Cardiometabolic disease is the leading cause of death in zoo apes; yet its etiology remains unknown. Here, we investigated compositional and functional microbial markers in fecal samples from 57 gorillas across U.S. zoos, 20 of which are diagnosed with cardiovascular disease, in contrast with 17 individuals from European zoos and 19 wild gorillas from Central Africa. Results show that zoo-housed gorillas in the U.S. exhibit the most diverse gut microbiomes and markers of increased protein and carbohydrate fermentation, at the expense of microbial metabolic traits associated with plant cell-wall degradation. Machine learning models identified unique microbial traits in U.S. gorillas with cardiometabolic distress; including reduced metabolism of sulfur-containing amino acids and hexoses, increased abundance of potential enteric pathogens, and low fecal butyrate and propionate production. These findings show that cardiometabolic disease in gorillas is potentially associated with altered gut microbial function, influenced by zoo-specific diets and environments.

Department of Animal Science University of Minnesota Saint Paul MN USA

Department of Biology University of Nebraska at Omaha Omaha NE USA

Department of Food Science and Technology University of Nebraska Lincoln Lincoln NE USA

Department of Food Science Czech University of Life Sciences Prague Prague Czech Republic

HWM and MDD Great Ape Heart Project Detroit Zoological Society Royal Oak MI USA

Institute of Parasitology Biology Centre Czech Academy of Sciences Brno Czech Republic

Institute of Vertebrate Biology Czech Academy of Sciences Brno Czech Republic

Liberec Zoo Liberec Czech Republic

Nebraska Food for Health Center University of Nebraska Lincoln Lincoln NE USA

Primate Microbiome Project University of Nebraska Lincoln Lincoln NE USA

The Marine Mammal Center Sausalito CA USA

University of Massachusetts Amherst Amherst MA USA

WWF Central African Republic Bayanga Central African Republic

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Dennis, P. M. et al. Cardiac disease is linked to adiposity in male gorillas (Gorilla gorilla gorilla). PLoS One14, e0218763 (2019). PubMed PMC

Lowenstine, L. J., McManamon, R. & Terio, K. A. Comparative pathology of aging great apes: bonobos, chimpanzees, gorillas, and orangutans. Vet. Pathol.53, 250–276 (2016). PubMed

McManamon & Lowenstine. Cardiovascular disease in great apes. Fowler’s zoo and wild animal.

Rush, E. M., Ogburn, A. L. & Monroe, D. Clinical management of a western lowland gorilla (Gorilla gorilla gorilla) with a cardiac resynchronization therapy device. J. Zoo Wildl. Med.42, 263–276 (2011). PubMed

Banerjee, S. & Peterson, L. R. Myocardial metabolism and cardiac performance in obesity and insulin resistance. Curr. Cardiol. Rep.9, 143–149 (2007). PubMed

Kenny, D. E. et al. Aortic dissection: an important cardiovascular disease in captive gorillas (Gorilla gorilla gorilla). J. Zoo Wildl. Med.25, 561–568 (1994).

Rush, E. M. et al. Surgical implantation of a cardiac resynchronization therapy device in a western lowland gorilla (Gorilla gorilla gorilla) with fibrosing cardiomyopathy. J. Zoo Wildl. Med.41, 395–403 (2010). PubMed

Nemet, I. et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell180, 862–877.e22 (2020). PubMed PMC

Romano, K. A. et al. Gut microbiota-generated phenylacetylglutamine and heart failure. Circ. Heart Fail.16, e009972 (2023). PubMed PMC

Tang, W. H. W. & Hazen, S. L. The contributory role of gut microbiota in cardiovascular disease. J. Clin. Invest.124, 4204–4211 (2014). PubMed PMC

Zhang, Y., Wang, Y., Ke, B. & Du, J. TMAO: how gut microbiota contributes to heart failure. Transl. Res.228, 109–125 (2021). PubMed

Krynak, K. L., Burke, D. J., Martin, R. A. & Dennis, P. M. Gut microbiome composition is associated with cardiac disease in zoo-housed western lowland gorillas (Gorilla gorilla gorilla). FEMS Microbiol. Lett. 364, (2017). PubMed

Boyd, R. et al. Great ape heart project guidelines for the echocardiographic assessment of great apes. J. Zoo Wildl. Med.50, 822–836 (2020). PubMed

Lukas, K. & Stoinski, T. AZA Gorilla Species Survival Plan. Gorilla Care Manual. (Silver Spring).

