Autonomic Neuroscience

Available online 13 September 2017

Cardiovascular autonomic regulation, inflammation and pain in rheumatoid arthritis

• Ahmed M. Adlan^a,
• Jet J.C.S. Veldhuijzen van Zanten^a,
• Gregory Y.H. Lip^b,
• Julian F.R. Paton^c,
• George D. Kitas^d,
• James P. Fisher^{a, ,}

https://doi.org/10.1016/j.autneu.2017.09.003

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory condition characterised by reduced heart rate variability (HRV) and increased pain.

Animal studies have demonstrated reciprocal relationships between parasympathetic activity and inflammatory cytokines, however this has not been assessed in humans with RA.

This is the first study to demonstrate that in RA low HRV was associated with increased serum inflammatory cytokine concentrations, and independently associated with increased reported pain.

• In our patients with RA, reductions in HRV were not compounded by the presence of hypertension.

Abstract

Background

Rheumatoid arthritis (RA) is a chronic inflammatory condition characterised by reduced heart rate variability (HRV) of unknown cause. We tested the hypothesis that low HRV, indicative of cardiac autonomic cardiovascular dysfunction, was associated with systemic inflammation and pain. Given the high prevalence of hypertension (HTN) in RA, a condition itself associated with low HRV, we also assessed whether the presence of hypertension further reduced HRV in RA.

Methods

In RA-normotensive (n = 13), RA-HTN (n = 17), normotensive controls (NC; n = 17) and HTN (n = 16) controls, blood pressure and heart rate were recorded. Time and frequency domain measures of HRV along with serological markers of inflammation (high sensitivity C-reactive protein [hs-CRP], tumour necrosis factor-α [TNF-α] and interleukins [IL]) were determined. Reported pain was assessed using a visual analogue scale.

Results

Time (rMSSD, pNN50%) and frequency (high frequency power, low frequency power, total power) domain measures of HRV were lower in the RA, RA-HTN and HTN groups, compared to NC (p = 0.001). However, no significant differences in HRV were noted between the RA, RA-HTN and HTN groups. Inverse associations were found between time and frequency measures of HRV and inflammatory cytokines (IL-6 and IL-10), but were not independent after multivariable analysis. hs-CRP and pain were independently and inversely associated with time domain (rMMSD, pNN50%) parameters of HRV.

Conclusions

These findings suggest that lower HRV is associated with increased inflammation and independently associated with increased reported pain, but not compounded by the presence of HTN in patients with RA.

Corresponding author at: College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

© 2017 Published by Elsevier B.V.

·  Evidence of giant viruses of amoebae in the human gut

Review Article

• Human Microbiome Journal
• Philippe Colson, Sarah Aherfi, Bernard La Scola

Abstract

The study of the gut microbiome and virome has developed dramatically since the beginning of the 21^st century. Nevertheless, giant viruses of amoebae, which are emerging viruses first described in 2003, have been largely neglected in virome investigations because they are bigger than classical viruses and devoid of ribosomal DNA. Dozens of these viruses have been isolated between 2003 and 2016, which were classified in 7 lineages including 3 new recognized virus families. These viruses challenge previous paradigms on viruses and share many characteristics with intra-cellular microbes. We reviewed here findings about the presence of these giant viruses of amoebae in the human gut, whose microbiota has been extensively studied during the last decade. Contrasting with what is currently done for classical viruses, many studies investigating the presence of giant viruses of amoebae have been conducted by culture on amoebae in first intention. To date, a mimivirus and a marseillevirus have been isolated from human feces, which indicates that they can still replicate after a stay in the gut. Besides, sequences related to giant viruses of amoebae have been detected in several metagenomes generated from human feces. Water is a likely source of human exposure to giant viruses of amoebae. The clinical or biological significance of the presence of these viruses in the human gut remains to be determined. Taken together, available findings warrant searching more extensively and systematically for giant viruses of amoebae in the human gut, along with in other body sites.

How the gut influences the brain: the intestinal microbiome as a new dimension for understanding mental health

Dinan TG
Cork University Hospital, Dept. of Psychiatry Unit GF, Cork, Ireland

Evidence is accumulating to suggest that gut microbes may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. Altogether the mass of intestinal bacteria represents a virtual inner organ with 100 times the total genetic material contained in all the cells in the human body. However, a disordered balance amongst gut microbes is now thought to be an associated or even causal factor for many chronic medical conditions as varied as obesity and inflammatory bowel diseases.

