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Diet is ONE of the MANY factors that are integral and multifaceted in its influence on the composition & function of the gastrointestinal microbiome/metabolome throughout life (Wastyk, H. C. et al., Cell, 2021)

Of which extends to the underlying interplay between the intestinal barrier & the immune system (Conlon, A and Bird, A. R., Nutrients, 2014; Rinninella, E et al., Best Pract Res Clin Gastroenterol, 2023).

Lifestyle shifts following ‘westernization’ has led to a significant rise in....

Dysbiosis

Metabolic (i.e., diabetes) & non-communicable chronic diseases (NCCDs)

Inflammatory markers

Body Mass Index (BMI)

Reduced microbial taxa (diversity) & Markers of host health

(Wastyk, H. C. et al., Cell, 2021)

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🎯Background Continued: Hm, What Is It that We WANT?

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🎯Background Continued: Hm, What Is It that We WANT?

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Knowing this, the hope is for the identification of dietary strategies that can restore or enhance interactions between the microbiota & host for improved outcomes in health.

→ Like, therapeutic strategies combatting pathogenesis (Wastyk, H. C. et al., Cell, 2021)!

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Characteristics of 'Westernized' Diets: HIGH in...

*(↓) indicates a reduction in beneficial microbial bacterium that were previously dominant in pre-'Westernized' diets.

(Statovci, D et al., Front Immunol, 2017)

Fatty processed/domesticated meat, red-meat (↓Streptococcus bovis/gallolyticus) (Severino, A et al., Best Pract Res Clin Gastroenterol, 2024)

Sugar/artificial sweeteners (↓Lactobacillus, ↓ Bifidobacteria) (Ruiz-Ojeda, F. J. et al., Adv Nutr, 2019), corn-derived fructose syrup

Salt (↓ Akkermansia) (Hamad, I et al., Nutrients, 2022)

Refined grains (↓Faecalibacterium)

Saturated fat (↓ Bacteroidetes) (Hamamah, S et al., Nutrients, 2023)

Overall, this diet is significantly LOW in fiber, fermented food, nutrient dense/diverse foods, fruits, whole grains, unsaturated fat, vegetables, omega-3 fatty acids, etc.,.

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Acknowledgement: Reference List was created by all group members for their respective citations.

1. Allan, S. M., & Rothwell, N. J. (2001). Cytokines and acute neurodegeneration. Nature Reviews Neuroscience, 2(10), 734–744. https://doi.org/10.1038/35094583

2. Balasubramanian, R., Schneider, E., Gunnigle, E., Cotter, P. D., & Cryan, J. F. (2024). Fermented foods: Harnessing their potential to modulate the microbiota-gut-brain axis for mental health. Neuroscience and biobehavioral reviews, 158, 105562. https://doi.org/10.1016/j.neubiorev.2024.105562

3. Caffrey, E. B., Sonnenburg, J. L., & Devkota, S. (2024). Our extended microbiome: The human-relevant metabolites and biology of fermented foods. Cell Metabolism, 36(4), 684–701. https://doi.org/10.1016/j.cmet.2024.03.007

4. Cantarel, B. L., Coutinho, P. M., Rancurel, C., Bernard, T., Lombard, V., & Henrissat, B. (2009). The carbohydrate-active enzymes database (CAZy): An expert resource for glycogenomics. Nucleic Acids Research, 37(Database issue), D233–D238. https://doi.org/10.1093/nar/gkn663

5. Chen, L., Liu, B., Ren, L., Du, H., Fei, C., Qian, C., Li, B., Zhang, R., Liu, H., Li, Z., & Ma, Z. (2023). High-fiber diet ameliorates gut microbiota, serum metabolism and emotional mood in type 2 diabetes patients. Frontiers in Cellular and Infection Microbiology, 13. https://doi.org/10.3389/fcimb.2023.1069954

6. Chen, Y.-R., Zheng, H.-M., Zhang, G.-X., Chen, F.-L., Chen, L.-D., & Yang, Z.-C. (2020). High Oscillospira abundance indicates constipation and low BMI in the Guangdong Gut Microbiome Project. Scientific Reports, 10(1), 9364. https://doi.org/10.1038/s41598-020-66369-z

7. Conlon, M., & Bird, A. (2014). The Impact of Diet and Lifestyle on Gut Microbiota and Human Health. Nutrients, 7(1), 17–44. https://doi.org/10.3390/nu7010017

8. Cotillard, A., Kennedy, S. P., Kong, L. C., Prifti, E., Pons, N., Le Chatelier, E., Almeida, M., Quinquis, B., Levenez, F., Galleron, N., Gougis, S., Rizkalla, S., Batto, J.-M., Renault, P., ANR MicroObes Consortium, Dore, J., Zucker, J.-D., Clement, K., & Ehrlich, S. D. (2013). Dietary intervention impact on gut microbial gene richness. Nature, 500(7464), 585–588. https://doi.org/10.1038/nature12480

