Speakers: Emeran Mayer (USA), Premysl Bercik (Canada)
Prof. Mayer gave an introductory overview of the different aspects of the topic, stressing that the tight interplay between brain, gut and gut microbiota is based on a highly complex network of bidirectional pathways, which run top down (from brain to gut) as well as bottom up (from gut to brain). Prof. Mayer pointed out that the role of the brain in functional bowel disorders has been accepted for quite a long time, while it is only recently that the gastrointestinal (GI) community is beginning to acknowledge that the brain also plays a role in other GI diseases.
However, it remains to be clarified what this role exactly comprises. While it can be demonstrated through neural imaging techniques that a number of GI diseases are accompanied by a remodelling of the brain network, the extent to which the brain plays a causal role or is only a bystander is still unclear. The same goes for the connections between gut microbial processes and brain-related processes, in particular psychiatric diseases such as autism and depression.
Prof. Mayer explained that the signalling from the nervous system to the gut microbiota can be performed either by intermediaries – the brain activates cells that release intermediating substances – or by direct interaction. Intestinal fluid, for example, is stimulated by influences of the brain; gastric and biliary secretions, as well as intestinal pH, are regulated by the autonomous nervous system. All these are examples of top-down influences, originating in the nervous system, which have an impact on the metabolism of the microbiota. The nervous system also plays an important role in modulating immune and bacterial functions in the gut, which includes direct effects on luminal bacterial behaviour. It is due to this interplay that probiotics can normalise or alter stress response, although the underlying mechanisms still remain unknown. Top-down mechanisms might also explain that probiotic placebos induce brain mechanisms that can exert an effect on the gut microbiota.
The bottom-up signalling – as opposed to the top-down direction – is made possible by the fact that the cells involved in the manifold pathways between gut, brain and gut microbiota can function not only as effector cells that are responding to input from the brain, but also as sensory cells that encode information from the gut level. Much of this information is constantly being encoded by sensory nerves of vagal and spinal afferents and carried through the vagus nerve and the spinal cord to centres within the brain stem, with projections all the way into forebrain structures and into limbic circuitry, which is involved in the generation and modulation of emotions. Thus, according to Prof. Mayer, the enteric nervous system can almost be viewed as an extension of the limbic system into the gut. Apart from that, the enteric nervous system is a highly complex information-processing network by itself, which encodes immune-, nutrient- and microbiota-related signals by a large number of subtypes of sensory and motor neurons, taking care of the basic digestive functions in a semi-autonomous fashion.
The complexity of the gut as a sensory organ is also based on its entero-endocrine system, whose cells – although they make up less than one per cent of total GI epithelial cells – combined form the largest endocrine organ within the human body. These cells contain 20 different hormones and signalling molecules, and they have different receptors that sense nutrients, bile salts, short-chain fatty acids, as well as bitter and sweet tastes, and thus are able to pick up signals of the luminal chemical milieu of the gut. Prof. Mayer found it remarkable that taste receptors are not only present in the oral cavity, but also in the GI tract (and in the respiratory system,) and that they are found on surfaces that contain a large part of the microbiota. The precise function of these receptors is unknown so far, but it is suggested that this is a mechanism for the gut microbiota to communicate with the endocrine cells.
Concluding his presentation, Prof. Mayer pointed out that a main task of ongoing research is to characterise which signalling molecules interact with which receptor types on which cell types to release which mediators from the gut lumen. In his opinion, the enteroendocrine cells are probably on top of this list, but immune cells are also likely to play a major role. Thus, much work is to be done in the upcoming years to unveil this hugely complex system.
In his talk, Prof. Bercik presented the audience with a number of mice trials, dealing with the interplay between the gut microbiota, the nervous system, and anxiety- or depression-related behaviour. He described two of the standard experimental set-ups that are being used to determine which kind of behaviour the animals display. One is the light-dark preference test, which is based on the conflict between the innate aversion of rodents to brightly illuminated areas combined with their preference of a darker sheltered room on the one hand and – on the other hand – on the wish to explore the well lit, but less sheltered environment. The first behavioural pattern is suggestive of anxiety-like behaviour, and the second one of a more active and exploratory behaviour. The same principle applies to the step-down test, where the mouse is placed on an elevated platform, while it is measured how quickly it steps down and starts exploring the environment.
