Gut microbiota #25

Gut microbiome is associated with recurrence-free survival in patients with resected high-risk melanoma receiving adjuvant immune checkpoint blockade

Usyk M, Hayes RB, Knight R, et al. Gut microbiome is associated with recurrence-free survival in patients with resected high-risk melanoma receiving adjuvant immune checkpoint blockade.

Immune checkpoint blockade (ICB) can be used to treat high-risk melanoma, but the results vary. About 25–40% of patients still have a recurrence of the disease, and some develop serious side effects. Therefore, better biomarkers are needed to predict who will benefit from the treatment, so that therapy can be tailored to each patient and work more effectively.

Increasing evidence suggests that the gut microbiome influences ICB treatment outcomes in melanoma patients. However, microbes as biomarkers have shown great variability between studies. In this study, fecal samples from 674 patients enrolled in a phase III clinical trial – investigating the combination of nivolumab plus ipilimumab vs. nivolumab alone across five geographic regions – were analyzed to evaluate the predictive potential of the gut microbiome.

Shotgun metagenome sequencing identified bacterial strains linked to recurrence after treatment. Eubacterium, Ruminococcus, Firmicutes, and Clostridium have previously been associated with immune checkpoint therapy outcomes. Eubacterium may enhance immunotherapy via anti-inflammatory effects, while Clostridium and Firmicutes influence T cell-mediated immune regulation. Ruminococcus shows mixed pro- and anti-inflammatory roles. Additional taxa associated with recurrence included Lawsonia, Bariatricus, and Blautia, the latter also previously linked to ICB treatment outcomes. Pathway analysis showed that Eubacterium and Ruminococcus correlated with carbohydrate metabolism that has been formerly linked to the microbiome and cancer treatment success.

Overall, the findings of the study suggest that gut bacterial markers can predict recurrence after adjuvant ICB treatment in melanoma, supporting their potential as clinically valid biomarkers to guide personalized therapy¹.

Microbiome signature of Parkinson’s disease in healthy and genetically at-risk individuals

Menozzi E, Ren Y, Geiger M, et al. Microbiome signature of Parkinson’s disease in healthy and genetically at-risk individuals.

Parkinson’s disease (PD) is a leading cause of disability, and its prevalence is growing fast worldwide. In PD, dopaminergic neurons of the substantia nigra are lost and aggregated -synuclein accumulate in brainstem and cortical regions. PD symptoms can be treated with levodopa, but to slow or prevent severe disability, early detection of individuals at risk would be crucial.

Genetic variants in the GBA1 gene, encoding glucocerebrosidase, are found in about 15% of PD cases. Evidence also supports the role of the microbiota-gut-brain axis in PD, and microbiome analysis might enable identification of healthy individuals at higher risk of neurodegeneration.

This cross-sectional, multicenter study analyzed patients with PD carrying a GBA1 gene variant, patients with PD not carrying the variant, healthy controls, and non-manifesting carriers of a GBA1 variant (i.e., not diagnosed with PD). A total of 540 participants were included.

Compared to healthy controls, non-manifesting carriers presented worse motor symptoms. Being a carrier or non-carrier of a GBA1 variant did not influence the microbiome, whereas beta-diversity difference between healthy controls and either group was significant. The authors then pooled all patients with PD regardless of their genetic status to identify a PD microbiome signature with an optimally powered analysis. In PD, Actinobacteriota, Bifidobacteriaceae, Streptococcus mutans, Bifidobacterium longum, Bifidobacterium dentium, and Lactobacillus paragasseri were enriched among many other taxa. In total, over 25% of the microbiome was altered compared to healthy controls.

An interesting finding was that the microbiome of non-manifesting carriers of a GBA1 variant was an "intermediate" between healthy controls and patients with PD. This was associated with disease progression and symptoms indicative of future development of PD. The same phenomenon was reproduced in three independent cohorts from the United States, Korea, and Turkey.

The authors reckon that gut microbiomes could be used to identify both genetically and non-genetically at-risk individuals who may be progressing toward PD and serve as an early disease marker¹.

Antibiotic use and gut microbiome composition links from individual-level prescription data of 14,979 individuals

Baldanzi G, Larsson A, Sayols-Baixeras S, et al. Antibiotic use and gut microbiome composition links from individual-level prescription data of 14,979 individuals.

Recurrent and long-term use of antibiotics is associated with many non-communicable diseases likely due to alterations in gut microbiome. Known short-term alterations include decrease in diversity and increased abundance of potential pathogens. However, large population-based investigations examining the long-term effects of antibiotics on gut microbiomes have not been conducted.

This study combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to investigate the associations between oral antibiotic use over 8 years and gut microbiome. Participants using antibiotics at the time of sampling or with an ongoing infection were excluded.

The authors observed that gut microbiome diversity decreased with each additional antibiotic course within three periods: < 1 year, 1–4 years and 4–8 years before fecal sampling. Of the different antibiotics, clindamycin, fluoroquinolones and flucloxacillin had the largest effect on diversity, whereas no associations were detected for extended-spectrum penicillins. Even a single course of tetracyclines, flucloxacillin, fluoroquinolones, clindamycin, sulfamethoxazole-trimethoprim, cephalosporins or macrolides less than 4 years or 4–8 years before sampling caused reduced diversity.

Taxonomically, use of clindamycin, fluoroquinolones and flucloxacillin was associated with a greater abundance of Enterocloster bolteae, E. citroniae, Flavonifractor plautii, Ruminococcus B gnavus and Eggerthella lenta, species previously associated with cardiometabolic risks. Overall, species negatively associated with antibiotic use were associated with better cardiometabolic and inflammatory outcomes.

The authors conclude that their results could inform future guidelines on outpatient antimicrobial practices, which should prioritize antibiotics that have a lower impact on the gut microbiome¹.