By: Levi Glover and Marton Toth, Ph.D.
Recently, there has been an increase in our awareness of the intricate relationship between gut health and overall well-being. Numerous vital processes unfold within the enteric nervous system, often called the ‘second brain’ of our complex gastrointestinal tract.
The lining of our intestines generally serves as a protective barrier, selectively permitting nutrients to pass through while preventing harmful substances from entering the bloodstream [1]. However, increased intestinal permeability, commonly called ‘leaky gut syndrome,’ can arise when this barrier becomes compromised.
Leaky gut syndrome occurs when the tight junctions between the cells in the intestinal lining become loose or damaged [2] and may result from imbalances in the diversity of the flora of the vast community of microorganisms residing in our intestines. Disruptions in the microbiome’s diversity can lead to an overgrowth of harmful microbes, compromising the integrity of the gut lining [2].
Certain medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) [3], antibiotics [2], and proton pump inhibitors (PPIs) [2], have also been identified as potential culprits causing leaky gut syndrome. Additionally, chronic inflammation, which often results from poor diet and lifestyle choices [1], as well as environmental factors like exposure to toxins, pollutants, and certain food additives [1], can also contribute to the development of leaky gut syndrome.
When the intestinal barrier is compromised, a range of substances typically eliminated from the body can access the bloodstream. These substances include undigested food particles, harmful microbial products, toxins, and antigens. Consequently, a domino effect of adverse reactions can be set in motion, impacting various bodily systems and potentially triggering inflammation and other immune responses.
What are the Consequences of Increased Permeability?
Recent research studies have shed light on the profound link between the integrity of the intestinal barrier and a range of human disorders, including conditions such as inflammatory bowel disease (IBD) [4], celiac disease [2], irritable bowel syndrome (IBS) [4], neurodegenerative disorders [5], and cancer [5,6]. These findings underscore the significant need to identify ingredients and therapeutic interventions capable of reducing intestinal permeability and preserving gut barrier integrity.
Functional Ingredient Remedies to Heal the Gut:
Various functional ingredients have emerged as potential solutions to maintain or enhance gut barrier integrity. These include prebiotics, probiotics, postbiotics, phytochemicals, botanical extracts, metabolites, micronutrients, and synergistic combinations of these ingredients [4]. However, despite their promise, researching the efficacy of these functional ingredients poses challenges due to limitations in replicating the complex in vivo conditions necessary for the comprehensive analysis of leaky gut syndrome.
Pros and Cons of Traditional Leaky Gut Models
When studying the effects of functional ingredients on gut health, researchers have turned to various approaches to overcome the challenges of in-vivo studies. Invitro gut models, utilizing intestinal cell monolayers, have emerged as a cost-effective solution with higher throughput than in vivo studies. While these models provide valuable insights, they fall short of replicating the full complexity of a living organism, limiting our understanding of the intricate biological processes at play [7].
Alternatively, in-vivo studies using animal models, mainly rodents, offer a more accurate representation of the complex intestinal environment. These studies allow for a more comprehensive exploration of the interactions between the gut microbiota and the intestinal epithelium. However, rodent studies involve ethical considerations, higher costs, and limited scalability [7].
Why Study Leaky Gut in Nematodes?
To overcome these challenges, scientists have turned to a unique research tool: the nematode Caenorhabditis elegans. This tiny worm is widely used as a model organism in scientific research thanks to its well-understood biology and ease of cultivation. There is a lot of conserved biology between the worm and mammals, allowing us to take data from C. elegans studies and translate it to humans.
This worm also offers several advantages over traditional rodent models regarding the high-throughput screening of functional ingredients for gut health. Its microscopic size, shortened reproductive cycle, and large brood size allow for larger sample sizes than rodent studies. While its short lifespan of ~3 weeks accelerates the timeframe for generating data. Using the worm for gut health studies allows scientists to assess the impact of functional ingredients on gut barrier integrity, providing valuable insights in a time-efficient manner.
Despite the advantages of using C. elegans for screens of functional ingredients for improved gut health, some technical challenges persist in evaluating the loss of gut barrier integrity. Current methods involve multi-day maintenance of adult worms on agar plates, necessitating manual transfers to prevent progeny from growing up and confounding data. Using drugs to block reproduction might interact with the tested ingredients (e.g., probiotics), potentially altering their functional properties.
Furthermore, evaluating gut leakiness in C. elegans requires feeding the worms a non-absorbable dye and imaging them at specific times. The need for manual transfers limits the throughput of screening efforts to identify novel functional ingredients that mitigate intestinal permeability in the C. elegans gut.
NemaLife's patented organism-on-chip platform captures leaky gut at high definition providing living proof of the efficacy of functional ingredients to improve gut health. Nematodes with a healthy gut (above) retain gut barrier integrity with the green dye restricted to the intestinal lumen, while those with an unhealthy gut (below), experience the blue dye leaking to other body tissues.
NemaLife's Mission to Promote Gut Health by Functional Ingredients
NemaLife revolutionizes the process of ingredient discovery and development through its cutting-edge organism-on-chip platform. Our platform seamlessly integrates the biological advantages of C. elegans with AI-enabled microfluidic technology. By harnessing this proprietary platform, NemaLife expedites the pace of research and streamlines data analysis, significantly reducing labor-intensive experimental requirements associated with screening programs focused on gut health. NemaLife’s proprietary leaky-gut organism-on-chip assay enables in vivo testing of samples under conditions resembling those observed in mammals, albeit significantly faster and at a fraction of the cost.
NemaLife’s organism-on-chip platform incorporates microfluidic technology that provides an elegant solution to the problem of the multi-day culture of nematodes. Nematodes are housed in microfluidic chips that contain size-selective filters to remove progeny by fluid flow while retaining adults. This approach simplifies the daily husbandry of worms without the need for manual transfers or progeny-blocking drugs.
To demonstrate this proprietary platform’s capabilities and efficacy for evaluating leaky gut, NemaLife developed optimized protocols and a data analysis workflow. We have developed three translationally relevant models for the onset of leak gut syndrome caused by advanced age, poor nutrition/diet, or enteropathogenic infection. Each model exhibits differences in the age of onset and severity of the leaky gut phenotype. These distinct models allow a deeper understanding of the mechanism of action of each new functional ingredient tested on the NemaLife platform.
In conclusion, leaky gut syndrome is a critical indicator of gut health. It is associated with various human health disorders, underscoring the need for accurate model systems that facilitate the discovery of novel functional ingredients which can improve gut barrier integrity. NemaLife’s pioneering organism-on-chip platform offers a rapid approach to developing interventions targeting leaky gut caused by poor nutrition, pathogenic infection, or the effects of aging. By adopting this multi-pronged approach, NemaLife can identify groundbreaking functional ingredients that effectively combat leaky gut and ultimately enhance overall health. Through the synergy of cutting-edge technology and comprehensive research, NemaLife is forging a path toward a brighter future for gut health and well-being.
Citations
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