Lawsonibacter asaccharolyticus: A Microcosm of Our Limited Microbiome Knowledge

Dec 13 / Drs. Bryan & Julie Walsh

Introduction

Medical history is endlessly fascinating to us here at Metabolic Fitness, especially when we reflect on past treatments and interventions and how confident doctors were in them at the time. Like us today, they relied on the latest scientific evidence available. The difference is that we now have the benefit of hindsight, allowing us to view some of their practices as almost laughable or even absurd.

For example, two centuries ago, physicians routinely prescribed mercury for various ailments and performed bloodletting to balance the body's "humors." These practices were considered cutting-edge medical science at the time. Yet today, we look back at these interventions and marvel at how our predecessors could have been so certain about approaches we now know to be harmful or ineffective.

This brings us to Lawsonibacter asaccharolyticus, a gut bacterium first discovered in 2018 and named for its inability to break down sugars. Despite supposedly being prevalent in Western populations and showing intriguing associations with habits like coffee consumption, our understanding of this microbe remains remarkably limited. Its very discovery—a common gut inhabitant hiding in plain sight until recently—serves as a humbling reminder of how much we still have to learn about the human microbiome.

This revelation comes at a pivotal time, as the surge in microbiome testing and interventions in functional medicine often carries a level of confidence that may not yet align with the depth of our scientific understanding.

The story of L. asaccharolyticus isn't just about an interesting new bacterial species – it's a warning about the gaps in our knowledge and the potential risks of overconfidence in current microbiome-based functional medicine practices. As we explore this microbe and its implications, we're posed with a potentially uncomfortable parallel for some - Could our current certainty about microbiome testing and treatments someday be viewed with the same absurdity we view the medical practices of centuries past?

Before delving further into that topic, however, we will start with the technical side of recent studies.

Isolation and Basic Properties

Isolation

Lawsonibacter asaccharolyticus was first isolated in 2018 from human feces, marking a significant addition to our understanding of the human gut microbiome [1]. This discovery, made by Sakamoto et al., revealed a new bacterial species with distinct characteristics:
  • Gram-positive
  • Obligately anaerobic
  • Non-motile
  • Non-spore-forming bacillus
The isolation of L. asaccharolyticus was part of a broader effort to recover microbes with beneficial properties, such as butyrate production and flavonoid degradation [1]. The strain, designated 3BBH22T, was obtained from a faecal sample of a healthy Japanese woman and cultured under specific conditions.

Phylogenetic Analysis

Phylogenetic analysis of L. asaccharolyticus revealed its unique position within the family Ruminococcaceae. The 16S rRNA gene sequence analysis showed that strain 3BBH22T formed a monophyletic cluster with species in the genera Pseudoflavonifractor and Flavonifractor [1].

Specifically:
  • Highest similarity (96.7%) to Pseudoflavonifractor capillosus ATCC 29799T
  • 96.4% similarity to Flavonifractor plautii ATCC 29863T
  • 95.0% similarity to Intestinimonas butyriciproducens strain SRB-521-5-IT
This phylogenetic positioning highlights the novelty of L. asaccharolyticus and its potential importance in understanding the diversity of gut microbiota.

"The story of Lawsonibacter asaccharolyticus isn't just about an interesting new bacterial species – it's a warning about the gaps in our knowledge and the potential risks of overconfidence in current microbiome-based functional medicine practices."

Metabolic Capabilities

One of the most significant characteristics of L. asaccharolyticus is its ability to produce butyrate, a short-chain fatty acid crucial for gut health [1]. Butyrate is known to have several beneficial effects:
  1. Energy source for colonocytes
  2. Enhancement of intestinal epithelial cell integrity
  3. Increase in mucin production
  4. Induction of naive T cell differentiation [2]
However, beyond butyrate production, our understanding of L. asaccharolyticus's metabolic capabilities remains limited. The species is described as asaccharolytic, meaning it has limited ability to break down carbohydrates [1]. This characteristic is reflected in its name: 'a-' (not) 'saccharo-' (sugar) 'lytic' (breaking).

