Ubiquitous Microbiome: impact on health, sport performance and disease

Microbiome Mitochondria Feedback

The gut microbiome plays a key role in regulating the optimal degree of response to exercise required to stimulate desired adaptive changes.

We have at least as many bacterial cells as human cells in our bodies. We are all familiar with the effects of disturbing the balance of beneficial microbes in our gut. Beyond this, the gut microbiome (the range of microbes, their genetic material and metabolites) is essential for health. An interactive feedback exists between gut microbiota and functional immunity, inflammation, metabolism and neurological function

Sports performance: endurance exercise increases metabolic, oxidative and inflammatory stress, signalled by the release of exerkines from exercising tissue. This signalling network induces adaptive responses mediated via the Endocrine system. Maladaptation to exercise can be due either to an undesirable over-response or an insufficient response.

Intricate interactive feedback links exist between mitochondria and the gut microbiota. In addition to being the power generators of all metabolically active cells, mitochondria produce reactive oxygen species (ROS) and reactive nitrogen species during high intensity exercise. These oxidative stress signals not only mediate adaptive responses to exercise during recovery, but influence gut microbiota by regulating intestinal barrier function and mucosal immune response. Mitochondrial genetic variation could influence mitochondrial function and thus gut microbiota composition and function. Equally, the gut microbiota and its metabolites, such as short chain fatty acids, impact mitochondrial biogenesis, energy production and regulate immune and inflammatory responses in the gut to mitochondrial derived oxidative species. So nutritional strategies to support favourable gut microbiota would potentially support the beneficial effects of the interactions described above to optimise sport performance in athletes.

Conversely, disruption to favourable diversity of the gut microbiota, dysbiosis, is associated with increase in both inflammation and oxidative stress. Not a good situation for either health or sport performance. Alteration to the integrity of the intestinal wall increasing permeability can also be a factor in disrupting the composition of the gut microbiota. The resultant increased antigen load due to bacterial translocation across the gut wall is linked to increased inflammation, oxidative stress and metabolic dysfunction. “Leaky gut” can occur in high level endurance exercise where splanchnic blood flow is diverted away from the gut to exercising tissues for long periods of time, resulting in relative hypo-perfusion and an effective re-perfusion injury on stopping exercise. In the longer term the increased levels of inflammation, oxidative stress and antigen load impair adaptation to exercise and are associated with endocrine dysfunction in chronic disease states, for example autoimmune conditions, metabolic syndrome (type 2 diabetes mellitus, obesity) and depression.

Evidence links the composition of the gut microbiota to changes in circulating metabolites and obesity. For example, low abundance of certain species of gut microbiota reduces levels of circulating amino acid glutamine, which acts as a neurotransmitter precursor. Bariatric surgery is associated with changes in the release of gut hormones regulating food intake behaviour and energy homeostasis. In addition, beneficial changes are seen in the gut microbiota which could directly or indirectly support weight loss, via action on gut hormones.

Metformin is frequency used to improve insulin sensitivity in both type 2 diabetes mellitus and polycystic ovary syndrome. However, the mechanism is poorly understood. There is now evidence that the effect of metformin is mediated via changes in gut microbiota diversity. Transfer of stool from those treated with metformin improves insulin sensitivity in mice. In addition metformin regulates genes in some gut microbiota species that encode metalloproteins or metal transporters, which are know to be effective ligands. The pathophysiology of metabolic syndrome and obesity involves an inflammatory component which is triggered by gut dysbiosis and bacterial translocation, with increased generation of oxidative species. Probiotics have a potential role in regulating the redox status of the host via their metal ion chelating ability and metabolite production, which has an impact on the production of ROS and associated signalling pathways. Prebiotics found in dietary polyphenols promote these actions of favourable gut microbiota, which is of benefit in metabolic syndrome.

Recently it has been postulated that the gut microbiome, apart from playing a crucial role in health and pathogenesis of disease states, also impacts brain development, maturation, function and cognitive processes.

