Prebiotics Ingestion in Relevance to Lactose Intolerance Alleviation

doi:10.21203/rs.3.rs-4722898/v1

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Systematic Review

Prebiotics Ingestion in Relevance to Lactose Intolerance Alleviation

https://doi.org/10.21203/rs.3.rs-4722898/v1

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Lactose intolerance is a medical condition in which distress is experienced after lactose ingestion due to maldigestion or malabsorption, due to lack of persistent lactase or fermentation rates by gut microbiome that outweigh the colonic capacity to dispose residual fermentation products (He et. al., 2006). Multiple management approaches are applied according to case severity. A systematic review was conducted following the PRISMA 2020 guidelines (Page et. al., 2022), to outline the novel growing interest in fortifying dairy products with prebiotics to enhance the naturally occurring microbiota suggested to aid alleviating gastric distress symptoms.

Results showed that prebiotics had a positive effect on symptoms profile, where daily administration of lactose caused significant gut microbiota adaptation, which is the same objective as the previously suggested intervention using probiotics (Deng et. al., 2015). Daily lactulose implementation significantly increased fecal β-galactosidase during lactulose feeding period. Galacto-oligosaccharides were effective for alleviating symptoms while maintaining safety.

Galacto-oligosaccharides

lactulose

lactase-deficiency

Lactose-intolerance

Recently, a growing body of research has investigated the possible aiding effects of ingesting probiotics and/or prebiotics for individuals suffering from lactose intolerance. Despite not being a life-threatening condition, a common health problem still has a substantial effect on the diet quality of the vast majority of population. Considering that the genetic predesigned loss of lactase activity after whining affects more than 70% of adults worldwide (Suarez et. al., 1995), it is worth mentioning that, despite this, lactase persistence mutation has proven to be the dominant trait (Swallow, 2003), while lactase non-persistence is its recessive and ancestral allele trait (Szilagyi and Ishayek, 2018), as well, it has been previously reported that symptoms of discomfort usually occur only when lactase activity is less than 50% (Deng et. al., 2015). This in turn, sets a firm boundary against the public belief that has recently been disseminated, causing the vast majority of the public to think that consuming dairy post whining is in fact against our biological nature; hence, reducing dairy consumption and risking compromising bone health in favor of pop-health trends.

Multiple management approaches are applied according to symptoms severity, starting medical interference, i.e., supplementation with exogenous lactase enzyme (Baijal and Tandon, 2021), as well as altering gut microbiome with probiotics, down to complete or partial elimination of milk and dairy products (Obermayer-Pietsch et. al., 2004; Hertzler et. al., 1997). The hazardous side of such practices in the long run appears to be the elevated risk of developing osteoporosis, osteomalacia, and/or hypertension due to the continuation of reduced calcium and vitamin D intake, as discussed by (McCarron and Heaney, 2004) and (Intakes, 1997). Other strategies addressing the same problem include providing vitamin D and calcium supplements alongside lactose-containing food elimination from the diet (Suchy et. al., 2010; Szilagyi and Ishayek, 2018) in order to overcome the dairy-elimination approach weaknesses. Mostly, regimens involving lactose elimination are accompanied by gradual lactose re-exposure to determine the extent to which the intake is tolerable (Deng et. al., 2015). There are also other options for providing plant-based or lactose-free dairy substitutes; although these substitutes have chemical compositions and sensory characteristics that are completely different from those of milk or recombined milk, they can still be enriched with the main micronutrients for which dairy is considered crucial in the human diet, i.e., calcium and vitamin D (Brooker et. al., 2023). Despite being non-cost-efficient, a dietary product can still provide the illusion of consuming milk or dairy products on a daily basis for some consumers. Considering the cost-inefficiency concerns regarding other management strategies, the majority of the affected population lean on the easy solution of avoiding dairy, which in turn leads to decreased bone density, as reported in some developed countries as well as in the United States of America (Obermayer‐Pietsch et. al., 2004). Therefore, a recent approach was pursued by (Darwish et. al., 2023) to investigate the possibility of developing a processing methodology aimed at reducing the lactose content in milk by exploiting high heat treatment, which is a common step in dairy processing, to convert up to half of the lactose content to its synthetic reciprocal/lactulose within the raw milk. Therefore, lactulose is suggested to be a beneficial prebiotic alongside other prospective health benefits.