Morphological and Growth Characteristics

L. asaccharolyticus exhibits specific morphological and growth characteristics [1]:
  • Cells are non-pigmented straight rods
  • Found singly or in pairs, sometimes with swelling
  • Size ranges from 0.8-1.5 μm in width and 2.4-20.0 μm in length (average 1.0 x 10.0 μm)
  • Optimal growth temperature: 37°C
  • pH range for growth: 6.0-8.0 (optimum pH 7.0)
  • Colonies on agar plates after 4 days:
    • 0.5-1 mm in diameter
    • Grey to off-white-grey
    • Circular, slightly erose, slightly peaked, and smooth
These characteristics provide a basic understanding of the organism's physical properties and growth requirements, but they offer limited insight into its ecological role or interactions within the gut microbiome.

L. asaccharolyticus in Microbiome Research

Association with Coffee Consumption

Recent studies have revealed a curious association between L. asaccharolyticus and coffee consumption. A multi-cohort, multi-omic analysis involving over 22,000 participants from US and UK populations showed a strong link between coffee intake and the abundance of L. asaccharolyticus in the gut microbiome [3].

Key findings from this research include:
  1. L. asaccharolyticus showed the strongest association with coffee intake among 115 species-level genome bins (SGBs) positively associated with coffee consumption.
  2. The median abundance of L. asaccharolyticus was 4.5 to 8-fold higher in high coffee consumers compared to non-drinkers.
  3. The association was consistent across different cohorts and remained significant even when considering decaffeinated coffee consumption.
This association raises several questions about the potential role of L. asaccharolyticus in coffee metabolism or its response to coffee-induced changes in the gut environment. However, it's crucial to note that correlation does not imply causation, and the mechanisms underlying this association remain unclear.

Association with Exercise

While the previous study suggested that coffee consumption significantly increases the abundance of this bacteria [3], which might be a positive finding given the butyrate-producing , capabilities of L. asaccharolyticus, new research by Morwani-Mangnani et al. (2024) reveals an intriguing paradox: vigorous physical activity—which is generally considered beneficial for health—actually decreases the abundance of L. asaccharolyticus [9]. This presents a fascinating contradiction - two lifestyle factors widely recognized as health-promoting (coffee consumption and vigorous exercise) have opposing effects on the same bacterial species. Such findings underscore how preliminary our understanding of the gut microbiome really is, and how cautious we should be about making definitive claims about what constitutes a 'healthy' microbial profile.

Prevalence and Distribution

The prevalence of L. asaccharolyticus appears to be influenced by factors beyond just coffee consumption. A comprehensive analysis of public metagenomic data revealed interesting patterns in its distribution [3]:

High prevalence (>60%) in 52 out of 74 cohorts, primarily representing adult populations in urbanized Western-lifestyle environments
  • Low prevalence (median 2.4%) in individuals from rural societies with non-typically Western lifestyles
  • Rarely found in newborns and children
  • Detected in only one sample out of 201 from non-human primates
  • Found in only two out of 37 samples from ancient populations
These findings suggest that L. asaccharolyticus may be a relatively recent and geographically limited member of the human gut microbiome, potentially influenced by modern dietary habits and lifestyle factors.

Metabolic Associations

Beyond its association with coffee consumption, L. asaccharolyticus has been linked to specific metabolic processes. Plasma metabolomics studies have identified several metabolites enriched among coffee consumers and associated with L. asaccharolyticus [3]:
  • 1. Quinic acid
  • 2. Trigonelline
  • 3. Caffeine and its derivatives
  • 4. Several uncharacterized metabolites
Of particular interest is the association with quinic acid, a component of coffee that is metabolized by gut microorganisms. L. asaccharolyticus abundance was positively correlated with plasma levels of quinic acid and related compounds, suggesting a potential role in quinic acid metabolism.

In Vitro Studies

To further investigate the relationship between L. asaccharolyticus and coffee, in vitro experiments were conducted [3]. These studies revealed:
  1. Coffee supplementation stimulated the growth of L. asaccharolyticus on agar plates and in liquid media.
  2. The stimulatory effect was observed with both caffeinated and decaffeinated coffee preparations.
  3. The growth stimulation was specific to L. asaccharolyticus, as control species (Escherichia coli and Bacteroides fragilis) showed either no response or inhibition at higher coffee concentrations.
These findings provide experimental support for the observed association between coffee consumption and L. asaccharolyticus abundance in human gut microbiomes. However, they also highlight our limited understanding of the specific mechanisms and ecological implications of this relationship.

