the soma [body] and viscera [organs]."
And remarkably...
"Altered activations of these regions also may be present [even] in the absence of a noxious visceral stimulus."
A further indication of the relevance of these observations is that...
"Changes in rCBF [regional cerebral blood flow, a metric for brain function] of some of these regions have been associated with treatment response in IBS."
As in so many other clinical conditions, loss of cortical inhibitory function—the brain's great task of calming or attenuating incoming signals—is suggested here:
"A plausible hypothesis for the observations from brain imaging studies is that IBS patients demonstrate a compromised activation of pain inhibition circuits including those of the cortico-pontine circuit but increased activation of limbic and paralimbic circuits that may be related to pain facilitation."
The authors of a study published in the American Journal of Gastroenterology come to a similar conclusion. Importantly, they also note an association with fibromyalgia:
"Symptoms of irritable bowel syndrome (IBS) and fibromyalgia (FM) commonly coexist. We hypothesized that one of the mechanisms underlying this comorbidity is increased activation of brain regions concerned with the processing and modulation of visceral and somatic afferent information, in particular subregions of the anterior cingulate cortex (ACC)."
With their data they were able to discriminate between IBS and IBS + fibromyalgia in the modulation of brain responses to stimuli:
""Whereas the somatic stimulus was less unpleasant than the visceral stimulus for IBS patients without FM, the somatic and visceral stimuli were equally unpleasant in the IBS + FM group...There was a greater rCBF increase in response to noxious visceral stimuli in IBS patients and to somatic stimuli in IBS + FM patients."
Thus the authors conclude that exaggerated brain responses to peripheral stimuli play a role in both IBS and FM. In this context 'cognitive enhancement' means inhibition failure:
"Chronic stimulus-specific enhancement of ACC responses to sensory stimuli in both syndromes may be associated with cognitive enhancement of either visceral (IBS) or somatic (IBS + FM) sensory input and may play a key pathophysiologic role in these chronic pain syndromes."
Brain control of the immune system in the gut and disturbances in neuroimmune regulation that persist long after an initial insult such as GI infection are discussed in a paper just published in Nature Reviews Gastroenterology & Hepatology. The authors state:
"IBS is one of the most common functional gastrointestinal disorders worldwide and is thought to be the result of disturbed neural function along the brain–gut axis...important roles for low-grade inflammation and immunological alterations in the development of symptoms compatible with IBS have become evident."
As in so many other varied conditions and chronic pain syndromes, disturbance of the regulatory loop between the brain and periphery becomes the cause of chronic symptoms even long after the initial insult has resolved:
"The development of long-standing gastrointestinal symptoms after infectious gastroenteritis and patients with IBD [inflammatory bowel disease] in remission frequently having functional gastrointestinal symptoms support this hypothesis."
Loss of the barrier function of the lining of the intestine that separates its contents from the surrounding immune tissue—abnormal intestinal permeability—is a key feature of brain-gut neuroimmune dysfunction.
"In addition, studies have demonstrated that IBS may be associated with an activated adaptive immune response. Increased epithelial barrier permeability and an abnormal gut flora might lead to increased activation of the intestinal immune system. Functional and anatomical evidence for abnormal neuroimmune interactions has been found in patients with IBS."
Clinicians and patients alike with experience of complaints associated with intestinal permeability appreciate how vexing a problem this can be to manage. A fascinating paper published in the Journal of Neurotrauma sheds light on the usually overlooked yet critical role of the brain in maintaining and repairing the gut lining. The authors state:
"Traumatic brain injury (TBI) can lead to several physiologic complications including gastrointestinal dysfunction. Specifically, TBI can induce an increase in intestinal permeability, which may lead to bacterial translocation, sepsis, and eventually multi-system organ failure."
They examined animals subject to TBI for expression of the zonulin [ZO-1] and occludin, proteins critical for integrity of the intestinal lining, to determine if they decreased following TBI. They also looked for a subsequent increase in intestinal permeability. What did their data show?
