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Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration

Abstract: There is a growing realisation that the gut–brain axis and its regulation by the microbiota may play a key role in the biological and physiological basis of neurodevelopmental, age‐related and neurodegenerative disorders. The routes of communication between the microbiota and brain are being unravelled and include the vagus nerve, gut hormone signalling, the immune system, tryptophan metabolism or by way of microbial metabolites such as short chain fatty acids. The importance of early life gut microbiota in shaping future health outcomes is also emerging. Disturbances of this composition by way of antibiotic exposure, lack of breastfeeding, infection, stress and the environmental influences coupled with the influence of host genetics can result in long‐term effects on physiology and behaviour, at least in animal models. It is also worth noting that mode of delivery at birth influences microbiota composition with those born by Caesarean section having a distinctly different microbiota in early life to those born per vaginum. At the other extreme of life, ageing is associated with a narrowing in microbial diversity and healthy ageing correlates with a diverse microbiome. Recently, the gut microbiota has been implicated in a variety of conditions including depression, autism, schizophrenia and Parkinson's disease. There is still considerable debate as to whether or not the gut microbiota changes are core to the pathophysiology of such conditions or are merely epiphenomenal. It is plausible that such neuropsychiatric disorders might be treated in the future by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics. [...] In terms of genes we have over 100 times as many genes in our microbiome as we have in our genome. The total weight of these gut microbes is 1–2 kg, which is similar to the weight of the human brain (Stilling et al. 2014). Mammals have never existed without microbes, except in laboratory situations. The reality is that we have co‐evolved, and we are fundamentally dependent upon our colonisers for survival, as of course are they on us (Bordenstein & Theis, 2015). [...]


Development

Indeed, C. section results in an altered microbial composition in the neonate resembling that of the mother's skin [...] Moreover, this signature has been shown to persist into adulthood with a distinctly different faecal microbiota composition being detected in those individuals who have been born by C. section [...] Significant differences in microbiota composition have been described between preterm and normal‐term neonates [...] It is worth noting that there is a growing appreciation of the connection between microbial composition and the nutritional needs of the infant host (Voreades et al. 2014). Indeed exclusively breastfed infants display an increase in the relative composition of Bifidobacterium species that have evolved specifically to utilise human milk oligosaccharides [... **Indeed, an increase in the relative composition of strict anaerobes as a function of diet and environment occurs early in life, and a complex adult‐like microbiome emerges by the age of 1 year old. ** [...] Taken together it is clear that infancy is a critical period for both microbiota colonisation and neurodevelopment. [...] Major shifts in diet in adults likewise show dramatic changes in microbiota composition (David et al. 2014). It is clear from studies of remote hunter‐gatherer tribes that Western guts have undergone a significant reduction in bacterial diversity and globalisation is driving this trend forward [...] **Recent data using germ‐free animals have shown that neurogenesis is also regulated by the microbiome. ** [...] Intriguingly antibiotic administration, which depletes the microbiota, to adult animals actually decreases neurogenesis. Moreover, this effect was reversed by exercise or administration of a probiotic cocktail (Mohle et al. 2016).


Autism

[...] Although genetics is key in autism pathogenesis there is a very strong gene–environment interaction at play with over 50% of the neurobiology driven by non‐heritable factors (Chen et al. 2015). Moreover, up to 70% of patients with the syndrome co‐present with gastrointestinal symptoms and hence the view that a disruption of the gut–brain axis is involved [...] Another facet contributing to social deficits in this condition is a lack of social recognition, a symptom which can be modelled in animals. Our group examined the behaviour of germ‐free mice in the three‐chamber test, a well‐validated assay to assess social behaviour (Moy et al. 2004), where a germ‐free mouse was placed in the centre chamber with a familiar mouse in one chamber and a novel mouse in the other chamber (Desbonnet et al. 2014). Interestingly, germ‐free mice spent as much time with the familiar as with the novel mouse; this is in contrast to the behaviour of conventionally colonised mice who spend more time with the novel than the familiar mouse. Germ‐free mice are more likely to spend time with an object or an empty chamber than with another mouse, a decidedly abnormal behaviour for a sociable animal. Colonisation of the germ‐free mice does partially normalise their behavioural patterns especially in the context of sociability deficits and increased repetitive behaviours – hallmark traits of autism; however, social cognitive deficits remained despite colonisation (Desbonnet et al. 2014). These behavioural changes are also associated with significant alterations in underlying neurochemistry and gene expression (Stilling et al. 2015; Hoban et al. 2016). These findings of social deficits in germ‐free mice have recently been replicated (Buffington et al. 2016) but opposite findings have also been reported (Arentsen et al. 2015). [...] Dietary administration of the human commensal Bacteroides fragilis, given three times during adolescence, was sufficient to correct gut permeability as well as stereotyped and other abnormal behaviours. [...] intriguingly, a recent study demonstrated that a probiotic bacterium (Lactobacillus reutri) can influence hypothalamic posterior pituitary activity and increase oxytocin levels raising the possibility of influencing social behaviour by targeting the gut microbiota (Erdman & Poutahidis, 2014). Moreover, a recent study found that in a mouse model of maternal obesity (a risk factor for autism in humans) there were alterations in social behaviour, oxytocin cell numbers, synaptic plasticity and microbiota composition. Remarkably, Lactobacillus reuteri could reverse these changes (Buffington et al. 2016).