Cabana, F., Fidget, A., Krebs, E. & Kaumanns, W. Feeding: gorilla nutrition. EAZA best practice, (2017).

Gomez, A. et al. Temporal variation selects for diet–microbe co-metabolic traits in the gut of Gorilla spp. ISME J10, 514–526 (2015). PubMed PMC

Campbell, T. P. et al. The microbiome and resistome of chimpanzees, gorillas, and humans across host lifestyle and geography. ISME J14, 1584–1599 (2020). PubMed PMC

Johnson, A. J. et al. Daily sampling reveals personalized diet-microbiome associations in humans. Cell Host Microbe25, 789–802.e5 (2019). PubMed

Eschweiler, K. et al. Host identity and geographic location significantly affect gastrointestinal microbial richness and diversity in western lowland gorillas (Gorilla gorilla gorilla) under human care. Animals (Basel)11, 3399 (2021). PubMed PMC

Macfarlane, G. T., Gibson, G. R., Beatty, E. & Cummings, J. H. Estimation of short-chain fatty acid production from protein by human intestinal bacteria based on branched-chain fatty acid measurements. FEMS Microbiol. Ecol.10, 81–88 (1992).

Al Hinai, E. A. et al. Modelling the role of microbial p-cresol in colorectal genotoxicity. Gut Microbes10, 398–411 (2019). PubMed PMC

Dufrêne, M. & Legendre, P. Species assemblages and indicator species: the need for a flexible asymmetrical approach. Ecol. Monogr.67, 345–366 (1997).

Mallick, H. et al. Multivariable association discovery in population-scale meta-omics studies. PLoS Comput. Biol.17, e1009442 (2021). PubMed PMC

Nishida, A. H. & Ochman, H. Captivity and the co-diversification of great ape microbiomes. Nat. Commun.12, 5632 (2021). PubMed PMC

Narat, V. et al. A multi-disciplinary comparison of great ape gut microbiota in a central African forest and European zoo. Sci. Rep.10, 19107 (2020). PubMed PMC

Konishi, Y. & Kobayashi, S. Microbial metabolites of ingested caffeic acid are absorbed by the monocarboxylic acid transporter (MCT) in intestinal Caco-2 cell monolayers. J. Agric. Food Chem.52, 6418–6424 (2004). PubMed

Desai, R. L. & Shields, J. A. Makromol. Chem.122, 134–144 (1969).

Mountfort, D. O. & Asher, R. A. Isolation from a methanogenic ferulate degrading consortium of an anaerobe that converts methoxyl groups of aromatic acids to volatile fatty acids. Arch. Microbiol.144, 55–61 (1986).

Venkatesagowda, B. & Dekker, R. F. H. Microbial demethylation of lignin: evidence of enzymes participating in the removal of methyl/methoxyl groups. Enzyme Microb. Technol.147, 109780 (2021). PubMed

Dhingra, D., Michael, M., Rajput, H. & Patil, R. T. Dietary fibre in foods: A review. J. Food Sci. Technol.49, 255–266 (2012). PubMed PMC

de Oliveira, D. M. et al. Ferulic acid: A key component in grass lignocellulose recalcitrance to hydrolysis. Plant Biotechnol. J.13, 1224–1232 (2015). PubMed

Kummen, M. et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J. Am. Coll. Cardiol.71, 1184–1186 (2018). PubMed

Mayerhofer, C. C. K. et al. Low fibre intake is associated with gut microbiota alterations in chronic heart failure. ESC Heart Fail7, 456–466 (2020). PubMed PMC