Understanding the role of the gut microbiome on metabolism, inflammation and redox status is very relevant to athletes where an optimal response to exercise training supports adaptations to improve performance, whereas an over or under response in these pathways results in maladaptive responses.

For further discussion on Health, Hormones and Human Performance, come to the BASEM annual conference

References

Endocrine system: balance and interplay in response to exercise training Dr N. Keay

Inflammation: Why and How Much? Dr N.Keay, British Association of Sport and Exercise Medicine 2017

The Crosstalk between the Gut Microbiota and Mitochondria during Exercise Front Physiol. 2017

Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities Psychother Psychosom 2017

Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention Nature Medicine 2017

Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug Nature Medicine 2017

L’altération de la perméabilité intestinale : chaînon manquant entre dysbiose et inflammation au cours de l’obésité ? Med Sci (Paris)

Antioxidant Properties of Probiotic Bacteria  Nutrients 2017

The Impact of Gut Microbiota on Gender-Specific Differences in Immunity Front. Immunol 2017

Commentary: Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome Front. Immunol., 27 July 2017

Gut microbial communities modulating brain development and function Gut Microbes

 

 

Endocrine system: balance and interplay in response to exercise training

The process of homeostasis maintains a steady internal milieu. So how is it possible for adaptations to occur? What are the internal mechanisms that determine a good outcome versus a negative one?

Changes in the external environment, such as exercise training, challenge homeostasis, producing spatial and temporal responses in the internal environment. These cause interactions between muscle, bone and gut, modulated by the Endocrine system. The degree and nature of these responses dictate whether a positive adaptation occurs. An excessive response, or a response not in tune with the networks of the Endocrine system, can hinder adaptation or produce a maladaptive response. The balance and interplay of internal responses are crucial in determining the outcome to exercise training in the individual.

F=MA

Local responses in exercising tissues

Exercising tissues release exerkines (metabolites, nucleic acids, peptides) which are packaged in exosomes and microvesicles. The content of these vesicle packages increases with intensity of endurance exercise in a dose-dependent manner. These exerkines have autocrine and paracrine effects, which modulate systemic adaptations to endurance exercise in the tissues themselves and those in the vicinity.

The range of these molecular responses from exercising tissues has been identified applying multi-omics (epigenomic, transcriptomic and proteomic analyses). Furthermore variance in trainability has been shown to be correlated with the integrated responses of tissue molecular signalling pathways to endurance exercise.

In a similar manner, the degree of inflammatory response and production of reactive oxygen and nitrogen species (RONS) to exercise mediate favourable adaptations. Inter-individual variations in redox status has been shown to determine the ability to adapt to exercise training. However, unlimited increase in response does not necessarily produce a better outcome. An over response to exercise in these signalling pathways, hinders adaptation.

Exercise promotes bone adaptation in terms of bone material, structure and muscle action. Paracrine crosstalk occurs between muscle and bone. Muscle myokines and insulin like growth factor 1 (IGF1) favour bone formation, whilst inflammatory molecules, such as interleukin 6 (Il-6) released during muscle contractions, favour bone reabsorption. The balance between these opposing processes determines whether bone remodelling is effective, or whether bone stress reactions occur over a pathological continuum. These responses and adaptations occur on the background of lifespan Endocrine environment, which impacts the outcome.

Gut microbiota

The gut microbiota support the regulation of inflammation at the local and systemic level. Furthermore the communication between the gut microbiota and mitochondria has been described as an important interaction in facilitating adaptive responses to exercise. Mitochondria are organelles crucial for production of ATP, as well as RONS. The gut microbiota are involved in mitochondrial biogenesis by regulating key mitochondrial transcriptional factors and enzymes . Furthermore, the metabolites of the gut microbiota such as short chain fatty acids, modulate the inflammatory effects of mitochondrial oxidative stress. Conversely genetic variants in the mitochondrial genome could impact mitochondrial function and thus the gut microbiota in terms of composition and activity.