9. De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J. B., Massart, S., Collini, S., Pieraccinim G.,   Lionetti, P. (2010). Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences, 107(33), 14691–14696. https://doi.org/10.1073/pnas.1005963107

10. Delannoy-Bruno, O., Desai, C., Castillo, J. J., Couture, G., Barve, R. A., Lombard, V., Henrissat, B., Cheng, J., Han, N., Hayashi, D. K., Meynier, A., Vinoy, S., Lebrilla, C. B., Marion, S., Heath, A. C., Barratt, M. J., & Gordon, J. I. (2022). An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome. Proc Natl Acad Sci USA, 119(20). https://doi.org/10.1073/pnas.2123411119

11. Derrien, M., Belzer, C., & de Vos, W. M. (2017). Akkermansia muciniphila and its role in regulating host functions. Microbial Pathogenesis, 106, 171–181. https://doi.org/10.1016/j.micpath.2016.02.005

12. Dimidi, E., Cox, S. R., Rossi, M., & Whelan, K. (2019). Fermented Foods: Definitions and Characteristics, Impact on the Gut Microbiota and Effects on Gastrointestinal Health and Disease. Nutrients, 11(8), 1806. https://doi.org/10.3390/nu11081806

13. Granado-Serrano, A. B., Martin-Gari, M., Ssnchez, V., Riart Solans, M., Berdun, R., Ludwig, I. A., Rubio, L., Vilaprinyo, E., Portero-Otin, M., & Serrano, J. C. E. (2019). Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Scientific Reports, 9, 1772. https://doi.org/10.1038/s41598-019-38874-3

14. Hamad, I., Cardilli, A., Côrte-Real, B. F., Dyczko, A., Vangronsveld, J., & Kleinewietfeld, M. (2022). High-Salt Diet Induces Depletion of Lactic Acid-Producing Bacteria in Murine Gut. Nutrients, 14(6), 1171. https://doi.org/10.3390/nu14061171

15. Hamamah, S., Amin, A., Al-Kassir, A. L., Chuang, J., & Covasa, M. (2023). Dietary Fat Modulation of Gut Microbiota and Impact on Regulatory Pathways Controlling Food Intake. Nutrients, 15(15), 3365. https://doi.org/10.3390/nu15153365

16. Howard, E. J., Meyer, R. K., Weninger, S. N., Martinez, T., Wachsmuth, H. R., Pignitter, M., Auñon-Lopez, A., Kangath, A., Duszka, K., Gu, H., Schiro, G., Laubtiz, D., & Duca, F. A. (2024). Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites. The Journal of nutrition, 154(7), 2014–2028. https://doi.org/10.1016/j.tjnut.2024.05.003

17. Ionita-Mindrican, C.-B., Ziani, K., Mittitelu, M., Oprea, E., Neacsu, S. M., Moroson, E., Dumitrescu, D.-E., Rosca, A. C., Draganescu, D., & Negrei, C. (2022). Therapeutic benefits and dietary restrictions of fiber intake: A state of the art review. Nutrients, 14(13), 2641. https://doi.org/10.3390/nu14132641

18. Jeyaram, K., Lahti, L., Tims, S., Hans, Gelder, van, Willem, Smidt, H., & Zoetendal, E. G. (2025). Fermented foods affect the seasonal stability of gut bacteria in an Indian rural population. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-56014-6

19. Klimenko, N. S., Tyakht, A. V., Popenko, A. S., Vasiliev, A. S., Altukhov, I. A., Ischenko, D. S., Shashkova, T. I., Efimova, D. A., Nikogosov, D. A., Osipenko, D. A., Musienko, S. V., Selezneva, K. S., Baranova, A., Kurilshikov, A. M., Toshchakov, S. M., Korzhenkov, A. A., Samarov, N. I., Shevchenko, M. A., Tepliuk, A. V., & Alexeev, D. G. (2018). Microbiome responses to an uncontrolled short-term diet intervention in the frame of the citizen science project. Nutrients, 10(5), 576. https://doi.org/10.3390/nu10050576

20. Leeuwendaal, N. K., Stanton, C., O’Toole, P. W., & Beresford, T. P. (2022). Fermented Foods, Health and the Gut Microbiome. Nutrients, 14(7), 1527. https://pubmed.ncbi.nlm.nih.gov/35406140/

21. Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., Almeida, M., Arumugam, M., Batto, J.-M., Kennedy, S., Leonard, P., Li, J., Burgdorf, K., Grarup, N., Jorgensen, T., Brandslund, I., Nielsen, H. B., Juncker, A. S., Bertalan, M., Levenez, F., ... Pedersen, O. (2013). Richness of human gut microbiome correlates with metabolic markers. Nature, 500(7464), 541–546. https://doi.org/10.1038/nature12506

22. Li, C.-J. (Ed.). (2014). Butyrate: Food sources, functions and health benefits. Nova Science Publishers.

23. Liu, S., Li, E., Sun, Z., Fu, D., Duan, G., Jiang, M., Yu, Y., Mei, L., Yang, P., Tang, Y., & Zheng, P. (2019). Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Scientific Reports, 9, Article 287. https://doi.org/10.1038/s41598-018-38218-9

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Building onto the concept of gut microbiota adaptability following short-term changes in diet, the selected experiment focused on the effects of two microbiota targeted dietary interventions (fermented foods vs. plant-based fiber) on the immune system, and microbiome in healthy (human) adults (Wastyk, H. C. et al., Cell, 2021).

