Lactose intolerance, a common digestive disorder, is characterised by the inability to fully digest lactose, the main sugar found in milk and dairy products. This condition results from a deficiency in lactase, an enzyme essential for breaking down lactose into its basic monosaccharides, glucose and galactose, which are then absorbed by the small intestine. Undigested lactose ferments in the colon, causing a range of gastrointestinal symptoms. The severity and symptoms – such as flatulence, abdominal pain, and diarrhea – depend on the degree of lactase deficiency and the amount of lactose consumed.
Due to the widespread nature of lactose intolerance, understanding its complex causes – from genetic predispositions to acquired forms – is vital for effective management and dietary advice. While milk is nutritionally rich and important for growth and development, the increasing healthcare costs linked to lactose intolerance highlight the need for a clear understanding of its complexities for both healthcare professionals and those affected. Moreover, the global rate of lactase deficiency, especially primary lactase non-persistence affecting around 70% of the world’s population, highlights its significant public health implications.
Recent research has also pointed to the usefulness of genetic testing in spotting tendencies towards lactase non-persistence, providing a more precise diagnosis alongside traditional breath tests, although these genetic markers might not include all relevant single nucleotide polymorphisms.
Background on lactose intolerance
Lactose intolerance results from a deficiency of the enzyme lactase, which is responsible for breaking down lactose into absorbable monosaccharides within the small intestine. This enzymatic deficiency prevents the proper hydrolysis of lactose, leading to its accumulation in the gastrointestinal tract and subsequent fermentation by colonic bacteria. This fermentation process produces short-chain fatty acids and gases, which are the main causes of the uncomfortable symptoms experienced by people with lactose intolerance.
The resulting physiological response often discourages individuals from consuming dairy products, thereby potentially reducing their intake of essential nutrients such as calcium and vitamin D. However, this avoidance can be mitigated by strategies that either lower the lactose content in dairy products or improve an individual’s ability to digest lactose, such as consuming fermented dairy products.
Fermented milk products, such as yoghurt and acidophilus milk, are suitable for individuals with lactose intolerance due to their reduced lactose content and the presence of bacterial lactase. Specifically, certain lactic acid bacteria in fermented products like kefir assist in lactose digestion due to their natural lactase activity, improving tolerance in affected individuals. The addition of probiotic strains – particularly those commonly found in fermented dairy – helps maintain optimal intestinal function and further aids lactose metabolism. Modern consumers are increasingly seeking out probiotic-rich foods, driving a growing market for functional products, including innovative plant-based alternatives to traditional dairy products.
This demand has prompted extensive research into isolating and characterising novel bacterial strains from dairy sources, focusing on their probiotic potential and their ability to enhance nutrient bioavailability, such as folate synthesis. Additionally, some probiotic species, including Streptococcus thermophilus and Lactococcus lactis, are known for their significant production of folate, which can substantially enhance the nutritional value of fermented dairy products.
Beyond folate, lactic acid bacteria in these fermented foods also produce a variety of bioactive peptides through the proteolytic breakdown of milk proteins, providing diverse health benefits such as immunomodulatory, hypocholesterolaemic, and antioxidative effects. These beneficial molecules, together with the presence of live microbial cultures, emphasise the health-promoting qualities traditionally linked to fermented dairy foods.
Role of lactase enzyme
The enzyme lactase, a β-galactosidase, plays a crucial role in breaking down lactose by catalysing its hydrolysis into glucose and galactose, thereby aiding their absorption across the intestinal brush border (Figure 1). This enzymatic process is vital for nutrient absorption, and any deficiency directly affects the body’s ability to utilise the energy and carbon sources from lactose. The absence or decreased activity of this enzyme causes undigested lactose to remain in the gut lumen, which in turn draws water into the intestine osmotically and leads to bacterial fermentation.