The first issue Prof. Bercik dealt with were possible connections between inflammatory bowel diseases and behavioural changes. He referred to trials that showed that mice with acute GI infection, through inoculation with C. jejuni, spent more time in the dark than normal controls. The corresponding neuronal activation could be detected within hours after inoculation, which indicates that the neuronal system is probably able to detect pathogens within the lumen before the immune system is activated. Probably, vagal afferent pathways play a major role as a link between these areas. Prof. Bercik then reported on mice that were infected for months with chronic H. pylori infection showing abnormal mechanical sensitivity within the gut and a significant up-regulation of sensory nerves containing substance P-immunoreactive (IR) cells, which reached the spinal cord. The up-regulation of these sensory neuron transmitters remained to a certain degree even until two months after eradication.
Another trial, performed by Prof. Bercik and colleagues, showed that chronic GI infection can also alter feeding patterns. Mice infected with H. pylori mice ate more frequently than controls, but smaller amounts of food. This pattern was not reversed until at least two months after H. pylori had been eradicated. The same mice showed abnormal expression of certain regulatory peptides, which are involved in food intake, an outcome that is very similar to what can be observed in patients with functional dyspepsia. Looking into the median eminence – a brain region belonging to the circumventricular organs, where the blood-brain barrier is more permeable, thus allowing antigens and immune mediators to access the brain – the researchers observed a significant up-regulation of proinflammatory cytokine TNF-a as compared to healthy mice. Generally speaking, such regions appear to be pathways through which the gut relays information about pathogens to the brain through nerves or humoral factors.
Other trials Prof. Bercik referred to showed, as an effect of bowel inflammation, an increased production of kynurenine, which has neuroregulatory properties and leads to depression-like behaviour. Reversely, anti-TNF-a treatment normalised inflammation and behaviour. It could also be shown that the probiotic B. longum normalised mouse behaviour as well as corresponding levels of BDNF (brain-derived neurotrophic factor) in the hippocampus, although it did not improve the colitis.
Further trials aimed at unveiling the intricate links between the brain and the gut microbiota. Prof. Bercik presented a number of examples that showed how an induced disturbance of the gut microbiota composition, often combined with inflammation, corresponds to a change from normal to depression- or anxiety-related behaviour. On the other hand, normalisation of the microbiota went together with normalisation of behaviour – a process that was mirrored by the changing levels of various neurotransmitters in mood-related brain regions. Prof. Bercik hypothesised that bacterial metabolites play a causal role in these processes, while in some trials it could be proven that the vagus nerve – which in many cases is an important gut-brain path – was not involved.
Prof. Bercik then went on to describe the effects probiotics can have on GI disease-related abnormal behaviour. It could be shown that L. farciminis reduces neuronal activation in spinal sites that is induced by stress combined with colorectal distension. Another beneficial probiotic is the already- referred-to B. longum, which dissolved anxiety-related behaviour in mice with chronic low-grade colitis. These effects are mediated by the vagus nerve, as confirmed by comparisons with vagotomised mice. Another trial showed that B. longum supernatant reduced excitability of enteric neurons, so there might be some direct interaction with the sensory neurons within the gut, which might relay to the vagus nerve. Another probiotic that induced behavioural changes in mice is L. rhamnosus: the animals showed a more active behaviour after having been treated with this probiotic, accompanied by changes in the GABA (gamma-aminobutyric acid) receptors activity of the hippocampus.
Summing up, Prof. Bercik stressed the bidirectional character of the paths connecting gut, brain and the gut microbiota. According to him, part of the signalling from the gut through the vagus nerve reflects mainly the upper part of the GI tract, while in the case of the colonic microbiota some signalling is being performed through the spinal nerves. Concerning the clinical implications of the abundance of animal data, Prof. Bercik pointed out that there are not much data so far on connections between the gut microbiota and anxiety or depression in humans. However, there are multiple reports of antibiotic-induced psychosis in patients and a shift back to normal after stopping the antibiotic treatment. This indicates the clinical relevance of the findings provided by animal trials.
Written by Wolfgang Krischke, impressum health & science communication
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