The Limitations of Current Microbiome Knowledge

The Vast Unknown of the Gut Microbiome

The case of L. asaccharolyticus serves as a reminder of the vast unknowns that persist in our understanding of the human gut microbiome. Despite significant advances in microbiome research over the past two decades, our knowledge remains limited in several crucial aspects:
  1. Species Diversity: The human gut is estimated to contain over 1,000 bacterial species, many of which remain uncharacterized or poorly understood [4]. L. asaccharolyticus, discovered only in 2018, exemplifies how even prevalent species can elude scientific scrutiny for extended periods.
  2. Functional Roles: For the majority of gut microbes, including L. asaccharolyticus, we have limited understanding of their specific functional roles within the gut ecosystem. While we know L. asaccharolyticus produces butyrate, its broader metabolic capabilities and interactions with other microbes and host cells remain largely unknown.
  3. Ecological Interactions: The gut microbiome is a complex ecosystem with intricate interactions between different microbial species and with the host. Our understanding of these ecological dynamics, including competition, cooperation, and symbiosis, is still in its infancy.
  4. Temporal and Spatial Dynamics: The composition and function of the gut microbiome can vary significantly over time (temporal) and across different regions of the gastrointestinal tract (spatial). Our current sampling and analysis methods provide only snapshots of this dynamic system, often limited to fecal samples.
  5. Host-Microbe Interactions: While we know that gut microbes influence host physiology and vice versa, the specific mechanisms and extent of these interactions are not fully elucidated for most microbial species.

Challenges in Microbiome Research

As a broader discussion and an area where we might need to admit we know less than we think we do regarding the human microbiome, several factors contribute to the limitations in our current microbiome knowledge:
  1. Cultivation Difficulties: Many gut microbes, including L. asaccharolyticus, are obligate anaerobes that require specific growth conditions. This makes them challenging to isolate and study using traditional microbiological techniques [1].
  2. Genomic Complexity: The genetic diversity within microbial species and the prevalence of horizontal gene transfer complicate our ability to accurately classify and characterize gut microbes [5].
  3. Functional Redundancy: Many microbial functions in the gut are performed by multiple species, making it difficult to ascribe specific roles to individual microbes [6].
  4. Inter-individual Variability: The composition and function of the gut microbiome can vary significantly between individuals, complicating efforts to establish "normal" or "healthy" microbiome profiles [7].
  5. Technological Limitations: While advances in sequencing technologies have revolutionized microbiome research, current methods still have limitations in terms of resolution, accuracy, and the ability to capture functional information [8].

The Case of L. asaccharolyticus

The very recent discovery of L. asaccharolyticus serves as a microcosm of these broader limitations in microbiome research. Despite being a prevalent species in Western populations and showing strong associations with coffee consumption, our knowledge about this microbe remains remarkably limited:
  1. Functional Characterization: Beyond its ability to produce butyrate, we know little about the metabolic capabilities of L. asaccharolyticus or its potential impacts on host health.
  2. Ecological Role: The interactions of L. asaccharolyticus with other gut microbes and its specific role within the gut ecosystem remain poorly understood.
  3. Host Interactions: While associations with certain metabolites have been observed, the specific effects of L. asaccharolyticus on host physiology are largely unknown.
  4. Strain Diversity: The extent of genetic and functional diversity within the L. asaccharolyticus species has not been thoroughly explored.
  5. Temporal Dynamics: We lack information about how L. asaccharolyticus populations change over time within individuals and in response to various factors beyond coffee consumption.
These knowledge gaps for a single, prevalent species underscore the vast amount of information we still need to gather about the thousands of other microbial species inhabiting the human gut.

Implications for Functional Medicine and Microbiome Interventions

The Rise of Microbiome-Based Interventions

Gut health has been a mainstay of the nutritional and functional medicine world for a very long time but, with the advent of supposedly better testing methods available to today's practitioners, the growing recognition of the gut microbiome's importance, especially over the past decade, has led to a surge in microbiome-based practices and specialties within functional medicine.  However, the case of L. asaccharolyticus and our limited understanding of the gut microbiome raise important questions about the scientific basis and potential risks to clients, both physiologically and psychologically, with scientifically unvalidated testing and diagnosis, as well as nutritional and supplemental interventions. 

The Problem of Incomplete Knowledge

The limitations in our current microbiome knowledge have several implications for microbiome-based interventions:
  1. Diagnostic Uncertainty: Functional medicine microbiome tests often provide abundance data for various bacterial species, but the health implications of these abundances are not always clear. For example, while we know L. asaccharolyticus is associated with coffee consumption, we don't know whether its presence or abundance is beneficial, harmful, or neutral for health.
  2. Intervention Efficacy: Without a comprehensive understanding of microbial functions and interactions, interventions aimed at altering the microbiome may have unpredictable or unintended consequences. For instance, attempts to increase or decrease the abundance of specific bacteria might disrupt important ecological balances within the gut.
  3. Long-term Effects: The long-term impacts of microbiome manipulations are largely unknown. Given the complex and dynamic nature of the gut ecosystem, short-term changes might not translate to sustained health benefits and could potentially lead to unforeseen negative outcomes.
  4. Individual Variability: The high inter-individual variability in microbiome composition complicates the development of standardized interventions. What works for one person may not work for another, and we currently lack the tools to predict individual responses accurately.
  5. Oversimplification: Current approaches often focus on a handful of well-studied bacteria or broad taxonomic groups, potentially overlooking the importance of less-studied microbes like L. asaccharolyticus or complex ecological interactions.

"It's crucial to recognize that our current understanding of the gut microbiome is likely as primitive as medical knowledge was 100-200 years ago. Just as physicians of that era believed their practices were advanced, we must be cautious about overestimating our current capabilities in microbiome manipulation."

The Need for Caution

Given these limitations, there is a strong argument for a more cautious approach to microbiome interventions in functional medicine:
  1. Acknowledging Uncertainty: Practitioners should be transparent about the limitations of current microbiome knowledge and the potential risks and uncertainties associated with microbiome-based interventions with their clients.
  2. Evidence-Based Approaches: Interventions should be based on robust scientific evidence rather than speculation or oversimplified interpretations of microbiome data.
  3. Individualized Care: Given the high inter-individual variability in microbiome composition and function, a one-size-fits-all approach to microbiome interventions is likely inappropriate. Following principles, as a general rule, is better than following a protocol.
  4. Holistic Perspective: The microbiome should be considered as part of a broader health context, including diet, lifestyle, and other physiological factors, rather than as an isolated target for intervention.
  5. Professional Responsibility: Practitioners have an obligation to stay updated on the latest microbiome research and to adjust their practices as new evidence emerges.
  6. Avoiding Overreach: Claims about the efficacy of microbiome interventions should be tempered and aligned with the current state of scientific evidence.

Conclusion

The case of Lawsonibacter asaccharolyticus serves as a powerful reminder of the numerous unknowns that exist in our understanding of the human gut microbiome. Despite being a prevalent species in Western populations and showing intriguing associations with coffee consumption, our knowledge about L. asaccharolyticus remains remarkably limited. This exemplifies a broader issue in microbiome research - even for species that are common and potentially important, we often lack fundamental information about their functions, interactions, and impacts on human health.

The limitations in our microbiome knowledge have significant implications for the field of functional medicine and microbiome-based interventions. While the gut microbiome undoubtedly plays a crucial role in human health, our ability to manipulate it effectively and safely for therapeutic purposes is constrained by our incomplete understanding. The confidence with which some practitioners approach microbiome testing and intervention may be premature, given the complexity of the gut ecosystem and the many unknowns that remain.

This situation calls for a more cautious and nuanced approach to microbiome-based functional medicine claims and practices. Practitioners should acknowledge the limitations of current knowledge, base interventions on robust scientific evidence instead of what is 'trending', and consider the microbiome as part of a broader health context rather than an isolated target for manipulation. There is also an ethical imperative to ensure that patients are fully informed about the uncertainties and potential risks associated with microbiome interventions.

Looking forward, the case of L. asaccharolyticus highlights the critical need for continued research in microbiome science. As we uncover more about the myriad of microbial species inhabiting the human gut and their complex interactions with each other and the host, we will be better positioned to develop truly effective and personalized microbiome-based therapies. Until then, a healthy dose of scientific humility and caution is warranted in our approach to the gut microbiome in functional medicine.

It's crucial to recognize that our current understanding of the gut microbiome is likely as primitive as medical knowledge was 100-200 years ago. Just as physicians of that era believed their practices were advanced, we must be cautious about overestimating our current capabilities in microbiome manipulation. The recent discovery of L. asaccharolyticus, a prevalent species in Western populations, underscores how much we have yet to learn. This should give pause to functional medicine practitioners and nutritionists who rely heavily on stool tests and microbiome interventions. We may be only scratching the surface of microbiome complexity, and our interventions could have unforeseen consequences. As we continue to explore this fascinating field, maintaining a humble and critical perspective on our current knowledge and practices is essential.

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