Association of tryptophan pathway metabolites with mortality and effectiveness of nutritional support among patients at nutritional risk: secondary analysis of a randomized clinical trial.

Tryptophan is an essential amino acid and is the precursor of many important metabolites and neurotransmitters. In malnutrition, the availability of tryptophan is reduced, potentially putting patients at increased risks. Herein, we investigated the prognostic implications of the tryptophan metabolism in a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized, controlled trial comparing individualized nutritional support to usual care in patients at risk for malnutrition. Among 238 patients with available measurements, low plasma levels of metabolites were independently associated with 30-day mortality with adjusted hazard ratios (HR) of 1.77 [95% CI 1.05-2.99, p 0.034] for tryptophan, 3.49 [95% CI 1.81-6.74, p < 0.001] for kynurenine and 2.51 [95% CI 1.37-4.63, p 0.003] for serotonin. Nutritional support had more beneficial effects on mortality in patients with high tryptophan compared to patients with low tryptophan levels (adjusted HR 0.61 [95% CI 0.29-1.29] vs. HR 1.72 [95% CI 0.79-3.70], p for interaction 0.047). These results suggest that sufficient circulating levels of tryptophan might be a metabolic prerequisite for the beneficial effect of nutritional interventions in this highly vulnerable patient population.

ESPEN practical guideline: Nutritional support for polymorbid medical inpatients.

BACKGROUND: Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and healthcare costs. AIM: As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS: The 2023 update adheres to the standard operating procedures for ESPEN guidelines. We undertook a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g., published guidelines), until July 12th, 2022. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (including SIGN grading), which was followed by submission to Delphi voting. Here, the practical version of the guideline is presented which has been shortened and equipped with flow charts for patients care. RESULTS: 32 recommendations (7× A, 11× B, 10× O and 4× GPP), which encompass different aspects of nutritional support were included from the scientific guideline including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. Here, the practical version of the guideline is presented which has been shortened and equipped with flow charts for patients care. CONCLUSIONS: Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated practical guideline offers an evidence-based nutritional approach to polymorbid medical inpatients and may improve their outcomes.

Prognostic implications of the arginine metabolism in patients at nutritional risk: A secondary analysis of the randomized EFFORT trial.

BACKGROUND: Arginine, a conditionally essential amino acid, is key component in metabolic pathways including immune regulation and protein synthesis. Depletion of arginine contributes to worse outcomes in severely ill and surgical patient populations. We assessed prognostic implications of arginine levels and its metabolites and ratios in polymorbid medical inpatients at nutritional risk regarding clinical outcomes and treatment response. METHODS: Within this secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), we investigated the association of arginine, its metabolites and ratios (i.e., ADMA and SDMA, ratios of arginine/ADMA, arginine/ornithine, and global arginine bioavailability ratio) measured on hospital admission with short-term and long-term mortality by means of regression analysis. RESULTS: Among the 231 patients with available measurements, low arginine levels ≤90.05 µmol/l (n = 86; 37 %) were associated with higher all-cause mortality at 30 days (primary endpoint, adjusted HR 3.27, 95 % CI 1.86 to 5.75, p < 0.001) and at 5 years (adjusted HR 1.50, 95 % CI 1.07 to 2.12, p = 0.020). Arginine metabolites and ratios were also associated with adverse outcome, but had lower prognostic value. There was, however, no evidence that treatment response was influenced by admission arginine levels. CONCLUSION: This secondary analysis focusing on medical inpatients at nutritional risk confirms a strong association of low plasma arginine levels and worse clinical courses. The potential effects of arginine-enriched nutritional supplements should be investigated in this population of patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

Inflammation and response to nutrition interventions.

The complex interplay between nutrition and inflammation has become a major focus of research in recent years across different clinical settings and patient populations. Inflammation has been identified as a key driver for disease-related malnutrition promoting anorexia, reduced food intake, muscle loss, and on a cellular level, insulin resistance, which together stimulate catabolism. However, these effects may well be bidirectional, and there is strong evidence showing that nutrition influences inflammation. Several single nutrients and dietary patterns with either proinflammatory or anti-inflammatory properties have been studied, such as the long-chain ω-3 fatty acids eicosapentaenoic acid or docosahexaenoic acid. The Mediterranean diet combines several such nutrients and has been shown to improve medical outcomes in the outpatient setting. In addition, there is increasing evidence suggesting that inflammation affects the metabolism and modulates the response to nutrition support interventions. In fact, recent studies from the medical inpatient setting suggest that inflammation, mirrored by high levels of C-reactive protein, diminishes the positive effects of nutrition support. This may explain the lack of positive effects of some nutrition trials in severely ill patients, whereas similar approaches to nutritional support have shown positive results in less severely ill patients. The use of biomarkers, such as C-reactive protein, may help to identify patients with a lower response to nutrition, in whom other treatment options need to be used. There is need for additional research to understand how to best address the malnourished patient with inflammation by specifically lowering inflammation through anti-inflammatory medical treatments and/or nutrition interventions.