FIGURE 1. Structural and molecular organization of microvilli
A. Microvilli are stabilized by a core actin bundle, corresponding actin-bundling proteins (EPS8, villin, espin, fimbrin), and proteins connecting the actin bundle to the cell membrane [MYO1A, MYO6, ezrin]. The latter can be regulated by phosphorylation and dephosphorylation of ezrin by an ezrin kinase and protein phosphatase 1 (PP1); B. intermicrovillar adhesion is mediated by cadherin-related family member-2 (CDHR2) and CDHR5. Within the microvilli, MYO7B, Usher syndrome type I C (USH1C, harmonin), and ankyrin repeat and sterile alpha motif domain containing 4B (ANKS4B) interact with the intracellular portions of protocadherins and connect them to the actin bundle. The connections are mediated through multiple protein interaction motifs such as post-synaptic density protein 95, Drosophila disc large tumor suppressor, and zona occludens-1 protein (PDZ) domains in USH1C. CEN: central region; Ferm: 4.1 protein, ERM; SAM: sterile alpha motif; SH3: src homology 3. Taken from: Mödl B, Schmidt K, Moser D, Eferl R. The intermicrovillar adhesion complex in gut barrier function and inflammation. Explor Dig Dis. 2022;1:72–79. https://doi.org/10.37349/edd.2022.00006
Prevalence and symptoms
This process, characterised by symptoms such as bloating, flatulence, abdominal pain, and diarrhoea, varies in severity depending on the level of lactase deficiency and the amount of lactose ingested. Additionally, the appearance of these symptoms can be affected by the gut microbiome composition, with certain microbial profiles potentially worsening or reducing the physiological responses to undigested lactose. Genetic predisposition and epigenetic factors also significantly influence the onset and severity of lactase non-persistence, further complicating the clinical picture. The global prevalence of lactose intolerance, estimated to affect about 68%-70% of the world’s population, underscores its widespread impact on dietary habits and nutritional status, especially in regions where dairy products form a major part of the diet.
Lactase deficiency: genetic and acquired
Lactase deficiency, including both congenital alactasia and primary adult-type hypolactasia, encompasses a range of conditions characterised by reduced activity of lactase, an enzyme essential for breaking down lactose.
Congenital alactasia, a rare autosomal recessive disorder, presents at birth with severe symptoms following lactose intake, requiring a lifelong lactose-free diet. In contrast, primary adult-type hypolactasia, the most common form, involves a gradual decline in lactase activity after weaning, often becoming symptomatic in adolescence or adulthood due to decreased lactase gene expression. This age-related reduction in lactase production is largely genetically determined, usually associated with single-nucleotide polymorphisms upstream of the LCT gene.
Secondary lactase deficiency, however, results from damage to the small intestinal mucosa, often caused by conditions such as celiac disease, Crohn’s disease, or acute gastroenteritis, which can impair lactase production regardless of genetic predisposition. As a result, the clinical presentation of secondary lactase deficiency is often temporary, resolving once the underlying intestinal condition is effectively treated. This distinction is vital for diagnosis and management, as genetic testing can identify primary lactase non-persistence, while biopsies or clinical assessments are more suitable for secondary forms.
Lactase: structure, function, and mechanism
Lactase, also known as lactase-phlorizin hydrolase, is a transmembrane glycoprotein found in the brush border membrane of enterocytes in the small intestine, displaying a bifunctional catalytic activity. Its main role is to hydrolyse lactose into its constituent monosaccharides, glucose and galactose, while its hydrolase activity for phlorizin allows the breakdown of phlorizin and other β-glycosides. The enzyme’s complex structure supports its catalytic efficiency, with specific domains designated for substrate binding and hydrolysis, enabling the essential digestive process of disaccharide breakdown for subsequent absorption.
Genetic mutations, especially within the LCT gene, are commonly linked to variations in lactase activity, affecting an individual’s ability to digest lactose effectively into its monosaccharide components. This enzymatic process is vital for the absorption of glucose and galactose into the bloodstream via specific transporters such as GLUT2, which facilitate their movement across the basolateral membrane of enterocytes.