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Microbial profiles can change depending on the composition of diet--it has been identified that gut microbiota can be bettered following a ‘healthy diet' → allowing for possible disease/metabolic disorder combat (Conlon, A and Bird, A. R., Nutrients, 2014).

Exemplified in a random control trial involving patients with ulcerative colitis:

Anti-inflammatory diets in combination with fecal microbiota transplantations (FMT) exhibited greater results--better long-term remission maintenance--compared to that of standard (medical) treatment (Rinninella, E et al., Best Pract Res Clin Gastroenterol, 2023).

Highlighting the potential for human gut microbiota modulation (by diet) against disease. And, as each nutrient can possesses a distinct/certain effect on the gut microbiota, there is a rising interest in investigating the benefits of certain dietary combinations, patterns, and bases (Rinninella, E et al., Best Pract Res Clin Gastroenterol, 2023).

→ High-fermented food vs. high plant-based fiber.

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Abstract Figure (Wastyk, H. C. et al., Cell, 2021)

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Plant-Based Fiber Importance on Microbiota: Increased dietary fiber intake aids in...

Producing microbiota-accessible carbohydrates (MACs)--benefits metabolism of microbiota taxa (Wastyk, H. C. et al., Cell, 2021)

Increasing microbiome richness/diversity (increased beneficial bacterial taxa like that of Akkermansia, Bifidobacterium, Lactobacillus) (Howard, E. J. et al., J Nutr, 2024)

Lessening low-density lipoprotein cholesterol concentrations within the blood (Sidju, S. R. K. et al., Nutrients, 2023).

Enabling bacterial fermentation → Short-chain fatty acids (i.e., butryrate, propionate, acetate) = enhancing metabolic homeostasis = colonic gut peptide release (i.e., glucagon-like peptide-1 (GLP-1)) (Howard, E. J. et al., J Nutr, 2024)

Microbiota possessing distinct functionalities depending on fiber viscosity, type, & solubility (Howard, E. J. et al., J Nutr, 2024).

==> I.e., High viscosity, β-Glucan (soluble-fiber) from oats = enhanced glucose homeostasis

==> I.e., Low viscosity, dextrin (soluble-fiber) from wheat = enhanced insulin sensitivity

Modifying immune system function via metabolites = Reduces local & systemic means of inflammation (Wastyk, H. C. et al., Cell, 2021)

Exemplified by how in-vivo mice models with high-fiber diets defended against myocardial infarction—stopped unfavorable remodeling and diminished infarct size (Zhao, J et al., Front Microbiol, 2022).

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Abstract Figure (Wastyk, H. C. et al., Cell, 2021)

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Fermented Food Importance on Microbiota: Popularity resurged due to their historic potential (i.e., Lactobacillus) that has been LESSENED due to current diet (Wastyk, H. C. et al., Cell, 2021)

Microbial fermentation alters food properties—converts phenolic compounds + complex carbohydrates → bioactive metabolites (i.e., SCFA))—boosting immune function & response (Stiemsma, L et al., J Nutr, 2020)

==> More microbial metabolites like tryptophan (for serotonin), polyphenolic compounds (for bioavailability), and bile acids (for metabolism)) (Balasubramanian, R et al., Neurosci Biobehav Rev, 2024)

Pathway aid (gut-to-brain information communication/relay) (Balasubramanian, R et al., Neurosci Biobehav Rev, 2024)

Gut microbiome diversity (Wastyk, H. C. et al., Cell, 2021)

Nutrionally rich & environmentally sustainable alternative (i.e., protein-rich legume fermentation with lactic acid bacteria (LAB) OVER that of animal meat) for novel strains of probiotics (Valentino, V et al., Microb Biotechnol, 2024).

Anti-nutrient reduction (Dimidi, E et al., Nutrients, 2019), Anti-microbial peptides

Gut barrier maintenance & pH modification

Biogenic amines (Dimidi, E et al., Nutrients, 2019)

Probiotic effects (metabolic pathway reprogramming) (Dimidi, E et al., Nutrients, 2019)

Exemplified by how consuming kefir (a type of fermented food) can eradicate Helicobacter pylori, and malabsorption of lactose (Dimidi, E et al., Nutrients, 2019).

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What are the major findings and relevant critical analysis? 🧐

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What are the major findings and relevant critical analysis? 🧐

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🍽️Diet largely influences the host gut microbiota composition (diversity, species composition and density) & immune system (inflammation and health status).

