FXR mediates T cell-intrinsic responses to reduced feeding during infection

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.

Acute infection is often accompanied by physiological and behavioral alterations including changes in body temperature, anhedonia, and anorexia. Reduced feeding is a widely conserved manifestation of sickness behavior that affects host fitness in a context-dependent manner (1–3). While the effects of infection-induced anorexia on tissue function are well documented (2–5), its impact on immune responses remains poorly characterized. Despite enhancing bacterial clearance early during infection (6), starvation can reduce host resistance to subsequent challenges (7), suggesting that nutrient deprivation may limit adaptive immune responses.During an infectious challenge, adaptive lymphocytes quickly exit quiescence and undergo vigorous proliferation, with populations of antigen-specific cells expanding over 20,000-fold numerically (8). To support their heightened metabolic demands, activated lymphocytes greatly increase their glycolytic capacity and the ability to acquire nutrients from the environment (9). Although the connection between cell-intrinsic metabolism and the effector function of lymphocytes has been extensively investigated, the responses of immune cells to changes in the metabolic state of the host, particularly in the context of anorexia of infection, are not fully understood.We hypothesized that animals scale their immune responses according to nutrient availability and that lymphocytes display cell-intrinsic responses to the metabolic state of the host. We report that decreased feeding during infection causes a reduction in lymphocyte numbers that can be restored by provision of glucose. We further show that the nuclear receptor Farnesoid X Receptor (FXR), which regulates hepatic responses to fasting and refeeding (10, 11), is up-regulated upon T cell activation and plays a cell-intrinsic role in mediating starvation-induced loss of lymphocytes and in their fuel utilization. Impairing FXR-dependent T cell contraction in response to diminished nutrient availability resulted in greater weight loss and lower glycemia, indicating that the ability to scale the immune compartment according to food availability may affect organismal energy homeostasis during infection. Our results suggest that induction of FXR expression in activated T cells renders the effector T cell compartment sensitive to changes in host metabolism and that specific fuel utilization programs may support lymphocyte survival under nutrient-limiting conditions.     

Old or frail: what tells us more?

BACKGROUND: Selecting elderly persons who need geriatric interventions and making accurate treatment decisions are recurring challenges in geriatrics. Chronological age, although often used, does not seem to be the best selection criterion. Instead, the concept of frailty, which indicates several concurrent losses in resources, can be used. METHODS: The predictive values of chronological age and frailty were investigated in a large community sample of persons aged 65 years and older, randomly drawn from the register of six municipalities in the northern regions of the Netherlands (45% of the original addressees). The participants' generative capacity to sustain well-being (i.e., self-management abilities) was used as the main outcome measure. RESULTS: When using chronological age instead of frailty, both too many and too few persons were selected. Furthermore, frailty related more strongly (with beta values ranging from -.25 to -.39) to a decline in the participants' self-management abilities than did chronological age (with beta values ranging from -.06 to -.14). Chronological age added very little to the explained variances of all outcomes once frailty was included. CONCLUSIONS: Using frailty as the criterion to select older persons at risk for interventions may be better than selecting persons based only on their chronological age.     

Prevalence of left ventricular systolic dysfunction in pre‐dialysis and dialysis patients with preserved left ventricular ejection fraction

Aims

Patients with chronic kidney disease (CKD) have an excess of cardiovascular morbidity and mortality, with heart failure (HF) being particularly frequent. Reduced left ventricular ejection fraction (LVEF) defines left ventricular (LV) systolic dysfunction and is associated with poor prognosis. However, CKD patients may have HF symptoms with preserved LVEF. In this subgroup of patients, two‐dimensional speckle tracking echocardiography can detect LV systolic dysfunction by analysing LV myocardial deformation. The present study evaluated the prevalence of impaired LV global longitudinal strain (GLS) in CKD patients with preserved LVEF and its prognostic consequences.

Methods and results

Overall, 200 pre‐dialysis and dialysis patients (65% men, mean age 60 ± 14 years) with CKD stage 3b–5 and preserved LVEF (≥50%) were evaluated. Left ventricular systolic dysfunction despite preserved LVEF was defined by LV GLS ≤15.2% (cut‐off value derived from two standard deviations below the mean value of individuals without structural heart disease). Impaired LV GLS (≤15.2%) despite preserved LVEF was observed in 32% of patients. During a median follow‐up of 33 months (interquartile range 17–62 months), 47% of patients underwent renal transplantation, 9% were admitted with HF, and 28% died. Patients with LV GLS ≤15.2% showed significantly worse cumulative event‐free survival rates of the combined endpoint of HF hospitalization and all‐cause mortality compared to patients with LV GLS >15.2% (log‐rank P = 0.018).

Conclusion

The prevalence of impaired LV GLS despite preserved LVEF in pre‐dialysis and dialysis patients is relatively high. Patients with preserved LVEF but impaired LV GLS have an increased risk of HF hospitalization and all‐cause mortality.

     

Role of <Emphasis Type="Italic">cis</Emphasis>-Monounsaturated Fatty Acids in the Prevention of Coronary Heart Disease

The effects of cis-monounsaturated fatty acids (cis-MUFAs) on the risk of coronary heart disease (CHD) and on CHD mortality are not clear. Also, dietary recommendations for cis-MUFA as derived by various organizations are not in agreement. Earlier studies have mainly focused on the effects of cis-MUFA on serum lipids and lipoproteins. More recent studies, however, have also addressed effects of cis-MUFA on other non-traditional CHD risk markers such as vascular function markers, postprandial vascular function, and energy intake and metabolism. Although well-designed randomized controlled trials with CHD events as endpoints are missing, several large prospective cohort studies have recently been published on the relationship between cis-MUFA and CHD risk. The aim of this paper is to review these new studies that have been published in the last 3 years on the effects of cis-MUFA on cardiovascular risk markers and CHD.     

Gas-related symptoms after antireflux surgery

Background

Gas-related symptoms such as bloating, flatulence, and impaired ability to belch are frequent after antireflux surgery, but it is not known how these symptoms affect patient satisfaction with the procedure or what determines the severity of these complaints. We aimed to assess the impact of gas-related symptoms on patient-perceived success of surgery and to determine whether the severity of gas-related complaints after antireflux surgery is associated with objectively measured abnormalities.

Methods

Fifty-two patients were studied at a median of 27 months after antireflux surgery. The influence of gas-related symptoms on their quality of life and satisfaction with surgical outcome was assessed. The rates of air swallows and gastric and supragastric belches before and after surgery were assessed using impedance measurements.

Results

Bloating and flatulence were associated with a decreased quality of life and less satisfaction with surgical outcome. Notably, 9 % of the patients would not opt for surgery again due to gas-related symptoms. Antireflux surgery decreased the total number of gastric belches but did not affect the number of air swallows. The severity of gas-related symptoms was not associated with an increased number of preoperative air swallows and/or belches or a larger postoperative decrease in the number of gastric belches.

Conclusion

Gas-related symptoms are associated with less satisfaction with surgical outcome. The severity of gas-related symptoms is not determined by the number of preoperative air swallows or a more severe impairment of the ability to belch after surgery. Preoperative predictors of postoperative gas-related symptoms therefore could not be identified.