ESPEN guideline on nutritional support for polymorbid medical inpatients.

BACKGROUND: Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and cost of care. AIM: As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS: This update adheres to the standard operating procedures for ESPEN guidelines. We did a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until July 12th. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (incl. SIGN grading), which was followed by submission to Delphi voting. RESULTS: From a total of 3527 retrieved abstracts, 60 new relevant studies were analyzed and used to generate a guideline draft that proposed 32 recommendations (7x A, 11x B, 10x O and 4x GPP), which encompass different aspects of nutritional support including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. The results of the first online voting showed a strong consensus (agreement of >90%) on 100% of the recommendations. Therefore, no final consensus conference was needed. CONCLUSIONS: Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated guideline offers an evidence-based nutritional approach to the polymorbid medical inpatients and may improve their outcomes.

[Malnutrition in internal medicine : Screening, assessment and importance]. / Mangelernährung in der Inneren Medizin : Screening, Assessment und Bedeutung.

Disease-related malnutrition has a strong influence on the further course of the disease and mortality, especially in chronically ill patients. In recent years it could be shown in large randomized studies that an individual nutrition therapy could significantly and relevantly improve the clinical outcome of patients in internal medicine with a risk of malnutrition, both in hospital and in aftercare. Therefore, due to the increasing proportion of multimorbid patients the significance of malnutrition and its treatment is becoming increasingly more important in the practice and in research. Nutritional medicine should nowadays be considered as an effective and integral component of a holistic treatment in internal medicine; however, further research is necessary in order to investigate new nutritional biomarkers and for a better integration of an evidence-based personalized nutritional medicine into routine clinical practice.

Inflammation and Nutrition: Friend or Foe?

The importance of the interplay between inflammation and nutrition has generated much interest in recent times. Inflammation has been identified as a key driver for disease-related malnutrition, leading to anorexia, reduced food intake, muscle catabolism, and insulin resistance, which are stimulating a catabolic state. Interesting recent data suggest that inflammation also modulates the response to nutritional treatment. Studies have demonstrated that patients with high inflammation show no response to nutritional interventions, while patients with lower levels of inflammation do. This may explain the contradictory results of nutritional trials to date. Several studies of heterogeneous patient populations, or in the critically ill or advanced cancer patients, have not found significant benefits on clinical outcome. Vice versa, several dietary patterns and nutrients with pro- or anti-inflammatory properties have been identified, demonstrating that nutrition influences inflammation. Within this review, we summarize and discuss recent advances in both the role of inflammation in malnutrition and the effect of nutrition on inflammation.

The protective effect of betacellulin against acute pancreatitis is ERBB4 dependent.

BACKGROUND: The EGFR ligand betacellulin (BTC) has been previously shown to protect mice against experimentally induced acute pancreatitis (AP). BTC binds both autonomous ERBB receptors EGFR and ERBB4. In this study, we evaluated the mechanism underlying the protection from AP-associated inflammation in detail. METHODS: AP was induced with cerulein or L-arginine and investigated in a pancreas-specific ERBB4 knockout and in an EGFR knockdown mouse model (EgfrWa5/+). Pancreatitis was evaluated by scoring inflammation, necrosis, and edema, while microarrays were performed to analyze alterations in the transcriptome between mice with AP and animals which were protected against AP. The intracellular domain (ICD) of ERBB4 was analyzed in different cell compartments. RESULTS: While the pancreas of BTC transgenic mice in the background of EgfrWa5/+ is still protected against AP, the BTC-mediated protection is no longer present in the absence of ERBB4. We further demonstrate that BTC activates the ICD of ERBB4, and increases the expression of the extracellular matrix (ECM) proteins periostin and matrix gla protein as well as the ECM modulators matrix metalloproteinases 2 and 3, but only in the presence of ERBB4. Notably, the increased expression of these proteins is not accompanied by an increased ECM amount. CONCLUSIONS: These findings suggest that BTC derivates, as a drug, or the ERBB4 receptor, as a druggable target protein, could play an important role in modulating the course of AP and even prevent AP in humans.

Metamizol Relieves Pain Without Interfering With Cerulein-Induced Acute Pancreatitis in Mice.

OBJECTIVES: Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP-associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed. METHODS: Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain. RESULTS: We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response. CONCLUSIONS: This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP.