Publications

Cancer cachexia is a multi-organ and multifactorial syndrome characterized by muscle wasting (with or without adipose tissue loss) and systemic inflammation in patients with advanced malignancies. Gut … microbiota dysbiosis, particularly the depletion of short-chain fatty acid (SCFA)-producing bacteria, may contribute to the progression of cancer cachexia. Studies in both murine models and humans consistently associate cachexia with a decline in SCFA-producing gut microbiota commensals and an overgrowth of pro-inflammatory pathobionts. These microbial imbalances may lead to reduced levels of SCFAs and branched-chain amino acids (BCAAs) and alter the normal bile acid profile. BCAAs and the maintenance of a normal bile acid profile are associated with muscle synthesis and decreased breakdown. While SCFAs (acetate, propionate, and butyrate), contribute to intestinal barrier integrity and immune regulation. SCFA depletion may increase gut permeability, allowing bacterial endotoxins, such as lipopolysaccharide (LPS), to enter the bloodstream. This may lead to chronic inflammation, muscle catabolism, and impairment of anabolic pathways. Interventions targeting gut microbiota in preclinical models have mitigated inflammation and muscle loss. While clinical data are limited, it suggests an improvement in immune functions and better tolerance to anticancer therapies. Current evidence is predominantly derived from cross-sectional studies suggesting associations without causality. Thus, future longitudinal studies are needed to identify biomarkers and optimize personalized therapy.

Importance The proportion of colorectal cancer (CRC) cases attributable to excess weight, known as population attributable fraction (PAF), has been commonly based on measures of body mass index (BMI). …. Central obesity metrics, such as waist circumference (WC) and waist to hip ratio (WHR), are potentially better indicators of adiposity and have demonstrated stronger associations with CRC incidence. Objectives To examine PAFs of CRC cases that are attributable to high WC and WHR and compare them to those attributable to high BMI. Design, Setting, and Participants This population-based UK Biobank cohort study included 458 543 individuals aged 40 to 69 years at recruitment (March 2006 to July 2010) living within a reasonable distance of the 22 assessment centers across the UK. The analyses were conducted between May and July 2024. Exposures Exposures were BMI, as a measure of general obesity, and WC and WHR, as indicators of central obesity. Main Outcomes and Measures Hazard ratios (HRs) and corresponding 95% CIs were calculated for the associations of BMI, WC, and WHR with CRC incidence. The PAFs and 95% CIs of CRC cases attributable to high BMI, WC, and WHR were also calculated. Results A total of 458 543 participants (median [IQR] age, 57 [50-63] years; 244 351 [53.3%] female) were included in the study. During a median follow-up of 11.8 (IQR, 10.9-12.5) years, 5944 participants were diagnosed with CRC. The HRs for the association with CRC incidence were notably smaller for BMI (HR for the highest vs lowest BMI quartile, 1.23; 95% CI, 1.14-1.33) than for WC (HR for the highest vs lowest WC quartile, 1.37; 95% CI, 1.27-1.49) and WHR (HR for the highest vs lowest WHR quartile, 1.40; 95% CI, 1.29-1.51); these associations became comparable only after accounting for possible reverse causality by excluding the initial years of follow-up. Similarly, the PAF of CRC for high BMI was 9.9% (95% CI, 5.5%-14.4%), substantially lower than the PAFs for high WC and WHR, which were 17.3% (95% CI, 12.3%-22.1%) and 17.6% (95% CI, 12.9%-22.2%), respectively. After excluding the initial 7 years of follow-up, PAF estimates became analogous across all measures of obesity and were 15.7% (95% CI, 8.9%-22.4%) for BMI, 16.9% (95% CI, 9.8%-23.8%) for WC, and 18.0% (95% CI, 11.5%-24.6%) for WHR. Conclusions and Relevance In this cohort study of approximately half a million participants, the PAF of CRC attributable to excess weight, defined as high BMI, was considerably underestimated. The PAFs attributable to WC and WHR were consistent and much higher, underlining the importance of efforts to limit and overcome the obesity epidemic in CRC prevention.

Metabolic exchanges between strains in gut microbial communities shape their composition and interactions with the host. This study investigates the metabolic synergy between potential probiotic bacteria … and Saccharomyces boulardii, aiming to enhance anti-inflammatory effects within a multi-species probiotic community. By screening a collection of 85 potential probiotic bacterial strains, we identified two strains that demonstrated a synergistic relationship with S. boulardii in pairwise co-cultivation. Furthermore, we computationally predicted cooperative communities with symbiotic relationships between S. boulardii and these bacteria. Experimental validation of 28 communities highlighted the role of S. boulardii as a key player in microbial communities, significantly boosting the community’s cell number and production of anti-inflammatory effectors, thereby affirming its essential role in improving symbiotic dynamics. Based on our observation, one defined community significantly activated the aryl hydrocarbon receptor—a key regulator of immune response—280-fold more effectively than the community without S. boulardii. This study underscores the potential of microbial communities for the design of more effective probiotic formulations.