🥦After High-fiber diet intervention: No diversity increase.

Due to:

Short 10-week intervention is too hurried for microbiota reconstruction*

Modern excessive sanitation measures (e.g. overuse of food chemical sanitizers) reducing bacterial diversity & exchanging

Insufficient gut bacteria cultivation requiring simultaneous ingestion of fiber-rich foods & desired bacteria

Caucasian genetic deficiency of certain bacterial species that Caucasian subjects lost some bacteria that can metabolize glycans.

*microbiota reconstruction: change in modeling of microbiota diversity, density & composition (i.e. various species)

🧀After High-fermented-food diet intervention: there is an increase in gut microbiota diversity & decrease in inflammatory proteins synthesis & NCCDs incidence (Wastyk, H. C. et al., Cell, 2021).

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1. The process of bacterial diversity increase is sluggish = stubbornness of fast microbiota reconstruction caused by diet alteration.

2. The fermented foods are not the main providers of new bacteria = eating high fermented food does not have an direct influence on microbiota reconstruction.

3. The origin of newly acquired taxa remains ambiguous, but maybe these new taxa are from the surroundings, or they have already existed before the study starts just without detection.

(Wastyk, H. C. et al., Cell, 2021).

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Figure 1A (Wastyk, H. C. et al., Cell, 2021)

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Total 17-week protocol (10-week dietary intervention) with participants (N = 381 → 39) randomized by number generator to the high-fiber diet (n = 21) OR high-fermented foods diet (n = 18) (Wastyk, H. C. et al., Cell, 2021).

⭐️Final Participant Characteristics:

(Analysis used (n=18) in each arm)

Average BMI 25 ± 4 kg/m²

Average age 51 ± 12 years

73% Female

81% Caucasian

(Wastyk, H. C. et al., Cell, 2021)

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What is the significance/major contributions of the study? 👍

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What is the significance/major contributions of the study? 👍

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👩🏼‍🏫Enhancing understanding of distinct individual participant's gut bacterial and immune response to diet change = promoting personalized diet recommendation

🦠Construction of mechanistic models: to investigate the causality between diet and host response = enabling global health improvement and health burden alleviation (Wastyk, H. C. et al., Cell, 2021).

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Figure 1B (Wastyk, H. C. et al., Cell, 2021)

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BASELINE (W-2) to END OF MAINTENANCE (W10):

⭐️VARIABLES:

*Collected stool (microbiota metabolic output, function, and composition) and blood samples (immune system markers) (Wastyk, H. C. et al., Cell, 2021)

Primary Outcome Variable: Cytokine Response Score (CRS)

Secondary Outcome Variable: Change in gut microbiome composition/diversity

⭐️DIET:

*High fiber/fermented food consumption increased every two weeks.

High Fiber Diet:

Vegetables, nuts, grains, fruits, seeds, etc.,

Baseline: Mean 21.5 ± 8.0g/day

Maintenance: Mean 45.1 ± 10.7g/day

High Fermented-Foods Diet:

Fermented vegetables, cottage cheese, vegetable brine, kombucha, fermented non-alcoholic beverages, etc.,

Baseline: Mean 0.4 ± 0.6g/day

Maintenance: Mean 6.3 ± 2.9g/day

(Wastyk, H. C. et al., Cell, 2021)

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Figure 1C-D (Wastyk, H. C. et al., Cell, 2021)

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⭐️4 PHASES:

1. "Baseline": 3-Week Pre-Intervention

2. "Ramp": 4-Week Ramp Phase (progressive increase in respective diet (arm) intake)

3. "Maintenance": 6-Week Maintenance Phase (consistent consumption of respective diet (arm) at high levels)

4. "Choice": 4-Week Choice Period (respective diet (arm) level to the wanted extent of participants)

(Wastyk, H. C. et al., Cell, 2021)

⭐️ IMPORTANT NOTE:

*Participants did not increase consumption of food constituting the opposing arm. And, varied (no consistent subcategories) in types of fermented/fiber food consumed (Wastyk, H. C. et al., Cell, 2021).

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Any weaknesses that require improvement? 🙋🏼‍♀️

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Any weaknesses that require improvement? 🙋🏼‍♀️

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📊Small sample size with only 18 people per arm decreases statistical strength.

⏳Short study duration (10 weeks) cannot explore long-term efficacy, safety & stability.

🔕No control group cannot exclude impacts of confounding factors.

👩🏼Limited single subjects which are mainly healthy Caucasian women around age 51 (Wastyk, H. C. et al., Cell, 2021).

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What can be further investigated as the future directions? 🗺️

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What can be further investigated as the future directions? 🗺️

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1. The diet change effects on different subjects with disease, immune impairment and inflammation or on younger people with different races than white can be examined for efficacy & stability of dietary change.

2. The diet alteration with simultaneous consumption of high fiber and fermented food can be explored for its synergetic effects on host microbiota composition & immune status (Wastyk, H. C. et al., Cell, 2021).