"TBI caused a significant increase in intestinal permeability compared to sham animals 6 h after injury. Expression of ZO-1 was decreased by 49% relative to sham animals, whereas expression of occludin was decreased by 73% relative to sham animals."
This has great clinical significance: brain output is critical for maintenance of the intestinal epithelium. The authors conclude:
"An increase in intestinal permeability corresponds with decreased expression of tight junction proteins ZO-1 and occludin following TBI. Expression of intestinal tight junction proteins may be an important factor in gastrointestinal dysfunction following brain injury."
A paper published in the Journal of Physiology and Pharmacology describes one effect of disturbance of the brain-gut axis as an increase in visceral sensitivity. The authors note:
"Chronic abdominal pain is the most distressing symptom in patients with functional digestive disorders (FDD)...a chronic visceral hyperalgesia, in the absence of detectable organic disease, is implicated...Several lines of evidence suggest a strong modulatory or etiologic role of the central nervous system in the pathophysiology of IBS...These findings were consistent with an IBS model that includes both the exaggerated activation of a vigilance network (dorsolateral PFC) and a failure in pain inhibition network anterior cingulate cortex (ACC)."
They report their findings on using fMRI (functional magnetic resonance imaging) to characterize the areas of the brain activated by rectal distension in healthy volunteers and compared them with the activation patterns in a population of IBS patients. In the latter...
"...we did not observe any neuronal activation in locations activated in healthy volunteers (ACC [anterior cingulate cortex], dorsolateral PFC) while a significant deactivation was observed in the IC [insular cortex] and in the amygdala, a limbic structure with a role to assign emotional significance to a current experience related to anxiety and fear. Brain imaging techniques thus appear as useful tools to characterize normal and abnormal brain processing of visceral pain in patients with FDD."
Another study published recently in the same journal reported on the brain's output for stimulating the production of pancreatic digestive enzymes:
"Brain is also implicated in the regulation of pancreatic exocrine function. Dorsal vagal complex of the brainstem (DVC) appears the center of long vago-vagal cholinergic entero-pancreatic reflex."
It is of great practical importance for clinicians to bear in mind that the immune system is part of the brain-gut axis, and that there is a bi-directional communication between the enteric nervous and immune systems in the gut and the brain. Naturally brain-gut regulation is also influenced by emotion and cognition. A review just published in the journal Brain, Behavior and Immunity offers an aerial perspective:
"The role of central nervous system mechanisms along the "brain-gut axis" is increasingly appreciated, owing to accumulating evidence from brain imaging studies that neural processing of visceral stimuli is altered in IBS together with long-standing knowledge regarding the contribution of stress and negative emotions to symptom frequency and severity."
Regarding the role of the immune system:
"At the same time, there is also growing evidence suggesting that peripheral immune mechanisms and disturbed neuro-immune communication could play a role in the pathophysiology of visceral hyperalgesia."
The authors also assert that the higher level of "top-down" regulation must be considered:
"...recent advances in research on the pathophysiology of visceral hyperalgesia...support that in addition to lower pain thresholds displayed by a significant proportion of patients, the evaluation of pain appears to be altered...Disturbed "top-down" emotional and cognitive pain modulation in IBS is reflected by functional and possibly structural brain changes involving prefrontal as well as cingulate regions."
And, of course, it's a 'two-way street'—disturbed immune and neural signalling go the other way too:
"At the same time, there is growing evidence linking peripheral and mucosal immune changes and abdominal pain in IBS, supporting disturbed peripheral pain signalling. Findings in post-infectious IBS emphasize the interaction between centrally-mediated psychosocial risk factors and local inflammation in predicting long-term IBS symptoms."
The authors of a paper published in Gastroentérologie Clinique et Biologique also comment on this two-way channel:
"There is a bidirectional relation between the central nervous system and the digestive tract, i.e., the brain-gut axis. Numerous data argue for a dysfunction of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS). Visceral hypersensitivity is a marker of IBS as well as of an abnormality of the brain-gut axis. This visceral hypersensitivity is peripheral and/or central in origin and may be the consequence of digestive inflammation or an anomaly of the nociceptive [pain-sensing] message treatment at the spinal and/or supraspinal level."
