Gut microbiota #24

Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy

Sedentary lifestyle increases cancer risk, and exercise is known to enhance immune checkpoint inhibitor (ICI) efficacy. However, the mechanisms have remained largely unknown. Gut microbiota promotes antitumor immunity and exercise modulates gut microbiota, but
whether these factors are linked has not been studied. Phelps et al. used preclinical cancer models to explore possible connections.

They found that prolonged exercise limited melanoma tumor growth without affecting body weight. Exercise also boosted CD4 and CD8 T cells in tumor-draining lymph nodes. Importantly, this effect required gut microbiota, which was involved in exercise-induced antitumor activity. To establish causality, the authors performed fecal microbial transplantations (FMTs) into antibiotic-treated mice using feces from exercised and sedentary donors. FMT from exercised mice suppressed tumor growth, prolonged survival, and enhanced tumor immunity. While bacterial cell wall components are known to increase immune responses, the exercise- FMT effect appeared dependent on microbiota-derived metabolites.

Indeed, oral administration of microbial metabolites from exercised mice’s feces restrained melanoma tumor growth. To understand the role of metabolites, the authors used targeted metabolomics of 1-carbon (1C) metabolites and found that mainly precursors of the folate-dependent 1C pathway were diminished in exercised mice. Further experiments revealed that elevated formate levels promoted antitumor immunity and restrained tumor growth, and that exercise specifically increased formate. In addition to melanoma,
these effects were observed in adenocarcinoma and lymphoma models. Formate also dramatically reduced lung metastases. Formate’s effect on antitumor immunity was mediated via nuclear factor erythroid 2-related factor-2. Ultimately, they provide some translational evidence that high-formate-producing human microbiota is associated with enhanced tumor suppression and immunity.

Phelps CM, Willis NB, Duan T, et al. Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell 2025; 188: 5680-700.

Temporal dynamics and microbial interactions shaping the gut resistome in early infancy

Antibiotic resistance stems from antibiotic resistance genes (ARGs), which enable bacteria to withstand antibiotics. ARGs existed before human antibiotic use, but modern overuse has amplified their prevalence globally. When resistance reaches pathogenic microbes, it threatens public health by undermining antibiotics. However, more studies, especially in infancy are needed to understand gut resistome’s role in spreading antimicrobial resistance (AMR).

This study investigated infant gut resistome dynamics in a birth cohort with longitudinally collected fecal samples 8 times from birth up to five years of age. Early in infancy (3–6 days to 2 months), ARG richness showed a bimodal pattern, which disappeared by 6 months as most infants exhibited high ARG counts. At 12 months, bimodality reappeared, followed by a decline of ARGs at 60 months. ARG abundance relative to total genes was highest in the first 6 months and dropped after 12 months. Absolute ARG abundance varied largely between infants during the first 2 months of life, peaked at 6 months, and then dropped at 12 months.

It was further found that ARGs conferring resistance against tetracyclines, fluoroquinolones, penams, and cephalosporins were the most common and the most abundant until 6 months of age. ARGs against tetracyclines and fluoroquinolones remained the most common across all ages. ARG relative and absolute abundance did not differ between antibiotic- naïve infants and those exposed to antibiotics before the 1st sample at 3–6 days of life. Interestingly, microbial composition and birth mode seem to influence ARG diversity, while only few bacterial taxa have high number of ARGs. To conclude, this study revealed key temporal patterns and microbial interactions that shape the early-infant gut resistome, suggesting opportunities for targeted strategies to limit AMR during this critical developmental stage.

Chatzigiannidou I, Johansen PL, Dehli RK, et al. Temporal dynamics and microbial interactions shaping the gut resistome in early infancy. Nat Commun 2025; 16: 8139

Quantifying the varying harvest of fermentation products from the human gut microbiota

The gut microbiota influences the host largely through the exchange of fermentation products, mainly short-chain fatty acids produced by microbes in the large intestine. The microbes metabolize complex carbohydrates from plant-based foods, as well as dietary proteins that escape digestion in the small intestine. While metabolomics can identify a wide variety of compounds, it gives only snapshots and provides little insight into the overall flux of fermentation products that microbes produce and that host’s body takes up. To overcome this limit, this study established orthogonal approaches to quantify this flux, integrating data on bacterial metabolism, digestive physiology, and metagenomics.

This framework allowed creating many important findings. For instance, the bulk of carbon in microbiota-available carbohydrates, 90%, ended up in fermentation products, which were mostly taken up by the host. Variation in diet largely determined the total yield of fermentation products. Low yields may occur when diets are rich in highly processed foods lacking complex carbohydrates or when they include carbohydrates that resist digestion and pass through the gut unchanged. Somewhat surprisingly, the microbes themselves had less impact on the total daily fermentation product harvest, excluding some specific fermentation products, such as butyrate and lactate.

Arnoldini M, Sharma R, Moresi C, et al. Quantifying the varying harvest of fermentation products from the human gut microbiota. Cell 2025 ; 188 : 5332-42.