The gut microbiome consists of a multi-kingdom microbial community. Whilst the role of bacteria as causal contributors governing host physiological development is well established, the role of fungi remains to be determined. Here, we use germ-free mice colonized with defined species of bacteria, fungi, or both to differentiate the causal role of fungi on microbiome assembly, immune development, susceptibility to colitis, and airway inflammation. Fungal colonization promotes major shifts in bacterial microbiome ecology, and has an independent effect on innate and adaptive immune development in young mice. While exclusive fungal colonization is insufficient to elicit overt dextran sulfate sodium-induced colitis, bacterial and fungal co-colonization increase colonic inflammation. Ovalbumin-induced airway inflammation reveals that bacterial, but not fungal colonization is necessary to decrease airway inflammation, yet fungi selectively promotes macrophage infiltration in the airway. Together, our findings demonstrate a causal role for fungi in microbial ecology and host immune functionality, and therefore prompt the inclusion of fungi in therapeutic approaches aimed at modulating early life microbiomes.

BACKGROUND: Pulmonary rehabilitation (PR) is an effective therapeutic strategy to improve health outcomes in patients with chronic obstructive pulmonary disease (COPD); however, there is insufficient PR capacity to service all COPD patients, thus necessitating creative solutions to increase the availability of PR.OBJECTIVE: To examine the efficacy of PR delivered via Telehealth (Telehealth-PR) compared with PR delivered in person through a standard outpatient hospital-based program (Standard-PR).METHODS: One hundred forty-seven COPD patients participated in an eight-week rural PR program delivered via Telehealth-PR. Data were compared with a parallel group of 262 COPD patients who attended Standard-PR. Education sessions were administered two days per week via Telehealth, and patients exercised at their satellite centre under direct supervision. Standard-PR patients viewed the same education sessions in person and exercised at the main PR site. The primary outcome measure was change in quality of life as evaluated by the St George’s Respiratory Questionnaire (SGRQ). A noninferiority analysis was performed using both intention-to-treat and per-protocol approaches.RESULTS: Both Telehealth-PR and Standard-PR resulted in clinically and statistically significant improvements in SGRQ scores (4.5±0.8% versus 4.1±0.6%; P<0.05 versus baseline for both groups), and the improvement in SGRQ was not different between the two programs. Similarly, exercise capacity, as assessed by 12 min walk test, improved equally in both Telehealth-PR and Standard-PR programs (81±10 m versus 82±10 m; P<0.05 versus baseline for both groups).CONCLUSION: Telehealth-PR was an effective tool for increasing COPD PR services, and demonstrated improvements in quality of life and exercise capacity comparable with Standard-PR.

Purpose.To examine cardiovascular function and risk profile of postmenopausal women treated with chemoendocrine therapy (CET) for hormone receptor–positive operable breast cancer. Methods.Forty-seven breast cancer patients and 11 age-matched healthy controls were studied. Participants performed a cardiopulmonary exercise test with expired gas analysis and impedance cardiography to assess peak aerobic power (VO_2peak) and cardiovascular function (stroke volume, cardiac output, cardiac power output, and cardiac reserve). Traditional (i.e., body mass index, lipid profile, and fasting insulin and glucose) and novel (i.e., C-reactive protein, brain natriuretic peptide) cardiovascular risk biochemical factors were also assessed. Results.Breast cancer patients had significantly lower peak exercise stroke volume (68 ± 9 versus 76 ± 11 ml/beat), cardiac output (10.4 ± 1.5 versus 11.7 ± 2.4 l/minute), cardiac power output (3.0 ± 0.5 versus 3.5 ± 0.9 Watts), cardiac power output reserve (1.7 ± 0.6 versus 2.4 ± 0.8 Watts), and VO_2peak (1.3 ± 0.3 versus 1.6 ± 0.2 l·min⁻¹) than control subjects (p-values < .05). Patients with the greatest impairment in VO_2peak had the worse cardiovascular risk profile. Exploratory analyses revealed several differences in study outcomes between the 26 patients receiving hormonal therapy with tamoxifen (TAM) and the 21 patients receiving aromatase inhibitor (AI) therapy. Conclusion.Breast cancer patients treated with adjuvant CET have a significantly and markedly lower cardiorespiratory fitness and cardiac functional reserve compared with age- and sex-matched controls. AI therapy may be associated with a more unfavorable cardiovascular risk profile than TAM. Prospective studies are required to further investigate the clinical value of these findings.