However, dietary supplementation with pharmaceutical calcium does not perpetually enhance bone density or mineral deposition or lower the risk of fractures (Buchowski et. al., 2002; Suchy et. al., 2010) in a way that is capable of compensating for the prolonged restrictions of dairy intake. Accordingly, a lowered dietary calcium intake of 320 to 388 mg/day is obtained in lactose-intolerant individuals compared to the recommended amount of 1000–1200 mg/day, (Carroccio et. al., 1998; Buchowski et. al., 2002) leading to a higher incidence of osteoporosis and its ramifications (Ross et. al., 2011), as well as osteomalacia and hypertension, as aforesaid (McCarron and Heaney, 2004; Institute of Medicine, 1997). Moreover, elimination of dairy products from the diet leads to a decreased count and variety of lactose-utilizing gut microbiota, which subsequently worsens the situation for individuals by increasing their sensitivity to lactose. This finding implies that microbial adaptation of the gut microbiota in the colon in reaction to the newly offered prebiotic therapy is a very promising approach (Briet et. al., 1995). Although the exact origin of gastric distress accompanied by lactose ingestion remains incompletely clear, it is suggested that the osmotic load of residual lactose in the colon is not the sole reason for the symptoms’ appearance, as lactose maldigestion is barely related to distress symptoms (De Vrese et. al., 2001). Despite the fact that human intestinal-lactase activity is not inducible (Gilat et. al., 1972; Ravich and Bayless, 1983; Reddy and Pershad, 1972), milk has been used successfully as a malnutrition treatment for individuals who suffer from lactose intolerance to various extents while causing no more than a temporary worsening of symptoms (Reddy and Pershad, 1972; Habte et. al., 1973; Scrimshaw and Murray, 1988). Hence, long-term exposure of the colonic microbiota to various doses of lactose might be in charge of the observed improvements, due to gut microbiome adaptation (Hertzler and Savaiano, 1996). Typically, the symptoms of gastric distress are correlated with disturbances in the osmotic state of the colon due to the presence of lactose-containing fermentation products, i.e., CO₂, H₂, acetate, and CH₄ (Bond et. al., 1980), as well as short-chain fatty acids. This in turn can lead to uncomfortable abdominal symptoms, i.e., cramping, diarrhea, flatulence, and abdominal pain (Savaiano et. al., 2013). Recently, there has been growing evidence that altering the intestinal microbiota via certain treatment approaches can aid in improving various diseases either by reshaping the gut microbiota or by counteracting alterations in the normal microbiome due to illness (Chey et. al., 2020). However, diseases with which probiotics might have a significant effect include antibiotic-related diarrhea (Pochapin, 2000), inflammatory bowel diseases (Rembacken et. al., 1999; Schultz and Sartor, 2000) and infectious gastroenteritis (Saavedra, 2000) as well as lactose intolerance (Lee et. al., 2018).

Hence, various types of carbohydrates, such as fructo-oligosaccharides, xylo-oligosaccharides, galacto-oligosaccharides, polyols, and fibers, have been studied for their potential to act as prebiotics that enhance the effects of naturally occurring probiotics on lactose intolerance (Kolida et. al., 2000; Rashidinejad et. al., 2022). Considering that the vast majority of previously published systematic reviews on this subject have been conducted to summarize the available data regarding the efficiency of probiotic use in lactose intolerance treatment, some of which have considered prebiotics as a side subject of the analysis; however, to our knowledge, no studies have focused on summarizing the available data on prebiotics. Prebiotics may be more effective than probiotics in alleviating lactose intolerance symptoms and facilitating microbial adaptation in the colon (Szilagyi, 1999). We herein aimed to summarize the available research outcomes into one inclusive conclusion regarding the most investigated types of prebiotics relevant to lactose intolerance according to previous literature, i.e., lactose, lactulose, and galacto-oligosaccharides.

The selected type of study was a scoping review. “Scoping review or scoping study is a form of knowledge synthesis that addresses an exploratory research question aimed at mapping key concepts, types of evidence, and gaps in research related to a defined area or field by systematically searching, selecting, and synthesizing existing knowledge” (Colquhoun et. al., 2014). The research process was conducted using the Wiley, Springer, Taylor and Francis databases and the academic search engines EBSCOhost and Google Scholar, as well as manual searches.

For scientific publication, different combinations were used for the search keywords: Prebiotics, Lactose Intolerance, Lactase Deficiency, Probiotics, Functional Dairy Products, and Relevance with combined prefixes “AND” and “OR.” The research process had the following selection criteria: 1) included articles published in English with no time limit, full text; 2) excluded publications were categorized as textbooks, abstracts, manuals, and conference proceedings, and articles written in other languages. Additionally, articles that were identified as secondary literature were excluded by title. And considering (Daudt et. al., 2013) suggestions regarding the necessity of the presence of a criterion concerning the quality assessment of the included publications (Colquhoun et. al., 2014), we limited the inclusion of only in-vivo studies, as this would provide better results for our research question. The search method is reflected in a flowchart that includes the identification and selection process of the articles that were used for screening (Fig. 1).