Importantly, brain-gut axis dysregulation is also expressed through the autonomic (sympathetic and parasympathetic) nervous system...
"Disturbances of the autonomic nervous system are observed in IBS as a consequence of brain-gut axis dysfunction."
A study published in the journal Neurology offers additional evidence that the brain is a key component of chronic gastrointestinal and other chronic pain disorders . The authors recognize the link between this and fibromyalgia:
"Abnormal cortical pain responses in patients with fibromyalgia and conversion disorder raise the possibility of a neurobiologic basis underlying so-called “functional” chronic pain."
They used fMRI (functional MRI) to examine the brains of healthy subjects and those with IBS while stimulating with rectal distension. Their experiences with pain or urging were correlated with the fMRI data. There was a clear difference between the IBS and normal subjects:
"In IBS, abnormal responses associated with rectal-evoked sensations were identified in five brain regions. In primary sensory cortex, there were urge-related responses in the IBS but not control group. In the medial thalamus and hippocampus, there were pain-related responses in the IBS but not control group."
The authors concluded:
"Percept-related fMRI revealed abnormal urge- and pain-related forebrain activity during rectal distension in patients with irritable bowel syndrome (IBS)...abnormal brain responses in IBS may reflect the sensory symptoms of rectal pain and hypersensitivity, visceromotor dysfunction, and abnormal interoceptive processing."
The authors of another paper published in Gastroentérologie Clinique et Biologique came to similar conclusions regarding the interactions of the brain, immune system and higher functions. [For lay readers of this post: the enteric nervous system (the 'brain in the gut') is part of the autonomic nervous system that regulates all visceral functions including those in the gut].
"Hypersensitivity is due either to an afferent neurons dysfunction at the enteric nervous system level, either to an abnormal brain-gut axis processing of sensory or nociceptive inputs arising from the gut, at the spinal or supraspinal level. Disturbances of the autonomic nervous system occur in IBS as a consequence of this brain-gut axis dysfunction."
Moreover...
"Neurological abnormalities may be triggered by inflammation, mast cell [a type of immune cell] dysfunction or increased intestinal permeability while the neuro-immune consequences of stress (mainly chronic) play a major role..."
And of course...
"The role of emotions and mood disturbances cannot be omitted in the interpretation the central processing of digestive sensory inputs. Neurosciences, in particular brain imaging techniques, have contributed to this better understanding of irritable bowel syndrome pathophysiology."
A study published in The Journal of Neuroscience demonstrates how anticipation can affect brain regions that function to regulate sensory signals coming from the gut:
"Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention."
They too used brain fMRI to examine the differences in response to rectal distention between IBS patients and healthy controls. Their data showed marked differences in the ability to activate brain areas responsible for anticipatory calming and for inhibition of sensory signals coming from the intestines during distention:
"During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation...During subsequent distention, both groups showed activity increases...[relevant brain areas]...The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS."
The authors conclude that diminished inhibitory function may result in a heightened sensitivity to sensations from the gut:
"Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS."
A subsequent study published in the journal GUT, An International Journal of Gastroenterology and Hepatology specifically examines the effect of anxiety and depression on the central nervous system processing of visceral stimuli. The authors set out to...
"...address the role of anxiety and depression symptoms in altered pain processing in irritable bowel syndrome (IBS).
They too used fMRI to compare patients with IBS to normal controls for the experience of pain or discomfort in correlation with brain activation. As before the data told an unambiguous story:
"Anxiety symptoms in IBS were significantly associated with pain-induced activation of the anterior midcingulate cortex and pregenual anterior cingulate cortex. Depression scores correlated with activation of the prefrontal cortex (PFC) and cerebellar areas within IBS. Group comparisons with the two-sample t test revealed significant activation in the IBS versus controls contrast in the anterior insular cortex and PFC."
This is certainly not earth-shaking news, but it does objectively show how anxiety and depression can affect brain function in such a way that visceral stimuli are permitted to bombard the senses abnormally:
"Altered central processing of visceral stimuli in IBS is at least in part mediated by symptoms of anxiety and depression, which may modulate the affective–motivational aspects of the pain response."
