Altered abundance in cancer patients gut of diadenylate cyclase-encoding bacteria.

A database of 4,228 diadenylate cyclases (DACs) was identified across 3,901 gut microbial species by mining the Unified Human Gastrointestinal Protein catalogue.

• DAC-encoding species were identified from the Unified Human Gastrointestinal Genome catalogue, which contains 4,744 species total.
• 3,901 out of 4,744 species (approximately 82%) present in the catalogue were found to encode DACs.
• The resulting database comprised 4,228 DAC sequences across these species.
• Mining was conducted specifically to identify bacterial species capable of synthesizing cyclic di-AMP (c-di-AMP).

DAC-encoding species were significantly more abundant in the gut microbiota of healthy subjects compared to cancer patients.

• The study analyzed metagenomic data from 190 healthy subjects and 569 cancer patients.
• Cancer patients included those with melanoma, non-small cell lung cancer (NSCLC), and renal carcinoma.
• The higher abundance of DAC-encoding species in healthy microbiota was described as statistically significant.
• This finding indicates that c-di-AMP-producing bacteria are depleted in cancer-associated microbiota.

No significant differences in DAC-encoding species abundance were observed between immunotherapy responders and non-responders.

• The analysis compared cancer patients who responded to immunotherapy versus those who did not respond.
• Immunotherapy evaluated included PD-1/PD-L1 blockade treatments.
• No differences in DAC-encoding bacterial abundance were found between these two patient subgroups.
• This result suggests that the depletion of c-di-AMP-producing bacteria is a general feature of cancer-associated microbiota rather than a predictor of immunotherapy response.

c-di-AMP is a bacterial second messenger recognized by host immune sensors including the STING pathway, linking gut microbiota activity to tumor immunity.

• The STING pathway is identified as a key host immune sensor for microbial c-di-AMP.
• Recent evidence cited in the paper shows that microbial c-di-AMP can enhance anti-tumor responses.
• Microbial c-di-AMP has been shown to improve the efficacy of PD-1/PD-L1 blockade and radiotherapy.
• This interaction is described as holding 'significant therapeutic potential particularly for oncologic patients.'

The depletion of c-di-AMP-producing bacteria in cancer patients supports further investigation into their role in modulating anti-tumor immunity.

• The findings are discussed in the context of the increasingly recognized relationship between gut microbiota and tumor immunity.
• The authors concluded that these findings support 'further studies on their role in modulating anti-tumor immunity.'
• The study covered three cancer types: melanoma, NSCLC, and renal carcinoma, suggesting the depletion is not cancer-type specific.
• The therapeutic potential of restoring c-di-AMP-producing bacteria is implied as a relevant area for future research.