How the right diet could support the gut bacteria that matter most

Review: Research advances in the identification of gut keystone bacteria and formulation of suitable dietary intervention strategies for restoring gut homeostasis. Image Credit: Maxx-Studio / Shutterstock

A recent article-in-press review published in the journal npj Biofilms and Microbiomes summarized recent developments in the identification of gut keystone bacteria and outlined targeted dietary interventions to restore gut homeostasis.

The structure and function of the gut microbiota are significantly influenced by specific species, known as the keystone taxa, which are vital to ensure gut ecosystem stability. However, keystone taxa are also implicated in the pathogenesis and progression of several diseases, making them promising targets for therapeutic interventions. In this review, the authors explored advances in identifying keystone bacteria and outlined targeted dietary interventions.

Evaluation of identification methods of keystone bacteria

Disease association studies link microbial characteristics to host phenotypes and identify recovery-related taxa but struggle to differentiate between correlation and causation. Moreover, they rely on resource-intensive and large-scale surveys, which could limit reproducibility. Meanwhile, co-occurrence network analyses offer efficient means to identify highly connected taxa and infer interactions, though they tend to be biased toward more abundant taxa.

While dynamic models (e.g., the Lotka-Volterra model) extend beyond static correlations, they are prone to spurious correlations and struggle to infer parameters from time-series data. Moreover, these models are centered on population dynamics and often restricted to sufficiently abundant taxa, thereby reducing the likelihood of detecting high-impact, less abundant keystone taxa.

Emerging deep learning and machine learning models are powerful at identifying complex patterns and assessing species' impacts, regardless of their abundance. However, they require large-scale, high-quality datasets for training, and their black-box nature may also obscure biological inference. Notably, species identified in synthetic model systems may not have the same role in vivo, as other taxa may compensate for their function.

As such, the role of candidate keystone bacteria should be causally determined in vitro through co-cultures and gene knockouts and validated in vivo via fecal microbiota transplantation or gnotobiotic animal models. In addition, clinical translation requires evidence that targeted modulation of keystone bacteria through diet, probiotics, or prebiotics results in beneficial outcomes in human trials.

Dietary modulation of keystone bacteria and targeted dietary interventions

Dietary composition directly influences luminal pH, thereby creating a selective environment for keystone bacteria. Diets rich in protein promote alkaline shifts, favoring the growth of Bacteroides and Proteobacteria. Such diets also activate glutamic acid decarboxylase, which lowers intracellular hydrogen ion concentration, thereby suppressing acidophilic bacteria, e.g., Streptococcus thermophiles and Lactobacillus.

Fermentable fiber-rich diets promote short-chain fatty acid (SCFA) production, reducing pH and fostering acidophilic bacteria, e.g., Lactobacillus and Bifidobacterium. Diet composition also modulates dissolved oxygen levels in the gut. For instance, high-fat diets increase dissolved oxygen levels, which promotes facultative anaerobes like Escherichia coli but suppresses obligate anaerobes like Bacteroides.

Further, dietary patterns could indirectly affect keystone bacteria by influencing body temperature. Dietary nutrients have profound effects on the function of keystone bacteria. Indeed, the production of microbial metabolites, such as bile acids, nitrogenous compounds, and SCFAs, by keystone bacteria heavily relies on dietary intake. The ketogenic diet (KD) is a low-carbohydrate, high-fat dietary pattern.

KD has been demonstrated to modulate gut microbiota by increasing Akkermansia muciniphila and SCFA production, with the review noting evidence in contexts such as drug-resistant seizures and inflammation-related microbial shifts. KD also stimulates ketone body production, altering gut microbial metabolism and increasing anti-inflammatory taxa while decreasing pro-inflammatory taxa, thereby promoting gut-health-associated microbial shifts. The Dietary Approaches to Stop Hypertension (DASH) diet is rich in polyphenols and has been linked to greater microbiota diversity.

The DASH diet reduces the abundance of Shigella and Allobaculum mucolyticum, which may help alleviate alcoholic liver disease. Likewise, the gluten-free diet, mainly composed of polysaccharides, can modify the intestinal nutrient milieu and impede the proliferation of harmful bacteria, although the review notes that it may also reduce beneficial taxa such as Bifidobacterium longum and Lactobacillus and increase E. coli and Enterobacteriaceae. The Chinese dietary pattern increases beneficial gut microbes, e.g., Lactobacillus and Bifidobacterium, and decreases pathogenic taxa, e.g., Clostridium and Streptococcus, thereby promoting SCFA production. The review also discusses other dietary and feeding patterns, including low-FODMAP, plant-based, and Mediterranean diets, high-fat and high-salt conditions, caloric restriction, and intermittent fasting.

Keystone bacteria as probiotics

Specific keystone bacteria harboring therapeutic functions, e.g., Christensenella minuta, A. muciniphila, and Faecalibacterium prausnitzii, could be developed as next-generation probiotics (NGPs). Studies have reported that C. minuta directly modulates host microbial community structure and adiposity, highlighting its potential as an NGP. Further, live A. muciniphila supplementation in mice has been shown to partially restore HFD-induced metabolic disturbances.

A randomized controlled trial showed that inactivated A. muciniphila supplementation significantly reduced systemic inflammation, improved insulin sensitivity, and lowered total cholesterol in obese or overweight individuals. Some dietary patterns can synergistically act with probiotics to ameliorate human diseases. For example, an energy-restricted diet along with a multi-strain probiotic was found to significantly improve glycated hemoglobin levels in obese or overweight individuals. However, the review emphasizes that these approaches remain translationally challenging because therapeutic effects depend on strain viability, delivery, colonization resistance, ecological niche, and the accompanying diet.

Concluding remarks

Overall, future research efforts should focus on developing high-resolution assays and more physiologically relevant models to uncover the relationships among host physiology, diet, and keystone bacteria. Moreover, designing evidence-based and effective diet-NGP interventions targeting keystone bacteria could be promising for the management and prevention of diseases related to the gut microbiota.

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