Despite advancements in understanding lactase deficiency and its management, many individuals still remain undiagnosed or inadequately treated, emphasising the need for improved diagnostic methods and personalised therapeutic strategies. Further research into the use of advanced technologies, such as machine learning for predictive diagnostics and innovative enzyme formulations, could refine treatment protocols and improve patient outcomes by enhancing the measurement and regulation of circulating lactate. This includes exploring engineered probiotics and prebiotics to modulate the gut microbiome, which could potentially reduce symptoms related to lactose intolerance and enhance overall gut health. Additionally, investigating the precise mechanisms by which specific lactic acid bacteria strains metabolise lactose and related oligosaccharides could lead to the development of targeted dietary interventions to alleviate lactose intolerance symptoms and provide further insight into health improvements. For example, understanding the genetic and metabolic engineering strategies that can be applied to lactic acid bacteria to boost their capacity for lactose conversion into various products beyond lactic acid offers promising possibilities for innovative therapeutic and food applications.
Current treatments and limitations
While dietary modifications, primarily lactose restriction or avoidance, remain the cornerstone of management for lactose intolerance, their effectiveness is often hindered by challenges in patient adherence and the widespread presence of lactose in processed foods. Furthermore, the use of exogenous lactase supplements, though beneficial, provides only temporary relief and does not address the underlying enzymatic deficiency, requiring ongoing administration.
This underscores the urgent need for more sustainable and targeted therapeutic options, including the potential for gene therapy or microbiome-based interventions, to offer long-term solutions for those affected. Emerging innovative strategies focus on modulating the gut microbiome to ease lactose intolerance, utilising microbial communities for lactose digestion. Specifically, the application of probiotics, such as Lactobacillus or Bifidobacterium, has attracted considerable attention due to their ability to help alleviate lactose intolerance symptoms by introducing beneficial microorganisms that aid in lactose breakdown. These microbes, especially lactic acid bacteria, are recognised for their capacity to modify the intestinal environment, inhibit harmful microbes, and restore gut microbiota balance, all of which contribute to overall digestive health. Additionally, research shows these probiotic strains can synthesise lactase themselves, assisting in breaking down undigested lactose in the gut and reducing discomfort. This enzymatic activity by certain probiotic strains presents a promising alternative to exogenous enzyme supplements, as it supplies a continuous source of lactase within the gut lumen.
Lactase supplementation is essential in managing lactose intolerance by assisting the body to break down lactose into easily digestible sugars, thereby reducing symptoms such as bloating, cramps, and diarrhoea. Regular use of lactase supplements can enhance dietary freedom and overall quality of life for individuals with lactose intolerance.
Potential therapeutic interventions
Beyond probiotics, prebiotics like polydextrose are also being studied for their ability to selectively stimulate the growth of beneficial gut bacteria, thereby indirectly improving lactose digestion and gut health. Galacto-oligosaccharides, derived from β-galactosidase-induced lactose conversion, are a particularly promising class of prebiotics because of their capacity to selectively promote the growth of beneficial Bifidobacterium and Lactobacillus species in the gut. These synbiotic approaches, which combine prebiotics and probiotics, provide a synergistic effect, fostering a stronger and more resilient gut microbiome capable of metabolising lactose more efficiently.
Furthermore, the development of live biotherapeutic products represents an innovative frontier, offering targeted delivery of specific microbial strains or communities designed to boost endogenous lactase activity or modify the gut environment to relieve lactose intolerance symptoms.
Conclusion
The accumulated evidence underscores the complexity of lactose intolerance and the pressing need for innovative, patient-centred solutions that extend beyond merely alleviating symptoms. Future research should aim to combine advanced multi-omics analyses with clinical outcomes to develop highly personalised diagnostic and therapeutic tools that address the various causes of lactose intolerance. This comprehensive approach, considering dietary, microbial, and genetic factors, is crucial for developing long-lasting and effective strategies to enhance the quality of life for individuals affected by this condition.
Additionally, progress in microbiome-modulating interventions, such as synbiotics, postbiotics, and genetically modified organisms, along with a renewed focus on polyphenols, fibre, and fermented foods, is set to transform the management of lactose intolerance by providing multiple avenues to boost microbial function and host interaction.
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