Amiri, P. et al. Role of butyrate, a gut microbiota derived metabolite, in cardiovascular diseases: A comprehensive narrative review. Front. Pharmacol.12, 837509 (2021). PubMed PMC

Tilves, C. et al. Increases in circulating and fecal butyrate are associated with reduced blood pressure and hypertension: Results from the SPIRIT trial. J. Am. Heart Assoc.11, e024763 (2022). PubMed PMC

Zhang, F. et al. Prolonged impairment of short-chain fatty acid and L-isoleucine biosynthesis in gut microbiome in patients with COVID-19. Gastroenterology162, 548–561.e4 (2022). PubMed PMC

Schirmer, M. et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat Microbiol.3, 337–346 (2018). PubMed PMC

Bartolomaeus, H. et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation139, 1407–1421 (2019). PubMed PMC

Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes.39, 424–429 (2015). PubMed PMC

Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes58, 1509–1517 (2009). PubMed PMC

Less, E. H. et al. Implementing a low-starch biscuit-free diet in zoo gorillas: The impact on health. Zoo Biol33, 74–80 (2014). PubMed

Hong, J. et al. Butyrate alleviates high fat diet-induced obesity through activation of adiponectin-mediated pathway and stimulation of mitochondrial function in the skeletal muscle of mice. Oncotarget7, 56071–56082 (2016). PubMed PMC

Naraoka, Y., Yamaguchi, T., Hu, A., Akimoto, K. & Kobayashi, H. Short chain fatty acids upregulate adipokine production in type 2 diabetes-derived human adipocytes. Acta Endocrinol.14, 287–293 (2018). PubMed PMC

Kircher, B. et al. Predicting butyrate- and propionate-forming bacteria of gut microbiota from sequencing data. Gut Microbes14, 2149019 (2022). PubMed PMC

Rogosa, M. Acidaminococcus gen. n., Acidaminococcus fermentans sp. n., anaerobic gram-negative diplococci using amino acids as the sole energy source for growth. J. Bacteriol.98, 756–766 (1969). PubMed PMC

Xu, H., Yang, F. & Bao, Z. Gut microbiota and myocardial fibrosis. Eur. J. Pharmacol.940, 175355 (2023). PubMed

von Buchholz, J. S. et al. Paracellular intestinal permeability of chickens induced by DON and/or C. jejuni is associated with alterations in tight junction mRNA expression. Microb. Pathog.168, 105509 (2022). PubMed

Lewis, C. V. & Taylor, W. R. Intestinal barrier dysfunction as a therapeutic target for cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol.319, H1227–H1233 (2020). PubMed PMC

Pastori, D. et al. Gut-derived serum lipopolysaccharide is associated with enhanced risk of major adverse cardiovascular events in atrial fibrillation: Effect of adherence to mediterranean diet. J. Am. Heart Assoc.6, e005784 (2017). PubMed PMC

Sandek, A. et al. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int. J. Cardiol.157, 80–85 (2012). PubMed

Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol.50, 1561–1569 (2007). PubMed

Zhan, S. et al. Intestinal fibrosis and gut microbiota: clues from other organs. Front. Microbiol.12, 694967 (2021). PubMed PMC

Costa, C. F. F. A. et al. Gut microbiome and organ fibrosis. Nutrients14, 352 (2022). PubMed PMC

Bowen, E. E., Hangartner, R. & Macdougall, I. Campylobacter-associated hemolytic uremic syndrome associated with pulmonary-renal syndrome. J. Gen. Intern. Med.31, 353–356 (2016). PubMed PMC

Filip, C. et al. Cardiovascular complications of hemolytic uremic syndrome in children. Maedica15, 305–309 (2020). PubMed PMC

Chen, J. & Vitetta, L. The role of butyrate in attenuating pathobiont-induced hyperinflammation. Immune Netw20, e15 (2020). PubMed PMC

Peng, L., Li, Z.-R., Green, R. S., Holzman, I. R. & Lin, J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr.139, 1619–1625 (2009). PubMed PMC