3. The long-term study (e.g. with duration of about four months dietary change intervention) may be conducted for long-term effectiveness, safety & clinical feasibility.

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Comparing and contrasting with the study of High-fiber diet ameliorates gut microbiota, serum metabolism and emotional mood in type 2 diabetes patients (Chen et al., Front Cell Infect Microbiol, 2023).

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Comparative analysis to other publication ⚖️

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Comparative analysis to other publication ⚖️

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Similarity:

1. Similar change of gut microbiota & inflammation condition in response to high-fiber diet: There was a study investigating the high-fiber diet effects on type II diabetes participants that high-fiber foods increased the density, diversity and composition of the participants’ gut microbiota and decreased the inflammation condition, which were similar to the results of our selected paper.

2. Small sample size: Chen’s research also adoped small sample size with only n=9 for treatment group and n=8 for control group, reducing the statistical power.

3. Short study duration (4 weeks of high-fiber-diet treatment) cannot explore long-term effectiveness, safety & stability.

4. Limited single subjects with only type II diabetes patients whose glycosylated hemoglobin (HbA1c) measurements are 6.5-12%, excluding those who suffered from other chronic diseases (including type I diabetes, severe mental disorders, liver cirrhosis, cancers, cardiovascular diseases, etc.) and ingested prebiotics and antibiotics three months ago. Maybe the subjects’ age, gender and race could be further clarified for reference.

Contrast:

1. Presence of control group: providing the baseline level for comparing the differences in effects (e.g. blood sugar & lipid levels) and eliminating the confounding factors’ impacts.

2. Different subjects: type II diabetes patients whose HbA1c measurements are 6.5-12%, which is different from our selected paper (subjects are mainly healthy Caucasian women around age 51 (Wastyk, H. C. et al., Cell, 2021)).

3. Metabolic improvement: However, in addition to the microbiota composition and immune change, the researchers found that participants’ blood sugar and lipid homeostasis were ameliorated with rised level of insulin and dropped level of triglyceride.

4. Mental improvement: They also explored the participants’ mood response to the dietary change, showing the improved anxiety and depression status.

5. Multiaspect understanding: The results enhance the understanding of diet alteration effects on microbiota composition, inflammation, metabolic and meatal health among chronic-diseased people, demonstrating a multiaspect appreciation of diet-indued health improvement.

6. Extensive enhancement of global health: A wider global health guidance can be proposed in terms of high-fiber diet recommendation for both type II diabetes patients and healthy people, and global health may be largely improved subsequently (Chen et al., Front Cell Infect Microbiol, 2023)

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Figure 3A (Wastyk, H.C. et al., Cell, 2021)

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Researchers hypothesized → alpha diversity would increase as fiber consumption increased

Results → hypothesis NOT supported ❌

📚 Previous literature has often linked high fiber diets to increased microbial diversity, based on both interventional animal studies and long term associations in humans (Sonnenburg, E., et al., Nature, 2016; De Filipo, C., et al., PNAS, 2010; Le Chatelier, E., et al., Nature, 2013). However, this was not consistent with the current study.

∴ Over the course of the intervention, there was no change in alpha diversity

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Figure 3B (Wastyk, H.C. et al., Cell, 2021)

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What About Microbial Proteins Per Gram Stool 🤔

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What About Microbial Proteins Per Gram Stool 🤔

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Researchers found → increase in microbial proteins per gram stool ✅

They inferred → it was bacteria already present that grew

∴ Since no new bacterial species were detected, and there was an increase in microbial proteins per gram stool (total bacterial biomass), it is likely bacteria already present in the microbiome that is growing.

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Figure 3C (Wastyk, H.C. et al., Cell, 2021)

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Growing Bacteria: Good or Bad at Fiber Degradation? 

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Growing Bacteria: Good or Bad at Fiber Degradation? 

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Researchers found → an increase in 11 types of carbohydrate active enzymes (CAZymes) ⬆️

Method → metagenomic sequencing 🧬

📚 Previous studies have also reported similar findings. For example, one study investigating fiber rich snacks found that increased consumption led to a significant increase in CAZyme gene abundance (Delannoy-Bruno, O., et al., Proc Natl Acad Sci USA, 2022).

∴ This suggests it was bacteria adept at fiber degradation that increased in abundance

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Figure 3D (Wastyk, H.C. et al., Cell, 2021)

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Researchers measured → fecal short-chain fatty acids (SCFAs)

Found mixed results →

Butyrate levels did not increase ❌

Three BCFAs decreased ✅

Isobuytric and isovaleric acid

Previously associated with hypercholesterolemia (Granado-Serrano, A., et al., Scientific Reports, 2019)

Valeric acid

Previously associated with autism spectrum disorder (Liu, S., et al., Scientific Reports, 2019)

📚 Previous studies on dietary fiber interventions have often reported increases in butyrate. For instance, one study observed elevated fecal butyrate levels following fiber consumption (So, D., et al., American Journal of Clinical Nutrition, 2018). This was not consistent with the current study.

