GI distress: A breath of fresh air in respiratory homeostasis

Unlike some subgroups of humans, bacteria live in “cultured” and highly diverse communities. About a decade ago, Sibley et al. [[1]Sibley C.D. Parkins M.D. Rabin H.R. Duan K. Norgaard J.C. Surette M.G. A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients.Proc Natl Acad Sci. 2008; 105: 15070-15075Crossref PubMed Scopus (266) Google Scholar] discovered that the composition of the bacterial population residing within the airways is an important determinant of lung infection severity and overall health of cystic fibrosis patients [[1]Sibley C.D. Parkins M.D. Rabin H.R. Duan K. Norgaard J.C. Surette M.G. A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients.Proc Natl Acad Sci. 2008; 105: 15070-15075Crossref PubMed Scopus (266) Google Scholar]. Accordingly, managing the composition of the microbial community was proposed to improve response to treatment when a given organism, such as Pseudomonas aeruginosa, becomes resistant to antibiotic therapy. Given that pulmonary infection is a primary complication of cystic fibrosis, the link between microbial diversity and a respiratory disorder was certainly obvious. From a conceptual perspective, however, the study of O'Connor et al published in this issue of EBioMedicine stands out as it clearly demonstrates that disruption of microbial diversity within the gut has more far reaching consequences as it is capable of disrupting the brain circuits that regulate breathing [[2]O'Connor K.M. Lucking E.F. Golubeva A.V. Strain C.R. Fouhy F. Cenit M.C. et al.Manipulation of gut microbiota blunts the ventilatory response to hypercapnia in adult rats.EBioMedicine. 2019; 44: 618-638Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. Although it is now well established that a broad range of respiratory and non-respiratory stressors (e.g. intermittent hypoxia, neonatal maternal separation, respectively) can impart plasticity in respiratory control, the link between changes in gut bacterial population dynamics and anomalies in respiratory reflexes is, at first, far from intuitive. However, in light of the recent wave of discoveries on microbiota-gut-brain signalling, this should not come as a surprise. To respiratory physiologists, the vagus nerve and its main projection site (the nucleus of the solitary tract) convey essential sensory signals to respiratory neurons; yet, these structures also happen to be the main pathways by which the bidirectional interactions between the gut and the brain take place [[3]Fülling C. Dinan T.G. Cryan J.F. Gut microbe to brain signaling: what happens in vagus….Neuron. 2019; 101: 998-1002Summary Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. Linking these concepts therefore makes for a novel and compelling hypothesis, but testing it rigorously is a different story. To achieve this feat, O'Connor et al at University College Cork combined their expertise in respiratory physiology, nutrition, psychiatry, and microbiology to determine whether manipulation of gut microbiota composition alters cardiorespiratory function at rest and in response to respiratory challenges. This was accomplished using adult rats receiving broad-spectrum antibiotics (4 weeks) vs. vehicle controls, and antibiotic treated and untreated rats receiving subsequent faecal microbial transfer from healthy donors. To demonstrate treatment efficiency, the authors provide a thorough quantification of the dramatic changes in microbiota composition and diversity in the gut resulting from antibiotics and fecal transplant. The impact on respiratory function was then meticulously analysed in intact animals; the use of anesthetised animals facilitated quantification of arterial blood gases and cardiovascular variables. Their demonstration that microbial manipulation had very specific consequences for respiratory function is remarkable and suggests that microbiota-gut-brain signalling has targeted effects on neural circuits for respiratory control (as opposed to non-specific outcomes). Microbial manipulation had no effect on breathing at rest, and attenuation of the hyperventilatory response to CO2 was the most important change in respiratory control observed. By contrast, the effects of treatment on the ventilatory responses to hypoxia, either tested acutely or intermittently, were modest. Considering the amount of work performed, this study is a goldmine of information. At a time when data reproducibility becomes a significant concern, this study raises important questions about the potential impact of diet and/or antibiotic administration on respiratory data. Furthermore, this study points to new and highly promising research avenues. For instance, data showing that the relative abundance of selected species of bacteria correlate with specific brainstem monoamines (but not noradrenaline or serotonin) raises the possibility that specific bacterial species could have profound effects on respiratory regulation. In light of the growing interest for the beneficial effects of “psychobiotics” on mental health [[4]Sarkar A. Lehto S.M. Harty S. Dinan T.G. Cryan J.F. Burnet P.W.J. Psychobiotics and the manipulation of bacteria–gut–brain signals.Trends Neurosci. 2016; 39: 763-781Summary Full Text Full Text PDF PubMed Scopus (490) Google Scholar], one cannot help but wonder if manipulating the microbiota via ingestion of “highly desirable species” or faecal microbiota transplant (as is currently done for the treatment of gastro-intestinal disease) could become a valuable clinical treatment for respiratory disorders related to neural control dysfunction. Considering that drastic changes in the gut microbiota have been observed in patients with multiple sclerosis [[3]Fülling C. Dinan T.G. Cryan J.F. Gut microbe to brain signaling: what happens in vagus….Neuron. 2019; 101: 998-1002Summary Full Text Full Text PDF PubMed Scopus (210) Google Scholar] and that this population shows a reduced ventilatory response to CO2 [[5]Tantucci C. Massucci M. Piperno R. Betti L. Grassi V. Sorbini C.A. Control of breathing and respiratory muscle strength in patients with multiple sclerosis.Chest. 1994; 105: 1163-1170Summary Full Text Full Text PDF PubMed Google Scholar] akin to the results reported by O'Connor et al., this “gutsy idea” may not be that far-fetched. As a whole, this study reminds us once again that despite their robustness, the neural networks regulating breathing abide to the basic principles shaping the rest of the brain. The author declared no competing interests. Manipulation of gut microbiota blunts the ventilatory response to hypercapnia in adult ratsChronic antibiotic administration and faecal microbiota transfer disrupt gut microbiota, brainstem monoamine concentrations and the ventilatory response to hypercapnia. We suggest that aberrant microbiota-gut-brain axis signalling has a modulatory influence on respiratory behaviour during hypercapnic stress. Full-Text PDF Open Access

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