Morales, C. et al. Characterization of microbial communities from gut microbiota of hypercholesterolemic and control subjects. Front. Cell. Infect. Microbiol.12, 943609 (2022). PubMed PMC

Litvak, Y., Byndloss, M. X., Tsolis, R. M. & Bäumler, A. J. Dysbiotic Proteobacteria expansion: a microbial signature of epithelial dysfunction. Curr. Opin. Microbiol.39, 1–6 (2017). PubMed

Halfvarson, J. et al. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol. 2, 17004 (2017). PubMed PMC

Funke, G., Frodl, R. & Bernard, K. A. Corynebacterium mustelae sp. nov., isolated from a ferret with lethal sepsis. Int. J. Syst. Evol. Microbiol.60, 871–873 (2010). PubMed

Michalovich, D. et al. Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients. Nat. Commun.10, 5711 (2019). PubMed PMC

Amato, K. R. et al. Habitat degradation impacts black howler monkey (Alouatta pigra) gastrointestinal microbiomes. ISME J7, 1344–1353 (2013). PubMed PMC

Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell167, 1339–1353.e21 (2016). PubMed PMC

Nagpal, R. et al. Obesity-linked gut microbiome dysbiosis associated with derangements in gut permeability and intestinal cellular homeostasis independent of diet. J Diabetes Res2018, 3462092 (2018). PubMed PMC

Salguero, M. V., Al-Obaide, M. A. I., Singh, R., Siepmann, T. & Vasylyeva, T. L. Dysbiosis of Gram-negative gut microbiota and the associated serum lipopolysaccharide exacerbates inflammation in type 2 diabetic patients with chronic kidney disease. Exp. Ther. Med.18, 3461–3469 (2019). PubMed PMC

Sun, M. et al. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation115, 1398–1407 (2007). PubMed

Edes, A. N. & Brand, C. M. Age, sex, and inflammatory markers predict chronic conditions, cardiac disease, and mortality among captive western lowland gorillas (Gorilla gorilla gorilla). Primates62, 931–943 (2021). PubMed

Gomez, A. et al. Temporal variation selects for diet-microbe co-metabolic traits in the gut of Gorilla spp. ISME J10, 514–526 (2016). PubMed PMC

Colaco, N. A. et al. Transmethylamine-N-oxide is associated with diffuse cardiac fibrosis in people living with HIV. J. Am. Heart Assoc.10, e020499 (2021). PubMed PMC

Li, X. et al. Trimethylamine N-oxide exacerbates cardiac fibrosis via activating the NLRP3 inflammasome. Front. Physiol.10, 866 (2019). PubMed PMC

Rath, S., Heidrich, B., Pieper, D. H. & Vital, M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome5, 54 (2017). PubMed PMC

Fennema, D., Phillips, I. R. & Shephard, E. A. Trimethylamine and trimethylamine N-oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host-microbiome metabolic axis implicated in health and disease. Drug Metab. Dispos.44, 1839–1850 (2016). PubMed PMC

Feng, Y. et al. Comparative genomics and proteomics of Eubacterium maltosivorans: functional identification of trimethylamine methyltransferases and bacterial microcompartments in a human intestinal bacterium with a versatile lifestyle. Environ. Microbiol.24, 517–534 (2022). PubMed PMC

Kushkevych, I. et al. Recent advances in metabolic pathways of sulfate reduction in intestinal bacteria. Cells9, 698 (2020). PubMed PMC

Shi, Y. et al. Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway. Ann Transl Med. 9, 1732 (2021). PubMed PMC

Wilcken, D. E. & Wilcken, B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J. Clin. Invest.57, 1079–1082 (1976). PubMed PMC

Liao, J. et al. Leonurine affected homocysteine-methionine metabolism based on metabolomics and gut microbiota studies of clinical trial samples. Clin. Transl. Med.11, e535 (2021). PubMed PMC

Wu, X. et al. Gut microbiota contributes to the methionine metabolism in host. Front. Microbiol.13, 1065668 (2022). PubMed PMC