Asthma accounts for 380,000 deaths a year. Carotid body denervation has been shown to have a profound effect on airway hyper-responsiveness in animal models but a mechanistic explanation is lacking. Here we demonstrate, using a rat model of asthma (OVA-sensitized), that carotid body activation during airborne allergic provocation is caused by systemic release of lysophosphatidic acid (LPA). Carotid body activation by LPA involves TRPV1 and LPA-specific receptors, and induces parasympathetic (vagal) activity. We demonstrate that this activation is sufficient to cause acute bronchoconstriction. Moreover, we show that prophylactic administration of TRPV1 (AMG9810) and LPA (BrP-LPA) receptor antagonists prevents bradykinin-induced asthmatic bronchoconstriction and, if administered following allergen exposure, reduces the associated respiratory distress. Our discovery provides mechanistic insight into the critical roles of carotid body LPA receptors in allergen-induced respiratory distress and suggests alternate treatment options for asthma.

Key points: Sympathetic nervous system activity causes tonic vasoconstriction in resting and contracting skeletal muscle. Vasoactive molecules released from the active skeletal muscle and/or endothelium have been shown to inhibit sympathetic vasoconstriction, a phenomenon defined as functional sympatholysis. A definitive mechanism responsible for functional sympatholysis has yet to be identified; however, nitric oxide (NO) appears to be involved. It is unknown whether exercise training alters the inhibition of sympathetic vasoconstriction and NO‐mediated sympatholysis in resting and contracting skeletal muscle. The present findings demonstrate that short‐term exercise training augments functional sympatholysis in a training‐intensity‐dependent manner through a NO‐dependent mechanism. These novel findings advance our understanding of the effects of exercise training on the regulation of sympathetic vasoconstriction in resting and contracting skeletal muscle. Abstract  We tested the hypothesis that short‐term mild‐ (M) and heavy‐intensity (H) exercise training would enhance sympatholysis through a nitric oxide (NO)‐dependent mechanism. Sprague–Dawley rats (n = 36) were randomly assigned to sedentary (S) or to M (20 m min⁻¹ 5% gradient) or H exercise training groups (40 m min⁻¹ 5% gradient). Rats assigned to M and H groups trained on 5 days week⁻¹ for 4 weeks, with the volume of training being matched between groups. Rats were anaesthetized and instrumented for stimulation of the lumbar sympathetic chain and the measurement of arterial blood pressure and femoral artery blood flow. The triceps surae muscle group was stimulated to contract rhythmically at 30 and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulation delivered at 2 and 5 Hz was determined at rest and during contraction at 30 and 60% MCF. The vascular response to sympathetic stimulation was reduced as a function of MCF in all rats (P < 0.05). At 30% MCF, the magnitude of sympatholysis (%FVC rest – contraction; Δ%FVC) was greater in H compared with M and S groups (Δ%FVC at 2 Hz, S, 9 ± 5; M, 11 ± 8; and H, 18 ± 7; and Δ%FVC at 5 Hz, S, 6 ± 6; M, 12 ± 9; and H, 18 ± 7; P < 0.05) and was greater in H and M compared with S at 60% MCF (Δ%FVC at 2 Hz, S, 15 ± 5; M, 25 ± 3; and H, 36 ± 6; and Δ%FVC at 5 Hz, S, 22 ± 6; M, 33 ± 9; and H, 39 ± 9; P < 0.05). Blockade of NO synthase did not alter the magnitude of sympatholysis in S during contraction at 30 or 60% MCF. In contrast, NO synthase inhibition diminished sympatholysis in H at 30% MCF and in M and H at 60% MCF (P < 0.05). The present findings indicate that short‐term exercise training augments sympatholysis in a training‐intensity‐dependent manner and through an NO‐dependent mechanism.