While evidence is still limited in psychiatric illnesses, there are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system. Studies in germ-free animals indicate aberrant development of the brain monoaminergic system together with memory deficits and autistic patterns of behaviour. These deficits can be partially normalised if there is early gut colonisation.

The gut is inhabited by 10¹³ – 10¹⁴ micro-organisms, which is ten times the number of human cells in our bodies and contains over 100 times as many genes as our genome. The estimated species number varies greatly but it is generally accepted that the adult microbiome consists of greater than 1,000 species and more than 7,000 strains. It is an ecosystem dominated by bacteria, mainly strict anaerobes, but also including viruses, protozoa, archae and fungi. The microbiome is largely defined by 2 bacterial phylotypes, Bacteroidetes and Firmicutes with Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia phyla present in relatively low abundance.

Colonisation of the infant gut commences at birth when delivery exposes the infant to a complex microflora and its initial microbiome has a maternal signature. The microbiome of unweaned infants is simple with high interindividual variability. The numbers and diversity of strict anaerobes increase as a result of diet and environment, and after 1 year of age a complex adult-like microbiome is emerging. Despite major individual variation in the enteric microbiota, there seems to be a balance that confers health benefits and an alteration in this ecosystem can negatively influence the wellbeing of the individual,increasing vulnerability to a range of diseases.

Recent pre-clinical studies suggest that certain Bifidobacteria may have anxiolytic or antidepressant activity while Bifidobacterium infantis has been found effective in treating patients with irritable bowel syndrome.

Metchnikoff was the first to observe the fact that those living in a region of Bulgaria who consumed fermented food in their diet tended to live longer. He first published his observations in 1908 and this gave rise to the concept of a probiotic or bacteria with a health benefit. That bacteria might have a positive mental health benefit is now becoming clear. Such bacteria may influence the capacity to deal with stress, reducing anxiety, perhaps positively impacting on mood and are now called psychobiotics. Whether, they are capable of acting like and in some circumstances replacing antidepressants remains to be seen.

At a time when antidepressant prescribing has reached exceedingly high levels, the emergence of effective natural alternatives with less side-effects would be welcome. It will be intriguing to investigate if psychobiotics [1] will be beneficial in other psychiatric domains. Indeed, very recently a Bacteroides fragilis given early in life was shown to correct some of the behavioural and gastrointestinal deficits in a mouse model of autism induced by maternal infection.

The mechanisms of psychobiotic action are gradually being unravelled. It has been shown that Lactobacillus rhamnosus has potent anti-anxiety effects in animals and does so by producing major changes in the expression of GABA receptors in the brain [2]. GABA is the most important inhibitory transmitter in the human brain and these are the receptors through which benzodiazepines such as diazepam and various anaesthetic agents act. The changes in these receptors are mediated by the vagus nerve which connects the brain and gut. When this nerve is severed no effect on anxiety or on GABA receptors is seen following psychobiotic treatment. An impact on obsessive compulsive disorder type symptoms has also been reported with a similar strain of psychobiotic.

Interestingly, Lactobacillus rhamnosus not only alters GABA receptors in the brain but has been shown to synthesise and release GABA. There is also evidence to support the view that gut bacteria may influence the brain in routes other than the vagus nerve, for example by immune modulation and by the manufacture of short chain fatty acids.

Communication between the brain and gut is bidirectional and complex. Increased understanding of this axis and the role of the gut microbiota may aid the development of therapies not just for functional bowel disorders but for mood disorders also.

