Philipp Zimmer

Multiple sclerosis (MS) represents a multifaceted neuroinflammatory disease for which regular exercise is now recommended by many healthcare institutions. Although preclinical studies indicate robust immunomodulatory effects of exercise, evidence from human studies is lacking. In this randomized controlled trial, persons with MS (pwMS) were assigned to three months of high-intensity interval training or a passive control condition, with outcomes assessed at baseline, after intervention, and a fourweek follow-up. Additionally, a healthy matched control group was included. Besides exercise-induced sustained increases in physical fitness, systemic inflammation was diminished and the Treg-to-TH17.1 ratio improved after exercise. Untargeted proteomic analysis of peripheral blood mononuclear cells covering >7000 proteins revealed an exercise-induced decrease in proteins implicated in inflammatory diseases (i.e., MTHFD2). This was supported by inferred transcription factor activity analysis, which indicated enhanced polarization of immune cells toward anti-inflammatory phenotypes at follow-up. Using flow cytometry, we identified an LFA-1αhighCD4+ T-cell subset that was associated with disease biomarkers and exhibited increased CCR4 expression compared to healthy matched subjects which was reduced after exercise. Our findings significantly expand knowledge of how exercise training exerts immediate and sustained immunomodulatory effects in pwMS and thereby strengthens the mechanistic rationale for exercise recommendations made by healthcare professionals.

Tryptophan (TRP) is primarily metabolized via the kynurenine (KYN) pathway, which plays a central role in energy homeostasis, as well as immune, inflammatory, and neurobiological regulation. Although a single exercise session may modulate this pathway, the magnitude and consistency of these responses remain unclear. Therefore, this meta‐analysis aimed to synthesize acute exercise–induced changes in KYN pathway metabolites. PubMed, Web of Science, and Scopus were searched from inception to June 2026. Clinical trials evaluating the effects of a single exercise session on circulating TRP and KYN pathway metabolites were included. Random‐effects meta‐analyses were performed using standardized mean differences (Hedges' g). Outcomes were analyzed separately for immediate post‐exercise responses (≤ 5 min) and recovery responses (> 5 min to 3 h). Prespecified subgroup analyses examined population characteristics, training status, and exercise modality. Of 3203 records, 24 clinical trials ( n = 695) were included in the systematic review, and 20 provided data for meta‐analysis. Immediately after exercise, TRP decreased, whereas KYN, KYN/TRP, kynurenic acid (KYNA), and quinolinic acid (QA) increased. During recovery, reductions in TRP and elevations in KYN/TRP persisted, whereas KYN and QA returned toward baseline. KYNA remained elevated, while QA/KYNA remained unchanged. Subgroup analyses suggested larger responses in healthy individuals, trained participants, and following aerobic exercise, particularly for TRP and KYNA. Exercise induces heterogeneous changes in KYN metabolism, characterized by reduced TRP and increased KYN/TRP ratio and downstream metabolites. These responses are transient and context‐dependent, reflecting acute changes in metabolic flux rather than sustained pathway remodeling. Trial Registration: PROSPERO, identifier CRD42022351481

Cancer survivors frequently experience cancer‐related cognitive impairment (CRCI), but the contributions of different anti‐cancer therapies remain unclear. Patients with breast or gynaecological cancer were recruited before any anti‐cancer treatment. Cognitive function was assessed by objective and subjective measures pre‐treatment (T0), post‐treatment (T1), and 1 year after T1 (T2). Objective measures include Hopkins Verbal Learning Test‐Revised (HVLT‐R), Trail Making Test (TMT), Controlled Oral Word Association Test (COWA), and Mnemonic Similarity Task (MST). Subjective measures include Functional Assessment of Cancer Therapy—Cognitive scale (FACT‐Cog) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30). Linear mixed models were performed. Patients ( n = 234) were of age 55.4 ± 11.6 years. At T1, chemotherapy was associated with worse visual searching and motor speed (TMT‐A: β = 0.36, 95% CI: 0.03–0.69), perceived global function (FACT‐Cog Global Function: β = −0.39, 95% CI: −0.67 to −0.11), and cognitive function (EORTC QLQ‐C30: β = −0.50, 95% CI: −0.82 to −0.18) compared to endocrine therapy. At T2, endocrine therapy was associated with poorer verbal learning and memory performance (HVLT‐R total recall: β = −0.40, 95% CI: −6 to −0.03) and higher perceived cognitive impairments (FACT‐Cog PCI: β = 0.34, 95% CI: 0.05–0.63). In conclusion, CRCI may occur during certain types of chemotherapy but appears to ameliorate over time. Ongoing endocrine therapy may have longer‐lasting impact on cognitive function. Appropriate counselling for informed decision making and good supportive care is needed.

