Habitual coffee intake shapes the gut microbiome and modifies host physiology and cognition
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IntroductionCoffee is a plant-based beverage made from processed coffee beans. Its flavour and composition vary based on the bean type, ripeness, processing, roasting, and brewing methods1. Key phytochemicals in coffee include alkaloids (like caffeine), (poly)phenols (such as phenolic acids), diterpenes, and melanoidins formed during roasting1,2. Moderate coffee consumption is associated with various health benefits, including reduced risks of type 2 diabetes, liver disease, cardiovascular diseases, and cancer3. In a large cross-sectional study of 468,629 individuals without clinical cardiovascular disease, light-to-moderate coffee consumption was linked to lower rates of all-cause mortality, cardiovascular mortality, and stroke incidence4. Furthermore, coffee intake is consistently associated with a reduced risk of Parkinson’s disease in a dose-dependent manner, across multiple human cohorts5,6,7. Meta-analyses have also found that coffee consumers face a lower risk of depression8,9, and one meta-analysis of cohort studies examining cognitive decline, showed that coffee consumption accounted for a 27% reduction in the incidence of Alzheimer’s disease10.These systemic benefits are paralleled by evidence that coffee impacts the brain directly, shaping both neural activity and cognitive outcomes. Functional MRI studies show that habitual coffee drinkers exhibit altered functional connectivity in regions linked to sensory, motor, and emotional processing. These changes appear to depend on frequency of intake, suggesting that regular coffee consumption may influence brain function and emotional regulation11. Recent data show a positive correlation between cognitive performance, particularly memory and processing speed, in older adults12. Coffee consumption causes a temporary rise in cortisol levels, followed by normalization with habitual use, indicating physiological adaptation13. However, the effects of coffee on stress remain inconclusive, with studies showing mixed results14,15,16.Coffee also affects the gastrointestinal tract. It increases stomach acidity and stimulates the release of hormones that aid digestion. Both caffeinated and decaffeinated coffee promote the contractility of ileal and colonic smooth muscle, helping prevent constipation17,18. It is becoming clear that coffee influences human health and physiology through both direct and indirect mechanisms. Direct effects arise from interactions between coffee compounds or their circulating metabolites and specific biological targets, while indirect effects involve changes to systems such as possibly via the gut microbiome.
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A growing body of evidence from in vitro, animal, and human studies suggests that the microbes in the gut are also reactive to coffee, and that coffee has prebiotic-like effects on the gut microbiome19. This is primarily due to its fiber-like compounds and phenolics such as chlorogenic acids (CGAs) including caffeoylquinic, feruloylquinic, and coumaroylquinic acids. For example, melanoidins in coffee may increase serum short-chain fatty acid (SCFA) levels by promoting the growth of SCFA-producing bacteria20,21,22. Moreover, some studies suggest that coffee consumption promotes growth of Bacteroides and probiotic species belonging to the Bifidobacterium and Lactobacillus genera20,23,24,25,26,27,28. The bioavailability and metabolism of coffee (poly)phenols vary widely between individuals, a phenomenon influenced by the gut microbiome29,30. Coffee phenolics may also reduce neuroinflammation by activating antioxidant response factors in the brain31,32,33,34A recent metagenomics study involving over 1000 participants examined the relationship between more than 150 dietary components and the composition of the gut microbiome. This study identified coffee consumption as the most strongly correlated food item in a dose-dependent manner; subsequently validating it in a second cohort35. It is possible that coffee’s influence on cognition is mediated by its interaction with the gut microbiome. For instance, coffee consumption is linked to higher levels of beneficial butyrate-producing gut bacteria such as Lawsonibacter asaccharolyticus36. Indeed, there is a growing appreciation of the importance of the impact of food and beverages on the bidirectional signalling pathways that make up the microbiota-gut-brain axis37.Although epidemiological and mechanistic studies strongly associate coffee intake with improved health outcomes, key gaps remain. First, the temporal dynamics of coffee consumption, withdrawal, and reintroduction remain poorly understood. Second, the role of individual variability in metabolizing coffee phenolics, shaped by the gut microbiome, has not been systematically examined. Finally, the contribution of the microbiome as a mediator between coffee intake and brain function has yet to be established.
