Gut bacteria responding to dietary change encode sialidases that exhibit preference for red meat-associated carbohydrates

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Dietary habits have been associated with alterations of the human gut resident microorganisms contributing to obesity, diabetes and cancer1. In Western diets, red meat is a frequently eaten food2, but long-term consumption has been associated with increased risk of disease3,4. Red meat is enriched in N-glycolylneuraminic acid (Neu5Gc) that cannot be synthesized by humans5. However, consumption can cause Neu5Gc incorporation into cell surface glycans6, especially in carcinomas4,7. As a consequence, an inflammatory response is triggered when Neu5Gc-containing glycans encounter circulating anti-Neu5Gc antibodies8,9. Although bacteria can use free sialic acids as a nutrient source10,11,12, it is currently unknown if gut microorganisms contribute to releasing Neu5Gc from food. We found that a Neu5Gc-rich diet induces changes in the gut microbiota, with Bacteroidales and Clostridiales responding the most. Genome assembling of mouse and human shotgun metagenomic sequencing identified bacterial sialidases with previously unobserved substrate preference for Neu5Gc-containing glycans. X-ray crystallography revealed key amino acids potentially contributing to substrate preference. Additionally, we verified that mouse and human sialidases were able to release Neu5Gc from red meat. The release of Neu5Gc from red meat using bacterial sialidases could reduce the risk of inflammatory diseases associated with red meat consumption, including colorectal cancer4 and atherosclerosis13.

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Fig. 1: Composition of gut microbial community of mice fed on soy, PSM or EBN diet.
Fig. 2: Characterization of sialidases preference for Neu5Ac- or Neu5Gc-containing substrates.
Fig. 3: Screening for Neu5Gc-preferring sialidases in human and environmental samples.

Data availability

Sequencing data supporting the findings of this study are available under accession number PRJNA505660. X-ray crystallographic data that support the findings of this study have been deposited in the RCSB (Research Collaboratory for Structural Bioinformatics) Protein Data Bank (accession codes: 6MRX, 6MRV, 6MYV and 6MNJ).

Code availability

The code used to generate the figures and for statistical analysis can be accessed from the corresponding author upon request.


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We thank all Zengler-, Varki- and Chang-lab members for helpful discussions. Research was supported in part by the National Institutes of Health under award no.R01GM32373 (to A.V.) and by the National Science Foundation under award no. IOS-1444435 (to G.C.). C.M. was supported by grants from the National Institutes of Health, USA (NIH grant no. T32GM8806) and by a Chancellor’s Research Excellence Scholarship (UCSD). F.A.-S. was partly supported by the Program Science Without Borders Bex 9254-13-7-Capes Brazil.

Author information

L.S.Z., C.M., F.A.-S., A.V. and K.Z. conceptualized the study. L.S.Z., F.A.-S. and K.Z. wrote the manuscript with input from all authors. L.S.Z. and C.M. performed and analysed the microbiome experiments. L.S.Z. and S.L.D. performed the enzymatic characterization. L.S.Z., F.A.-S. and P.S. performed the animal work. S.D.R. performed the protein expression and crystallization experiments, assisted by J.H. and D.S. C.Z. performed the metabolic model analysis. L.C., M.B.G. and C.H.T. constructed the fosmid library and performed the compost sialidase activity assays. C.H.T., G.C., A.V. and K.Z. provided resources and supervised the study.

Correspondence to Karsten Zengler.

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Competing interests

L.S.Z., C.M., F.A.-S., S.R., S.L.D., G.C., A.V. and K.Z. have filed a patent application (number pending) that claims the use of sialidases to reduce Neu5Gc.

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Supplementary Data, Discussion, Figs. 1–16, Tables 1–5 and References.

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