The gut microbiota have a role in regulating intestinal permeability. Leaky gut is where epithelial integrity is lost at the tight junctions between cells in the gut lining. Leaky gut can occur in gut dysbiosis and also following endurance exercise where re-perfusion injury produces acute hyper-permeability. In these instances, increased gut permeability augments the antigen load and causes increased systemic inflammation and potentially can trigger autoimmune disease. This demonstrates that an excessive inflammatory response to exercise can hinder positive adaptation

Metabolic adaptations

Metabolic flexibility, the ability to respond and adapt to changes in metabolic demand, is enhanced with exercise training through these autocrine, paracrine and Endocrine mechanisms. Metabolic flexibility supports energy availability and fuel selection during exercise. Exercise mimetics, such as artificial metabolic modulators, have been reported to up-regulate gene expression to shift metabolism to fat oxidation in exercising muscle. This would potentially extend the limit of endurance exercise. However this “short cut” to adaptation favouring improved sport performance is illegal, with such molecular ligands on the World Anti-Doping Agency (WADA) banned list.

Hierarchy of control

There is a hierarchy of control in modulating multi-system adaptations to exercise. The Endocrine system is key. Exercise per se produces an Endocrine response, for example exercise is a key stimulus for growth hormone release via the hypothalamus, the neuroendocrine gatekeeper. Growth hormone supports the anabolic response to exercise. In addition, the Endocrine milieu during the lifespan has an impact on response and adaptations to exercise. Any disruption in the Endocrine system hinders adaptive changes. Endocrine dysfunction may occur as a result of non-integrated periodisation of exercise/nutrition and recovery as seen in relative energy deficiency in sports (RED-S). Dysfunction can also occur due to an Endocrine pathology.

Conclusion

Changes in external stimuli, such as exercise and nutrition, produce internal responses on autocrine, paracrine and Endocrine levels. These molecular signalling pathways drive adaptive changes through integrated, network effects. However any imbalances in these interactive responses can hinder desired adaptive changes and even result in negative maladaptive outcomes to exercise training.

For further discussion on Endocrine and Metabolic aspects of SEM come to the BASEM annual conference 22/3/18: Health, Hormones and Human Performance

References

Keay N, Logobardi S, Ehrnborg C, Cittadini A, Rosen T, Healy ML, Dall R, Bassett E, Pentecost C, Powrie J, Boroujerdi M, Jorgensen JOL, Sacca L. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sport: a double blind, placebo controlled study. Journal of Endocrinology and Metabolism. 85 (4) 1505-1512. 2000.

Sport Endocrinology presentation London 7/7/2017

Sports Endocrinology – what does it have to do with performance? Dr N.Keay, British Journal of Sport Medicine

Balance of recovery and adaptation for sports performance Dr N.Keay, British Association of Sport and Exercise Medicine

Inflammation: Why and How Much? Dr N.Keay, British Association of Sport and Exercise Medicine

Clusters of Athletes – A follow on from RED-S blog series to put forward impact of RED-S on athlete underperformance  Dr N.Keay, British Association of Sport and Exercise Medicine

Optimal Health: For All Athletes! Part 4 – Mechanisms Dr N.Keay, British Association of Sport and Exercise Medicine

The potential of endurance exercise-derived exosomes to treat metabolic diseases Nature Reviews Endocrinology

Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise Cold Spring Harbor Perspectives in Medicine

Genomic and transcriptomic predictors of response levels to endurance exercise training
Journal of Physiology

Adaptations to endurance training depend on exercise-induced oxidative stress: exploiting redox inter-individual variability Acta Physiologica

Mechanical basis of bone strength: influence of bone material, bone structure and muscle action Journal of Musculoskeletal and Neuronal Interactions

The Crosstalk between the Gut Microbiota and Mitochondria during Exercise Frontiers in Physiology

Leaky Gut As a Danger Signal for Autoimmune Diseases Frontiers in Immunology

Metabolic Flexibility in Health and Disease Cell Metabolism

Hormones and Sports Performance

PPARδ Promotes Running Endurance by Preserving Glucose Cell Metabolism