References

Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat
J.R. Kelly1,2 °, Y. Borre1, S. El Aidy1,4, J. Deane3, E. Patterson3, P.J. Kennedy1, S. Beers1, K. Scott1,
G. Moloney1, L. Scott2, P. Ross3, C. Stanton3, G. Clarke1,2, J.F. Cryan1,5, T.G. Dinan1,2.
1APC Microbiome Institute, University College Cork, Cork Ireland;
2University College Cork, Department of Psychiatry and Neurobehavioural Science, Cork,
Ireland;
3Teagasc Food Research Centre, Moorepark, Fermoy, Ireland;
4Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen,
Groningen, The Netherlands;
5University College Cork, Department of Anatomy and Neuroscience, Cork, Ireland

Introduction: The gut microbiota is a complex metabolic ecosystem, which interacts with the host via neuroimmune, neuroendocrine and neural pathways. These pathways are integral components of the brain-gut-microbiota axis and pre-clinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour [1,2].
Although it is well acknowledged that the pathophysiology of depression involves neuroimmune-endocrine dysregulation [3,4], the extent to which changes in the gut microbiota composition and function mediate dysregulation of these pathways in depression is currently unknown.

Objectives: To determine the composition of the gut microbiota and its relationship to immune activity (plasma cytokines), hypothalamic-pituitary-adrenal axis (HPAaxis) function and tryptophan metabolism in depressed patients. Furthermore, to determine the behavioural and physiological effects of a fecal microbiota transplantation from depressed patients and health controls to a
microbiota-deficient antibiotic rat model.

Methods: Thirty-four patients with DSM IV major depression and 33 healthy subjects matched for gender, age and ethnicity were recruited. Plasma C-reactive protein (CRP) and a panel of cytokines were measured ELISA.
Salivary cortisol levels were determined by ELISA. Plasma tryptophan and kynurenine were determined HPLC.
Plasma Lipopolysaccharide binding protein (LBP) was determined by ELISA. Fecal samples were collected for 16sRNA metagenomic sequencing. A fecal microbiota transplant was prepared from a sub group of depressed patients and controls and transferred by oral gavage to a microbiota-deficient antibiotic rat model.

Results: We demonstrate that depression is associated with altered gut microbiota composition, richness and phylogenetic diversity. Moreover, we show that fecalmicrobiota transplantation from depressed patients to microbiota-deficient rats can induce the development of
behavioural and physiological features of depression in the recipient animals. This includes anhedonia, indicated by reduced sucrose preference (p = 0.022) and anxiety like
behaviours, indicated by a decrease in visits to the open arms in the elevated plus maze (p = 0.029) and a decrease in time spent in the open field (p = 0.013). Physiologically, rats that received the depressed fecal microbiota had increased plasma kynurenine levels (p = 0.029) and an
increased kynurenine/tryptophan ratio (p = 0.008).

Conclusion: Our results confirm that depression is associated with a distinct microbial signature which is capable of inducing alterations in behaviour and physiology when transferred to microbiota-deficient animals. This suggests that the gut microbiota may play a causal role in the development of core behavioural and neurobiological features of depression and may provide a tractable target in the treatment and prevention of depression.

Reference(s)
[1] Cryan, J.F. & Dinan, T.G., Mind-altering microorganisms: the impact of the gut microbiota on
brain and behaviour, 2012. Nat Rev Neuroscience., 13(22968153): p. 701–712.
[2] Dinan, T.G. & Cryan, J.F., Melancholic microbes: a link between gut microbiota and depression?. 2013. Neurogastroenterology and Motility, 2013. 25(9): p.713−9.
[3] Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., & Lanctot, K. L., 2010. A meta-analysis of cytokines in major depression. Biological Psychiatry. 67(5): p. 446−57.
[4] Lupien, S.J., McEwen, B.S., Gunnar, M.R., & Heim, C., 2009. Effects of stress throughout the
lifespan on the brain, behaviour and cognition. Nat Rev Neuroscience. 10(6): p. 434−45.
Disclosure statement: The authors are funded by Science Foundation Ireland (SFI), through the Irish Governments National Development Plan in the form of a centre grant (Alimentary Pharmabiotic Centre Grant Number SFI/12/RC/2273). The Alimentary Pharmabiotic Centre has conducted studies in collaboration with several companies including GSK, Pfizer, Cremo, Suntory, Wyeth and Mead Johnson.
TGD has until recently been on the Board of Alimentary Health.
Funding is also provided by the Health Research Board (HRB) through Health
Research Awards (HRA_POR/2012/32 JFC, TGD and HRA-POR-2-14-647: GC, TGD).
GC is supported by a NARSAD Young Investigator Grant from the Brain and Behaviour Research Foundation (Grant Number 20771).