📚 Previous studies also have also linked dairy as sources of BCFAs (Taormina, V., et al., Nutrients, 2020).

🔍 Note → As participants reported a decrease in animal protein consumption, its possible the observed decrease in BCFAs can be due to this dietary change.

∴ Metabolic output shifted, but results were mixed.

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Let's Discuss → Fermented-Food Arm Results!

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Let's Discuss → Fermented-Food Arm Results!

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Figure 5A-C (Wastyk, H. C. et al., Cell, 2021)

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🦠 Fermented-food intake increases microbiota diversity 🦠 

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🦠 Fermented-food intake increases microbiota diversity 🦠 

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Overall ↑ in ɑ-diversity (as seen with observed ASVs, phylogenetic diversity and Shannon diversity testing)

This was exemplified in a more recent study; the fermented-food diet resulted in an increased ɑ-diversity (Leeuwendaal, N. K. et al., Nutrients, 2022). Interestingly, in Wastyk et al.'s and Leeuwendaal et al.'s study alike, this same increase was not seen in the fibre-diet participants.

NO increase in relative abundance of microbial species per gram of stool.

(Wastyk, H. C. et al., Cell, 2021)

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Figure 5D (Wastyk, H. C. et al., Cell, 2021)

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🧬 Let's get specific: What Microbes Changed?

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🧬 Let's get specific: What Microbes Changed?

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9 ASVs (amplicon sequence variants) increased over the course of the intervention:

All in the Firmicutes phylum: (4) in the Lachnospiraceae family, (2) in the Ruminococcaceae family, and (1) in the Streptococcaceae family.

🔗 Link: Unno et al.'s study in healthy women between ages 20-24 shows that the ingestion of fermented-milk leads to a significant increase in Firmicutes (longitudinally), relative to Bacteroidetes (Unno, T. et al., JDS, 2015). These results mirror Wastyk et al.'s.

(Wastyk, H. C. et al., Cell, 2021)

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Figure 5E (Wastyk, H. C. et al., Cell, 2021)

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Insignificant/little overlap between increased microbiome ASVs and ASVs IN the fermented-foods → Indirect effect (Wastyk, H. C. et al., Cell, 2021).

🔍 Hypothesis: A study explains that even when fermented foods are injested by the host, they themselves become further fermented and interact with the GI tract in a novel way (Caffrey, E. B. et al., Cell Metab, 2024). This may lead to the creation and detection of new bacterial taxa.

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Figure S6A (Wastyk, H. C. et al., Cell, 2021)

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Fermented-food intake decreases CAZyme abundance 🥯 

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Fermented-food intake decreases CAZyme abundance 🥯 

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↓ Relative abundance 8 CAZymes (Wastyk, H. C. et al., Cell, 2021)

(3) starch-degrading and (5) plant degrading

🔗 Link & Further Study: A recent study of a rural Indian population in Manipur –a self-declared fermented-foods eating population (consuming mostly fermented soybeans and milk)– have gut microbiomes extremely abundant in Prevotella. Prevotella shows, amongst all Bacteroidota (in the phylum), the lowest potential to produce CAZymes and short-chain fatty acids (SCFAs) in the gut (Jeyaram, K. et al., Nat Commun, 2025). Thus, consuming a high-fermented-food diet may have increased Prevotella in the gut of participants. Further investigation is required to asses the existence of a correlation or causation.

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Figure 6A (Watyk, H. C. et al., Cell, 2021)

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🩹 Fermented-food intake decreases markers of inflammation 

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🩹 Fermented-food intake decreases markers of inflammation 

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↑ Cytokine levels at a steady state → low-grade inflammation (across the body)

Cytokine profiling → ↓ in 19/93 cytokines

Longitudinal decreases in pro-inflammatory cytokines, such as IL-6,  CXCL10,  IL-18, etc.

(Wastyk, H. C. et al., Cell, 2021)

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Figure 6 B&C (Wastyk, H. C. et al., Cell, 2021)

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🛡️ Changes in Immune Cell Abundance and Signalling 

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🛡️ Changes in Immune Cell Abundance and Signalling 

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↓ Decrease in overall endogenous signalling

↑ Effector memory CD4+ cell abundance

NO change in signalling capacity of immune cells (CD4+, CD8+, and B cells) in both arms.

(Wastyk, H. C. et al., Cell, 2021)

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Figure 2: Effects of diet on cognitive decline (Adapted from: Porras-García, E. et al., Front. Nutr., 2023).

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These inflammatory species (e.g. IL-6, CXCL10, etc.) are often observed as byproducts of M1 microglia, the “immune cells of the brain”. M1 over-activation can lead to neurodegeneration, and neuroinflammation (Alan, S. M. & Rothwell, N. J., Nat Rev Neurosci, 2001).