Barker, H. A. Amino acid degradation by anaerobic bacteria. Annu. Rev. Biochem.50, 23–40 (1981). PubMed

Bui, T. P. N. et al. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat. Commun.6, 10062 (2015). PubMed PMC

Tuerhongjiang, G. et al. Interplay between gut microbiota and amino acid metabolism in heart failure. Front Cardiovasc Med8, 752241 (2021). PubMed PMC

Wong, T.-T. Performance evaluation of classification algorithms by k-fold and leave-one-out cross validation. Pattern Recognit48, 2839–2846 (2015).

Gao, P. et al. An integrated multi-omics approach for AMR phenotype prediction of gut microbiota. in 2021 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) 2211–2216 (2021). 10.1109/BIBM52615.2021.9669397.

Konishi, Y. et al. Development and evaluation of a colorectal cancer screening method using machine learning-based gut microbiota analysis. Cancer Med. 11, 3194–3206 (2022). PubMed PMC

Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).

Pontzer, H., Wood, B. M. & Raichlen, D. A. Hunter-gatherers as models in public health. Obes. Rev.19, 24–35 (2018). PubMed

Rampelli, S. et al. Metagenome sequencing of the Hadza hunter-gatherer gut microbiota. Curr. Biol.25, 1682–1693 (2015). PubMed

O’Keefe, S. J. D. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun.6, 6342 (2015). PubMed PMC

Song, S. J. et al. Preservation methods differ in fecal microbiome stability, affecting suitability for field studies. mSystems1, e00021-16 (2016). PubMed PMC

Guan, H. et al. Comparison of fecal collection methods on variation in gut metagenomics and untargeted metabolomics. mSphere6, e0063621 (2021). PubMed PMC

Marotz, C. et al. Evaluation of the effect of storage methods on fecal, saliva, and skin microbiome composition. mSystems6, e01329 (2021). PubMed PMC

Mason, B. et al. Gastrointestinal symbiont diversity in wild gorilla: a comparison of bacterial and strongylid communities across multiple localities. Mol. Ecol.31, 4127–4145 (2022). PubMed

de Jonge, N., Carlsen, B., Christensen, M. H., Pertoldi, C. & Nielsen, J. L. The gut microbiome of 54 mammalian species. Front. Microbiol.13, 886252 (2022). PubMed PMC

Tung, J. et al. Social networks predict gut microbiome composition in wild baboons. Elife4, e05224 (2015). PubMed PMC

Bolyen, E. et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat. Biotechnol.37, 852–857 (2019). PubMed PMC

Callahan, B. J. et al. DADA2: High-resolution sample inference from Illumina amplicon data. Nat. Methods13, 581–583 (2016). PubMed PMC

McDonald, D. et al. Greengenes2 unifies microbial data in a single reference tree. Nat. Biotechnol.10.1038/s41587-023-01845-1 (2023). PubMed PMC

McIver, L. J. et al. bioBakery: a meta’omic analysis environment. Bioinformatics34, 1235–1237 (2018). PubMed PMC

Wood, D. E. & Salzberg, S. L. Kraken: ultrafast metagenomic sequence classification using exact alignments. Genome Biol. 15, R46 (2014). PubMed PMC

Beghini, F. et al. Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3. Elife10, e65088 (2021). PubMed PMC

R Core Team. R: A language and environment for statistical computing. https://www.R-project.org/ (2024).

Dinno, A. dunn. test: Dunn’s test of multiple comparisons using rank sums. R package version1, 1 (2017).

Oksanen, J. et al. vegan: Community ecology package. https://CRAN.R-project.org/package=vegan.

Russel, J. MicEco: Various functions for microbial community data. R package version 0.9.19, https://github.com/Russel88/MicEco (2016).

Rohart, F., Gautier, B., Singh, A. & Lê Cao, K.-A. mixOmics: An R package for ’omics feature selection and multiple data integration. PLoS Comput. Biol.13, e1005752 (2017). PubMed PMC