Background: In professional soccer, the use of external measures such as GPS data and functional performance screenings to control load, recovery and injury prevention is well established. However, internal biomarkers have so far only been used to a limited extent, as their collection is usually invasive, cost-intensive and difficult to implement at high-frequency. This work aims to present a first practical approach for high-frequency, saliva-based multi-omics biomarker monitoring in professional soccer and explores potential applications. Methods: Twenty-six male first-team players were monitored over an entire season, providing 3-5 saliva samples per week, resulting in 2,554 samples analyzed for 92 biomarkers. Samples were collected using Salivette® Cortisol swabs and analyzed via liquid chromatography-tandem mass spectrometry (intra-assay CV <5%). Individual reference ranges were calculated using a Bayesian inference model with adaptive temporal weighting and outlier detection, combining individual and population data to derive 95% confidence intervals. The analyses focused on selected biomarkers related to hydration, metabolism, stress, and inflammation. Results: Four representative cases showed marked deviations from their individual 95% reference ranges, each linked to distinct physiological conditions: temporary dehydration (total protein: team average 0.49±0.38 mg/ml; individual range 0.33-2.27 mg/mL), incorrect use of dietary supplements (melatonin: 0.28±5.17 ng/mL; 0.001-123.016 ng/mL), elevated stress (cortisol: 3.76±3.39 ng/mL; 0.004-41.836 ng/ml) and medication influences (cortisone: 9.53±5.82 ng/ml; 0.002-10.737 ng/ml). Conclusion: This study represents a first promising attempt to implement saliva-based biomarker assessment in professional soccer, which can support medical staff, nutritionists, and coaches in identifying early signs of maladaptation, optimizing recovery strategies, and enabling timely, individualized interventions throughout the season. Further research is needed to validate these findings and investigate their scalability to other sports. Key Words: Internal Load, Biomarker, Training, Nutrition

Determining physiological stress at high resolution is crucial across diverse settings to enable informed decision-making in the context of health and disease. Saliva-based targeted multi-omics testing provides a powerful, non-invasive method to quantify physiological stress and circadian dynamics at high-frequency. In a laboratory crossover trial with 24-hour sampling comprising 413 saliva samples, we demonstrate high analytical reliability, distinct molecular individuality, and robust acute and delayed responses to physical exercise across proteins, metabolites, and lipids. Moreover, we present the most comprehensive existing dataset describing 24-hour molecular kinetics across these three omics layers. Leveraging this controlled setting, we applied machine learning to single-timepoint saliva samples to accurately predict recent physical exercise both immediately after and 24 hours later. Next, we translated this analytical framework to a real-world longitudinal setting of elite football players monitored over 16 months, comprising over 12,000 saliva samples. Despite increased biological and contextual variability, the model retained robust discrimination between exercise and rest on the following day. Based on prediction probabilities, we introduce a saliva-based internal strain metric, that captures internal load and can be harnessed to monitor physical exercise and recovery. Model robustness was further supported through out-of-sample validation using previously unseen observations. Our findings demonstrate that saliva-based targeted multi-omics reliably captures physical exercise and recovery states in both laboratory and real-world environments, providing a scalable framework for monitoring physical performance. This non-invasive approach holds broad potential for physiological monitoring and can serve as a blueprint for health- and disease-related contexts.

Aim: Indoles are tryptophan (Trp)‐derived metabolites that are produced by the gut microbiota and may influence the gut‐microbiota‐brain axis in multiple sclerosis (MS). Indole‐3‐lactate (ILA) is reduced in persons with MS and improves MS clinical scores in animal models via its anti‐inflammatory remyelinating properties. The ILA/indole‐3‐acetate (IAA) (ILA/AA) index is considered a neuroprotection index. Physical exercise and diet can modify gut microbiota and indole metabolism. Methods: This secondary analysis of a randomized control trial aimed to assess the effects of acute and chronic exercise on serum indoles in relapsing–remitting MS (RRMS). Thirty‐one RRMS patients (≥ 70% session attendance) completed a 10 week multimodal functional training (60 min, 3×/week) vs. a waitlist control group. Blood samples were collected at baseline and compared to a matched healthy control group, and after 10 weeks for the assessment of chronic effects. Additionally, acute effects of a single bout of exercise were assessed with a blood sample before, during, and immediately after one interim training session. Serum indole concentrations were measured using LC–MS/MS. Results: Baseline indole levels in RRMS patients differed from those of matched healthy controls, and reduced ILA levels were observed. The 10 week intervention increased the ILA/IAA index, while a single exercise bout induced an increase in both ILA and ILA/IAA. Conclusion: Multimodal functional training over 10 weeks led to an improved ILA/IAA index suggesting a neuroprotective shift in gut microbiota composition, and a single bout acutely increases the circulating level of ILA. Study registration number: DRKS00017091.

The positive effect of exercise on the immune system is widely acknowledged, but the molecular response of immune cells to exercise remains largely unknown. Here, we perform mass-spectrometry-based proteomic analysis on peripheral blood mononuclear cells (PBMC) at a depth of >6000 proteins. Comparing high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MICE), matched for time and workload, we identify versatile changes in the proteomic makeup of PBMCs and reveal profound alterations, related to effector function and immune cell activation pathways within one hour following exercise. These changes are more pronounced after HIIE compared to MICE and occur despite identical immune cell mobilization patterns between the two exercise conditions. We further identify an immunoproteomic signature that effectively predicts cardiorespiratory fitness, thus allowing insights into potential exercise-triggered adaptations and immunological health benefits that are mediated by exercise. This study provides a reliable data resource that expands our knowledge on how exercise modulates the immune system, and delivers biological evidence supporting the WHO 2020 guidelines, which highlight exercise intensity as a relevant factor to maintain health.

In our study, we provide detailed serum kinetics of energy-related metabolites during acute aerobic exercise and after 1 h of recovery. Semantic interpretation of our results against the backdrop of fundamental principles of exercise biochemistry indicate that serum metabolites mirror skeletal muscle energy metabolism, thus providing new insights into systemic energy homeostasis and interorgan crosstalk.