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In this study, we aim to explore the temporal effects of coffee consumption, withdrawal, and reintroduction on cognition, mood, and behavior through self-reported questionnaires in the context of the microbiota-gut-brain axis. Thus, concurrent with behavioural analysis, we simultaneously profile the gut microbiota of healthy, adult, moderate coffee drinkers compared with non-coffee drinkers, using shotgun metagenomics, and targeted/untargeted metabolomics. In addition, different pathways of the microbiota-gut-brain axis such as stress, inflammation, and microbial-derived metabolites are explored38. We aim to interrogate the overlap between coffee’s influence on the microbiome and cognition through several mechanisms. Through (poly)phenols39, by the positive benefit of increased butyrate-producing bacteria36 or alteration of the gut-brain axis with coffee altering neuroactive compounds such as SCFAs or γ-aminobutyric acid17. Furthermore, we probe the inter-individual variability in the metabolism of coffee phenolics and how the microbiome may influence this. While this study considers the role of caffeine, coffee, as a complex mixture, contains many other compounds that may influence the gut.We hypothesize that coffee consumption will have distinct effects on the gut microbiome, increasing microbial diversity and beneficial mediators of gut health, some of which may depend on caffeine, while others may not. These changes may contribute to improved brain function via enhanced stress resilience and cognitive performance, thereby linking coffee consumption to the microbiota–gut–brain axis via a unique interaction between coffee, the microbiome, and cognition.ResultsThis prospective study had three phases each evaluating cognition, stress, physical health, mood, immune function, gut microbiome, dietary intake, and metabolite composition (see Fig. 1 for design). Firstly, we compared non-coffee drinkers (NCD, n = 31) with coffee drinkers (CD, n = 31), then the CD group abstained from coffee for 14 days. Following this washout period, participants reintroduced either decaffeinated (n = 15) or caffeinated coffee (n = 16) for 21 days (Fig. 1A). Participants in the NCD group did not participate in any subsequent phases of the study. Overall, more females participated, and most participants were born per vaginum (Table 1).
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At baseline, CD participants consumed more caffeine daily than NCDs, and NCDs gave up more caffeine before the baseline visit (Table 1, Supplementary Data 1), though the level given up was substantially lower than what would be considered addictive. Alcohol consumption, education years, Childhood Trauma Questionnaire (CTQ) sub-scores, and predicted IQ (measured using the National Adult Reading Test (NART)) did not differ between groups (Table 1). When comparing these metrics between caffeinated and decaffeinated coffee drinkers during the intervention phase of the study, daily caffeine intake, the amount of caffeine abstained from, alcohol consumption, education years, CTQ sub-scores, and predicted IQ did not differ between these groups (Supplementary Data 15). All participants were genotyped for caffeine sensitivity-related SNPs rs2298383 and rs5751876 of the ADORA2A gene. NCDs had a higher percentage of the C/C haplotype in rs2298383, while CDs had more C/T. For rs5751876, NCDs had more T/T, and CDs had more C/T (Table 1, Supplementary Fig. 1). In previous research, the T/T haplotype has been associated with higher coffee intake40. This discrepancy may suggest that contextual, environmental, or sample-specific factors moderated the relationship between genotype and caffeine consumption in this population.Fig. 1: Coffee consumption, abstinence and reintroduction influences cognition, physiology, and craving.The alternative text for this image may have been generated using AI.Full size imageA Experimental overview, NCD and CD drinkers at baseline (V2), CD drinkers following 2 weeks without coffee (V3) and 3 weeks following reintroduction of caffeinated or decaffeinated coffee. Sample type, questionnaire type are indicated in each panel along with day of study. B Heatmap of questionnaire results relative to baseline CD. Horizontal bars within the same cell represent values of individual participants. For the coffee drinker subset, which features repeated measurements, measurements from the same participant are aligned on the y-axis. Red colour indicates positive effect size while blue reflects negative effect size, with intensity of red or blue corresponding to increased or decreased effect sizes respectively and white reflecting zero effect.
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Panels containing a text box with numbers reflects those comparisons with a Cohen’s d effect size of > 0.5 reflecting medium sized effects. Column one represents questionnaire completed, column two = NCD, column three = CD, column four washout period for CD and column five reintroduction of caffeinated or decaffeinated coffee. C Heatmap of questionnaire responses to craving and fatigue symptoms following caffeine abstinence and reintroduction of caffeinated or decaffeinated coffee for CD. Column one represents the questionnaire completed, column two = washout period for CD and column three reintroduction of caffeinated or decaffeinated coffee. Comparisons are NCD v CD, washout v CD baseline and CAF or DECAF v CD baseline values. n = 31 at baseline for CD and NCD, n = 31 during washout period, n = 15 during reintroduction of decaffeinated coffee and N = 16 during reintroduction of caffeinated coffee. Abbreviations: UPPS-P, urgency premeditation perseverance sensation seeking positive urgency impulsive behaviour scale; ERS, emotional and reactivity scale, PASAT, paced auditory serial addition test; ModRey, modified auditory verbal learning test, STAI (Trait), state trait anxiety inventory; PSS, perceived stress scale; BDI, Beck’s depression inventory; GIS-VAS, gastrointestinal symptoms visual analogue scale; HSCL GSI, Hopkins symptom checklist general severity index; PSQI, Pittsburgh sleep quality index; IPAQ, international physical activity questionnaire; QCC, questionnaire of caffeine cravings, CWSQ, caffeine withdrawal symptom questionnaire, V visit.Table 1 Demographic characteristics of non-coffee drinker and coffee drinker participants at baselineFull size tableParticipants’ food intake was monitored for 7 days with a weighted food diary before each study visit (See Supplementary File). No differences in dietary intake were observed when comparing CD participants with NCD participants (Supplementary Data 2a). After 2 weeks of caffeine abstinence, dietary intake remained largely unchanged within CD, though the caffeinated group reported slightly lower magnesium intake, which remained unchanged until the end of the study, while the decaffeinated group had a slight increase in selenium intake from their baseline to their endpoint visit (Supplementary Data 2b–e).