🔍 Link & Hypothesis: Fermented foods may have a neuroprotective effect, by way of immune system modulation. Further supported by a moderately-well established relationship in the literature; a fermented-food diet leads to an increase in brain-derived neurotropic factor (BDNF; enhancing neuronal health and differentiation) and a decrease in cognitive decline symptoms and inflammation (Porras-García, E. et al., Front Nutr, 2023).

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25. Rinninella, E., Tohumcu, E., Raoul, P., Fiorani, M., Cintoni, M., Mele, M. C., Cammarota, G., Gasbarrini, A., & Ianiro, G. (2023). The role of diet in shaping human gut microbiota. Best practice & research. Clinical gastroenterology, 62-63, 101828. https://doi.org/10.1016/j.bpg.2023.101828

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27. Rossio, J. L. (1999). Cytokines and Nutritional Status: Possible Correlations and Investigations. In https://www.ncbi.nlm.nih.gov/books/NBK230989/. National Academies Press (US).

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29. Sidhu, S. R. K., Kok, C. W., Kunasegaran, T., & Ramadas, A. (2023). Effect of Plant-Based Diets on Gut Microbiota: A Systematic Review of Interventional Studies. Nutrients, 15(6), 1510.

30. Sonnenburg, E. D., Smits, S. A., Tikhonov, M., Higginbottom, S. K., Wingreen, N. S., & Sonnenburg, J. L. (2016). Diet-induced extinctions in the gut microbiota compound over generations. Nature, 529(7585), 212–215. https://doi.org/10.1038/nature16504

31. So, D., Whelan, K., Rossi, M., Morrison, M., Holtmann, G., Kelly, J. T., Shanahan, E. R., Staudacher, H. M., & Campbell, K. L. (2018). Dietary fiber intervention on gut microbiota composition in healthy adults: A systematic review and meta-analysis. The American Journal of Clinical Nutrition, 107(6), 965–983. https://doi.org/10.1093/ajcn/nqy041

32. Statovci, D., Aguilera, M., MacSharry, J., & Melgar, S. (2017). The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces. Frontiers in immunology, 8, 838. https://doi.org/10.3389/fimmu.2017.00838

33. Stiemsma, L. T., Nakamura, R. E., Nguyen, J. G., & Michels, K. B. (2020). Does Consumption of Fermented Foods Modify the Human Gut Microbiota? The Journal of Nutrition, 150(7). https://doi.org/10.1093/jn/nxaa077

34. Taormina, V. M., Unger, A. L., Schiksnis, M. R., Torres-Gonzalez, M., & Kraft, J. (2020). Branched-chain fatty acids: An underexplored class of dairy-derived fatty acids. Nutrients, 12(9), 2875. https://doi.org/10.3390/nu12092875

35. Unno, T., Choi, J.-H., Hur, H.-G., Sadowsky, M. J., Ahn, Y.-T., Huh, C.-S., Kim, G.-B., & Cha, C.-J. (2015). Changes in human gut microbiota influenced by probiotic fermented milk ingestion. Journal of Dairy Science, 98(6), 3568–3576. https://doi.org/10.3168/jds.2014-8943

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37. Wastyk H. C., Fragiadakis G. K., Perelman D., et al. Gut-microbiota-targeted diets modulate human immune status. (2021). Cell. 2021;184(16):4137–4153. doi:10.1016/j.cell.2021.06.019

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39. Valles-Colomer, M., Falony, G., Darzi, Y., Tigchelaar, E. F., Wang, J., Tito, R. Y., Schiweck, C., Kurilshikov, A., Joossens, M., Wijmenga, C., Claes, S., Van Oudenhove, L., Zhernakova, A., Vieira-Silva, S., & Raes, J. (2019). The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology, 4(4), 623–632. https://doi.org/10.1038/s41564-018-0337-x

40. Zhao, J., Cheng, W., Lu, H., Shan, A., Zhang, Q., Sun, X., Kang, L., Xie, J., & Xu, B. (2022). High fiber diet attenuate the inflammation and adverse remodeling of myocardial infarction via modulation of gut microbiota and metabolites. Frontiers in microbiology, 13, 1046912. https://doi.org/10.3389/fmicb.2022.1046912

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Figure 5E (Wastyk, H.C. et al., Cell, 2021)

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Did Participants Bite More Than They Could Chew?

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Did Participants Bite More Than They Could Chew?

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Researchers questioned → why there wasn't a larger microbiota response to the fiber 🤔

Hypothesized → fiber intake exceeded the microbiome's fermentation capabilities

Method → analyzed stool carbohydrates using HP - LC

Results → positive correlation found between fiber intake and stool carbohydrate levels ✅

📚 Previous literature also suggests when fiber intake is increased rapidly or in large amounts, the microbiome may not have the enzymatic capabilities to ferment all of it, possibly leading to digestive symptoms, such as bloating and diarrhea (Ionita-Mindrican, C., et al., Nutrients, 2022). As stool carbohydrates increased as fiber intake increased, this was consistent with the study's findings.