The authors of a review published in Psychopharmacology document how the stress of maternal separation can cause brain-gut axis dysfunction. Referring to early life stress they state...
"...stress during this critical period also induces alterations in many systems throughout the body...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."
Having reviewed the relevant data, they...
"...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..."
What are practitioners to make of all this when endeavoring to help someone with a chronic gastrointestinal complaint? Having investigated for gross pathologies, infections, and food allergies or intolerances, the science indicates that we must accept the role of the brain-gut axis in enteric immune function, maintaining the gut epithelium, and regulating digestive function and sensory phenomena. The brain-gut axis, like all sentient biological entities, is an emergent system. A quote from David Brooks writing in the New York Times offers a working definition:
"Emergent systems are ones in which many different elements interact. The pattern of interaction then produces a new element that is greater than the sum of the parts, which then exercises a top-down influence on the constituent elements...Emergent systems are bottom-up and top-down simultaneously. They have to be studied differently, as wholes and as nested networks of relationships."
Realistically, case management of brain-gut axis disorders requires attending to the multiple factors that influence brain function (a brief overview is available as the Parents' Guide To Brain Health; it pertains equally to adults). Bottom-up and top-down simultaneously in this case implies that the physiological capacity of the brain to inhibit and stimulate appropriately, and cognition/emotion, are given equal treatment with the condition of the gut microbial ecology and factors that may 
promote a local inflammatory response. A full treatment of this topic is at least a weighty volume, but there are some recent reports of practical clinical significance on centrally acting therapies for the brain-gut axis worth mentioning in this context. The authors of a paper published in Gastroenterology Clinics of North America state:
"Irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders typically defy traditional diagnostic methods based on structural abnormalities, and has led to the emergence of the discipline of neurogastroenterology or the study of the "brain-gut axis," which is based on dysregulation of neuroenteric pathways as a key pathophysiological feature of IBS. Centrally acting treatments can influence these pathways and improve the clinical manifestations of pain and bowel dysfunction associated with this disorder. To successfully implement these treatment strategies, it is important to recognize their dual effects on brain and gut...
In this respect we can appreciate the key role of the autonomic nervous system since there are practical ways to objectively evaluate ANS function in an office-based practice (heart rate variability analysis) and non-invasive therapies that modulate the brain and ANS through sensory-based peripheral modalities (all kinds of peripheral stimuli applied to elicit a corrective central response). The author of a paper published recently in La revue de médecine interne notes:
"Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system...has also anti-inflammatory properties both through the hypothalamic pituitary adrenal axis (through its afferents) and the cholinergic anti-inflammatory pathway (through its efferents). The sympathetic nervous system has a classical antagonist effect on the parasympathetic nervous system at the origin of an equilibrated sympathovagal balance in normal conditions."
This invites another look at an earlier post documenting the anti-inflammatory role of the parasympathetic nervous system and the use of heart rate variability analysis to objectively evaluate its function. The ANS is the neural communicating channel between the brain and the gut, offering therapeutic access to both...
"The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex (insula, prefrontal, cingulate) and in return to modify the autonomic nervous system and the hypothalamic pituitary adrenal axis in the frame of physiological loops. A dysfunction of these brain-gut interactions, favoured by stress, is most likely involved in the pathophysiology of digestive diseases such as irritable bowel syndrome or even inflammatory bowel diseases. A better knowledge of these brain-gut interactions has therapeutic implications in the domain of pharmacology, neurophysiology, behavioural and cognitive management."
This gives us background to appreciate a fascinating study published recently in The Journal of Trauma—Injury Infection & Critical Care offering evidence that ANS, specifically vagal, stimulation can prevent the loss of intestinal barrier function associated with traumatic brain injury. The authors state:
"Traumatic brain injury (TBI) causes gastrointestinal dysfunction and increased intestinal permeability. Regulation of the gut barrier may involve the central nervous system. We hypothesize that vagal nerve stimulation prevents an increase in intestinal permeability after TBI."