After applying the selection criteria according to the research aim, 579 records were found. A total of seventy-six publications were excluded because of duplication, and 436 publications were excluded by title, forty-four of which were rejected because the abstracts did not correspond to the topic. Hence, fifteen articles’ full texts were excluded because they did not correspond to the investigated research question. Eight full-text articles were left for analysis. Excluded publications were not included in the bibliography.

In the screened literature, three prebiotics with potential benefits for lactose intolerance symptom alleviation were investigated in clinical trials: lactose itself, lactulose, and RP-G28, a novel galacto-oligosaccharide. Table 1 provides a brief summary of the analyzed publications regarding the investigated prebiotic, the aim of the research, the specific type of the study, the main findings, and the methods that were used to assess the outcome. Altogether, the common parameters that were used for assessing the effect of lactose as a prebiotic were symptom intensity, breath hydrogen, and β-galactosidase activity. For the main findings reported by the studies, both studies reported overall milder symptom profiles with no significant effect on diarrhea, while (Hertzler and Savaiano, 1996) specifically mentioned nonsignificant differences between symptoms reported by individuals who ingested lactose and those who ingested dextrose, taking dextrose into consideration, in their study to determine whether the changes occurring can be attributed solely to lactose. Additionally, they reported a nonsignificant effect of both treatments on abdominal pain. For the BH₂ test results in both trials, (Briet et. al., 1997) reported a significant alteration, while (Hertzler et. al., 1997) reported a decrease. However, β-galactosidase activity was reported to be elevated by (Briet et. al., 1997) and to rapidly change in response to lactose absence or presence in the medium by (Hertzler et. al., 1997), which is a direct indication to the occurrence of metabolic adaptation in the guts. Regarding the screened literature on lactulose as a prebiotic, all three studies reported a significant increase in β-galactosidase activity and a decrease in the BH₂ profile. (Szilagyi et. al., 2001) reported a reduced overall symptom profile over three weeks of lactulose implementation to attain tolerance. Despite the fact that through the process, three subjects experienced minimal symptoms during additional milk consumption, by the end of the experiment, eight out of nine patients reported decreased symptoms, and three patients no longer met the criteria for lactose maldigestion.

(Flourie et. al., 1993) reported a decrease in osmotic diarrhea alongside pain and borborygmus with an elevated incidence of flatulence and bloating. This finding aligns with the decrease in the total carbohydrate output, which tended to decrease, leading to a better symptom profile and a significant decrease in the fecal pH reported in the same study, which suggests the opposite outcome regarding symptoms. Subsequently, this leads us to the fact that the results reported by (Florent et. al., 1985) do not integrate a direct measure of symptom scoring. Rather, the study reported several parameters that can indirectly indicate the extent of diarrhea incidence, i.e., decreased occurrence of carbohydrate output in the stool, and a decrease in the pH of cecum fluid and fecal water which were not significantly affected by lactulose maintenance, indicating that the incidence of diarrhea is less likely to occur because it is associated with a significant increase in carbohydrate presence in the stool with a significant decrease in the fecal pH. In contrast, the study reported one patient who experienced mild diarrhea due to mild acidity in the fecal pH that vanished by the third day. For the investigation of GOS-RP-G28, all screened studies agreed on symptom alleviation after following a regimen of GOS implementation in the diet as well as when the dairy products were reintroduced. One study reported a greater decrease in BH₂ in the treatment group than in the placebo group (Savaiano et. al., 2013). (Chey et. al., 2020) and (Azcarate-Peril et. al., 2017) used HBT testing as an inclusion criterion to determine the eligibility of patients for the trial prior to treatment. Relying on the thorough inspection and gut microbiome analysis carried out by their studies, (Azcarate-Peril et. al., 2017) and (Chey et. al., 2020) have discarded the HBT testing results after treatment as well as the quantification of fecal β-galactosidase. One additional parameter that was assessed regarding the use of the GOS was safety and the side effects of the treatment. (Savaiano et. al., 2013) and (Chey et. al., 2020) have used various methods to assess safety, reporting the use of the GOS as an overall safe intervention with minimal to no significant side effects on the tested population.

Table 1. Summaries of analyzed publications.