∴ Participants' microbiomes were unable to fully break down the increased fiber.

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Figure 4B (Wastyk, H.C. et al., Cell, 2021)

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Researchers used →

O-link (multiplex proteomic platform) to measure circulating cytokines

CyTOF (single-cell mass cytometry) to measure cell frequency & endogenous signalling

Flow cytometry to evaluate signalling capacity

Participants grouped based on changes in steady-state immune system activation →

1. High inflammation group

2. Low inflammation group I

3. Low inflammation group II

🔍 Note → Variation in fiber subtypes consumed may have contributed to differences in immune responses.

∴ Researchers identified three distinct immune response groups, suggesting participants differed in how their immune system reacted to the high fiber intervention.

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Figure 4D (Wastyk, H.C. et al., Cell, 2021)

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Did Alpha Diversity Differ Between The Groups 🤔

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Did Alpha Diversity Differ Between The Groups 🤔

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Researchers measured → ASVs across the three inflammation groups at baseline ⚖️

Found →

No significant difference between high inflammation and low inflammation I groups ❌

Low inflammation II showed significantly higher alpha diversity ✅

∴ The low inflammation group II had significantly higher alpha diversity as baseline, suggesting it may be associated with a more regulated or less inflammatory immune response profile.

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Figure 4E (Wastyk, H.C. et al., Cell, 2021)

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Researchers found →

Coprococcus, Ruminococcus, Oscillospira, and Anaerostipes were more prevalent in low inflammation groups

These taxa have previously been linked to higher quality of life, better metabolic health, and increased butyrate production (Valles-Colomer, M., et al., Nature Microbiology, 2019; Klimenko, N., et al., Nutrients, 2018; Chen, Y., et al., Scientific Reports, 2020; Li, Butyrate: Food Sources, Functions and Health Benefits, 2014).

Akkermansia was more abundant in the high inflammation group

Previously been positively associated with metabolic health (Derrien, M., et al., Microbial Pathogenesis, 2017)

📚 Previous literature investigating fiber rich diets have also reported similar taxa. For example, a recent study examining fiber rich snacks made from peas and oranges observed a significant increase of Lachnospiraceae and Ruminococcus (Delannoy-Bruno, O., et al., Proc Natl Acad Sci USA, 2022).

∴ Low inflammation groups were enriched in beneficial taxa linked to gut health and butyrate production, while high inflammation participants a different microbial profile. This suggests that people can respond differently to fiber depending on their individual microbiota.

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Intake of High-Fiber diet Arm 🍌:

↑ Carbohydrate, vegetable protein, and calories, iron, magnesium, potassium, vitamin C, & calcium

↓ Animal protein, & sodium

Intake of High-Fermented-foods diet Arm 🧫 :

↑ Animal protein (by virtue of eating more fermented foods like yogurt, kefir, etc.)

(Wastyk, H. C. et al., Cell, 2021)

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Primary Outcomes! – What was observed in the Immune System?

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Primary Outcomes! – What was observed in the Immune System?

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Primary 1️⃣ Outcome:

Cytokine response from baseline to end-of-intervention was not statistically different in both treatment arms.

⇨ Simultaneously, NO changes in overall general health, perceived stress, well-being, fatigue, physical activity levels or cognition throughout the study (Wastyk, H. C. et al., Cell, 2021).

🔍 Hypothesis: Long-term changes in diet (e.g. chronic nutrient deficiencies) can alter immune responses unfavourably, impairing cytokine production and response (Rossio, J. L. 1999). The short duration of the study may not have been long enough to see beneficial effects on the immune system (e.g. increased cytokine production, etc).

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Figure 2C (Wastyk, H. C. et al., Cell, 2021)

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Secon-dairy Outcomes! – What happened in the gut?

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Secon-dairy Outcomes! – What happened in the gut?

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Secon-dairy 2️⃣ Outcomes:

Summary in the high-fibre arm 🍌 :

↑ in the genus Lachnospira;

↑ stool softness (as per GSRS).

Summary in the high-fermented-food arm 🥛 :

↓  in the genus Lachnospira;

↓ inflammatory markers;

↑ microbiota diversity;

↑ initial bloating (as per GSRS; subsided by the end of the maintenance phase).

(Wastyk, H. C. et al., Cell, 2021)

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Regardless of diet changes, the Microbiota stayed INDIVIDUALIZED!

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Regardless of diet changes, the Microbiota stayed INDIVIDUALIZED!

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No major clustering based on the treatment arm was observed (Wastyk, H. C. et al., Cell, 2021).

🔗 This reinforces the idea that the gut microbiome is altered by factors outside of just dietary habits.

This is concurrent with studies that show that a complex microbial community can be altered by many factors like lifestyle, genetics and even mode of delivery at birth (Wen, L., & Duffy, A., J. Nutr, 2017; Stiemsma et al., J. Nutr, 2020).