They subjected their study animals to TBI after a selected cohort had undergone electrical stimulation of the cervical vagus nerve. They subsequently measured intestinal permeability, tumor necrosis factor-α (an inflammatory cytokine) and, very interestingly, glial fibrillary acidic protein (GFAP) which is a marker of enteric glial activity. What did they find?
"TBI increased intestinal permeability compared with sham...Vagal stimulation prevented TBI-induced intestinal permeability. TBI animals had an increase in intestinal tumor necrosis factor-α 6 hours after injury compared with vagal stimulation + TB...intestinal GFAP was 18.0-fold higher at 4 hours compared with sham and 1.6-fold higher than TBI alone."
This has profound and practical clinical implications:
"In a mouse model of TBI, vagal stimulation prevented TBI-induced intestinal permeability. Furthermore, vagal stimulation increased enteric glial activity and may represent the pathway for central nervous system regulation of intestinal permeability."
A paper published last summer in the Journal of Neurogastroenterology and Motility offers one example of a sensory-based peripheral modality that has a therapeutic effect on these central processes, in this case electroacupuncture.
"We evaluated the effect of acupuncture in treating visceral hyperalgesia in an animal model."
The authors applied either electroacupuncture (EA) or sham acupuncture at acupoint ST-36 to rats with prior neonatal maternal separation stress. The day after the acupuncture treatment they were subject to colorectal distension, comparing them for pain threshold and visceromotor response. They also measured serotonin and Fos expression by immunohistochemistry in the colon, brainstem and spinal cord.
"Rats in EA group had significantly higher pain threshold compared to those in sham acupuncture group...They also had lower visceromotor response as measured by electromyogram compared to those received sham acupuncture at all colorectal distension pressures."
Electroacupuncture is one of a number of ways to simulate the brain through sensory pathways. In this study the authors concluded:
"Electro acupuncture attenuates visceral hyperlagesia through down-regulation of central serotonergic activities in the brain-gut axis."
My heart goes out to these study animals, but we can accept the further evidence presented in another paper published recently in The Journal of Trauma—Injury Infection & Critical Care. In this study the authors demonstrated repair of the gut barrier through vagal stimulation after abnormal intestinal permeability induced by burn trauma:
"Severe injury can cause intestinal permeability through decreased expression of tight junction proteins, resulting in systemic inflammation. Activation of the parasympathetic nervous system after shock through vagal nerve stimulation is known to have potent anti-inflammatory effects...We postulated that vagal nerve stimulation improves intestinal barrier integrity after severe burn through an efferent signaling pathway, and is associated with improved expression and localization of the intestinal tight junction protein occludin."
The authors subjected their animals to burn injury after vagal nerve stimulation for 10 minutes. A separate underwent abdominal vagotomy before vagal nerve stimulation and burn. Intestinal barrier injury, histology, and changes in occludin expression were then assessed. The results were striking...
"Cervical vagal nerve stimulation decreased burn-induced intestinal permeability to FITC-dextran, returning intestinal permeability to sham levels. Vagal nerve stimulation before burn also improved gut histology and prevented burn-induced changes in occludin protein expression and localization. Abdominal vagotomy abrogated the protective effects of cervical vagal nerve stimulation before burn, resulting in gut permeability, histology, and occludin protein expression similar to burn alone."
Improving parasympathetic function in general and vagal function in particular is of paramount importance in the management of most chronic disorders. The authors conclude:
"Vagal nerve stimulation performed before injury improves intestinal barrier integrity after severe burn through an efferent signaling pathway and is associated with improved tight junction protein expression."
Actual case management of brain-gut axis disorders merits an entire textbook, but this can be borne in mind: diet, supplements, medicines, etc. are not enough—good gut function requires good brain output and autonomic regulation. Clinicians actively treating these conditions who are interested in how we apply functional testing for GI inflammation, infection, gut permeability, allergy, ANS function, the brain and brain-gut axis, etc.; and the various therapies brought to bear on the findings; are welcome to contact Lapis Light for collegial conversation.