The Brain-Gut Axis, Part 3 – The Gut Microbiota In Diseaseby Sara Adaes, PhD | August 20, 2015
In Part 2 of the brain-gut axis article series, I explained how the brain and the gut microbiota communicate. I will now talk about how this interaction can impact our health and risk of disease, based on what research has already unveiled.
So far, most microbiota-brain research has been carried out in mice. Studies on germ-free animals have shown that an adequate bacterial colonization of the gut is crucial to the proper development and maturation of both the enteric nervous system (ENS) and central nervous system (CNS). The absence of gut microbes leads to altered production of neurotransmitters in both nervous systems and to changes in sensory and motor functions in the gut, but this can be counterbalanced by replenishing the microbiota.
An amazing study recently showed that the microbiota substantially contribute to the maturation and activation of microglia in the central nervous system. Microglial cells are the macrophages of the CNS, and are therefore decisively involved in its diseases. This effect seems to be mediated by bacterial fermentation products released by the microbiota. The study showed that germ-free mice displayed significant defects in microglia but recolonization with a complex microbiota was able to partially restore microglia features, showing that intervening in the microbiota can have therapeutic effects.
These effects on the development and maturation of the nervous system strongly indicate that the gut microbiota can have a high impact on health from the early stages of post-natal development. But these effects are likely to continue throughout life.
Studies in humans have linked a lack of diversity in the microbiota to obesity, inflammatory diseases, and cognitive decline in elderly populations. A study published in 2012 that followed 178 people, comparing their health status with their gut composition, showed that a less diverse microbiota was linked to increased frailty. That diversity appeared to be mediated by diet – a more diverse diet seemed to lead to a more diverse ecosystem in the gut. These findings suggest that specific dietary interventions may potentially help improve health both in the elderly and in younger people.
Mood disorders are common across a diverse range of gastrointestinal disorders, including celiac disease, non-celiac gluten sensitivity, lactose intolerance, and irritable bowel syndrome (IBS), already mentioned in Part 1 of this article series.
Data has shown that dysfunctions occur in both brain-to-gut and gut-to-brain communication. The disruption occurring in the brain-gut axis alters intestinal motility and secretion, causes hypersensitivity and leads to endocrine and immune alterations. The microbiota may play a key role, since studies have shown that IBS patients have altered microbiota composition and that the visceral hypersensitivity characteristic of IBS can be transferred via the microbiota of IBS patients to previously germ-free rats.
Stress is known to affect the gut – it’s common knowledge. Different types of psychological stressors modulate the composition and total content of the enteric microbiota. The direct influence is mediated by the secretion, under the regulation of brain, of signaling molecules by neurons, immune cells, neuroendocrine cells and enteroendocrine cells. Research with germ-free animals has shown that these have a much greater stress response than normal bacteria-filled animals. When specific bacteria were supplied to those animals, stress responses were reduced. So this is a pathway that also seems to work both ways.
Scientists have also gathered evidence that gut bacteria can influence anxiety and depression. Strains of two bacteria, lactobacillus and bifidobacterium, also present in humans, reduce anxiety-like behavior in mice. In one study, gut bacteria were collected from a strain of mice prone to anxious behavior, and then transplanted into another strain tending to be calm. As a result, the calm animals became anxious.
Both of these microbes seem to be major players in the gut-brain axis. Experiments in which the effect of the administration of lactobacillus or bifidobacterium was compared with the effect of an antidepressant on the reaction to stressful situations, both the microbes and the drug were effective in reducing levels of hormones linked to stress. When gut bacteria was transferred from anxious humans into germ-free mice, these animals started to behave more anxiously.
This may be associated with the ability of the microbiota to modulate the production of serotonin, dopamine and GABA. These neurotransmitters are key modulators of mood and emotion and their altered levels can therefore lead to the development of anxiety or depression.
Studies conducted on germ-free animals have also demonstrated that the microbiota influences memory consolidation.
Memory dysfunction has been reported in germ-free animals and it has been linked to an altered expression of brain-derived neurotrophic factor (BDNF), one of the most important factors involved in memory. This molecule is mainly located in the hippocampus and cerebral cortex, regulating many aspects of neuronal activity and cognitive functions.
Autism also seems to have a strong connection to the gut. Around 75% of people with autism also have some gastrointestinal disorder – digestive difficulties, food allergies, or gluten sensitivity are among the most common ones. Several recent studies have shown that the microbiota of autistic patients is significantly altered.
One such difference is found, for example, in a common bacterial species called Bacteroides fragilis. This species is found in smaller quantities in some children with autism and it has been observed that administration of B. fragilis from humans to mice with symptoms similar to autism improved their behavior by making them less anxious, showing less repetitive behavior, and being more communicative with other mice.
This suggests a possible benefit of probiotic treatment on several of the autism-associated behaviors.
Eating disorders, including anorexia nervosa, bulimia and binge-eating disorder, have also been linked to the brain-gut-microbiota axis.
A study has identified a protein called ClpB, produced by the gut bacteria Escherichia coli, as a mimetic of the hormone alfa-melanocyte-stimulating hormone (alfa-MSH), known to be involved in the regulation of feeding and emotion. It was shown that the administration of that protein to mice could influence food intake, body weight and anxiety. Importantly, the study showed that plasma levels of the antibody against ClpB were increased in human patients with anorexia, bulimia and binge-eating disorder, suggesting that gut microbes may be involved in the etiology of eating disorders.
Fibromyalgia syndrome is characterized by chronic generalized pain, chronic fatigue, sleep disturbances, headaches and cognitive dysfunction. A significant percentage of patients with fibromyalgia also experience gastrointestinal symptoms, namely IBS. This gastrointestinal component of fibromyalgia is quite a relevant element of the overall pathology.
One of the potential explanations for this pattern of alterations in the brain-gut axis is the occurrence of small intestinal bacterial overgrowth or enteric infections such as giardiasis.
Exactly how microbes manage health and illness and whether they trigger disease or protect us from it (or both) remains mostly unknown. In the next years we will probably witness a flood of new information on this topic. It is likely that adjusting gut bacteria may become a treatment option for many diseases. They may even become the new Valium.
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