Schizophrenia

[...] Reviewing the clinical literature we have argued (Dinan et al. 2014) strongly that genomic studies in schizophrenia should include a study of microbial DNA. In support of this a recent investigation has found that antibiotic therapy that alters the gut microbiota can be used to potentiate the action of antipsychotics in patients with schizophrenia (Khodaie‐Ardakani et al. 2014).

Aging

[...] It is clear that neuroinflammatory processes play a key role in ageing, with a growing emphasis on the role of the brain's resident immune cells, the microglia (Jyothi et al. 2015). More recently, it has been shown that microglia activation is under constant regulation by the gut microbiome (Erny et al. 2015). These provocative findings suggest that it is possible to manipulate neuroimmune responses by targeting the gut microbiome. In particular, bacterial metabolites, especially short chain fatty acids, are crucial to these effects. [...] Another consequence of ageing and age‐related disorders such as Alzheimer's disease is the progressive leakiness of the blood–brain barrier (BBB). In a very provocative finding Braniste and colleagues have shown, using a variety of techniques, that the integrity of the BBB is dependent on appropriate microbiota composition in the gut (Braniste et al. 2014). Once again short chain fatty acids are key metabolites in mediating such effects.

Parkinson's

[...] The risk of developing Parkinson's disease was significantly decreased in patients who underwent a full truncal vagotomy compared to those who underwent a selective vagotomy. The latter had a risk similar to that of the general population. These data offer the suggestion that the vagus nerve may be critically involved in the pathogenesis of the disorder. This is particularly important given the key role of the vagus nerve in mediating microbiome‐to‐brain signalling (Bravo et al. 2011). In the first study of its kind the gut microbiota has recently been sequenced in patients with Parkinson's disease (Scheperjans et al. 2015). The microbiota of 72 patients and 72 matched controls were pyrosequenced. There was a major reduction in the levels of Prevotellaceae in the patients. There was a positive association between the levels of Enterobacteriaceae and the severity of postural instability and gait difficulty. The authors point out that their study does not address either the temporal or causal relationship between the gut microbiota and the core features of the disease. Another analysis of microbiota composition in Parkinson's disease (PD) pointed to a reduction in butyrate‐producing bacteria (Blautia, Coprococcus and Roseburia) in faeces and Faecalibacterium in the mucosa. This was coincident with an increase in Ralstonia in mucosal samples more abundant in mucosa of PD than controls (Keshavarzian et al. 2015).

Other reading

FDA Updates on FMT Donor Screening Recommendations https://www.raps.org/news-and-articles/news-articles/2019/6/fda-updates-on-fmt-donor-screening-recommendations

FDA also provided a list of the MDROs that donor stool should be tested for, which at a minimum should include ESBL-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA).

A review of antibiotics, depression, and the gut microbiome https://sci-hub.se/10.1016/j.psychres.2019.112691

Highlights • Disruptions to the intestinal flora play an important role in the pathogenesis of depression. • Antibiotics induce these disruptions and increase the risk of depression. • Antibiotics are associated with changes in gut microbiota diversity. • Associated dysfunctions in the brain–gut axis lead to a series of abnormalities.

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