Author, year	Evaluated prebiotic	Aim of the research	Study design	Outcome’s assessment parameters	Main findings
Hertzler and Savaiano, 1996	Lactose	- First study, determining if the associated colonic adaptation is due to a response to the ingested lactose in population with prerecorded lactose maldigestion. - Second study, evaluating if this adaptation further led to reduced lactose intolerance symptoms.	Blinded controlled crossover	- Fecal β-galactosidase activity. - BH₂ excretion. - Intolerance symptoms scoring.	- Study reported fecal β-galactosidase activity has been increased along lactose ingestion. - Rapid change in enzyme’s activity in relevance to lactose presence or absence. - Decreased excretion of BH₂ prior lactose ingestion. - No significant alterations in symptom evaluation on daily basis throughout the lactose and dextrose ingestion period. - Recorded drop in flatulence and gaseous symptoms with lactose ingestion. - Both abdominal pain and diarrhea have not been significantly affected by ingesting lactose or dextrose.
Briet et al., 1997	Lactose	Comparing the influence of lactose and sucrose ingestion on regular basis regarding aspects of tolerance and bacterial adaptation.	Double blind controlled	- Symptoms Score. - Number of stools. - Fecal weight. - Osmotic gap. - Fecal pH. - Orofecal transit time. - BH₂ excretion. - Fecal β-galactosidase activity.	- Study reported aside from diarrhea, symptoms were milder in the second lactose challenge. - During both challenges, number of deifications lessened. - Between first day and 15^th day, neither stool weight nor fecal osmotic gap has changed. - During second test, the majority of lactose subjects recorded a decrease in fecal weight. - Alteration of fecal pH and BH₂ exertion to a significant extent. - Increased activity of fecal β-galactosidase. - Occurrence of metabolic adaptation along ingestion of lactose.
Florent et al., 1985	Lactulose	Assessing the influence of oral ingestion of lactulose chronically on the intracolonic metabolic processes, in vivo.	Controlled clinical cohort	- Stool weight. - Fecal pH. - Carbohydrate outputs (lactulose, galactose, fructose, and glucose). - Fecal β-galactosidase activity. - Volatile fatty acids (acetic, propionic, isobutyric, butyric, isovaleric, and valeric acids). - Osmolality. - Lactic acid concentration. - BH₂ excretion.	- Study reported H₂ excretion in the two groups was alike. - Significant dropping of excess BH₂. - Significant increase in pulmonary excretion of ¹⁴CO₂. - Decrease in each of the fecal weight over 24 hours, fecal water, and carbohydrate outputs. - Fecal water pH number was unaffected by maintaining the lactulose dose. - Significant increase in the concentration of fecal β-galactosidase. - Lactic acid concentration increased throughout the sampling period. - From eighth on, acetic acid ratio and the total VFA concentration have increased. - No notable change took place regarding fecal pH number by maintaining the lactulose dose.
Flourie et al., 1993		Assessing how prolonged lactulose ingestion influences each of symptoms’ profile, clinical signs, composition of stool, and the transit time in case of diarrhea induced by ingesting of large loads of lactulose.	Controlled prospective clinical	- Water flow rates in terminal ileum. - Lactulose flow rates in terminal ileum. - Ileal contents’ transit time. - BH₂ excretion. - Clinical symptoms. - Stool composition (lactulose, D-galactose, D-fructose, D- and L lactic acid, and volatile fatty acids). - Orofecal transit time. - Osmolality. - Electrolytes (sodium, potassium). - Fecal pH. - Stool dry weight. - Water percentage in the stool. - β-galactosidase.	- Study reported no changes in the mean water flow through distal ileum. - No change in orocecal transit time. - BH₂ excretion decrease. - Decrease in fecal pH number was significant. - Less outputs of lactulose, galactose, fructose, and total hexose units in stools after lactulose feeding. - Increase in β-galactosidase between test period 1 to test period 2 was significant. - Decreased osmotic diarrhea, pain, and borborygmus. - Increased bloating and incidence of flatulence.
Szilagyi et al., 2001		Determination of the colonic adaptation associated with lactulose ingestion’s ability to alter lactose maldigestion and intolerance profile under controlled conditions.	Controlled clinical	- Dietary assessment questionnaire. - Three days diet recall. - BH₂ excretion. - Daily symptoms score sheet. - Fecal β-galactosidase.	- Study reported significant reduction in BH₂. - Increase in stool β-galactosidase activity up to threefold after three weeks of lactulose ingestion. - Increased lactulose tolerance with reduced symptoms over three weeks period. - Enhanced fecal β-galactosidase correlation with increased BH₂ on second testing. - 10 g lactulose twice daily decreased BH₂ and symptoms in eight out of nine cases. - Three subjects out ranged the criteria of lactose maldigestion. - Five subjects had minimal symptoms during extra milk consumption.
Savaiano et al., 2013	GOS - RP-G28	Evaluation of safety, efficacy, and tolerability of RP-G28 in subjects with reported lactose intolerance.	Proof-of-concept, randomized, double-blind, parallel group, placebo-controlled clinical trial.	- Lactose intolerance symptoms. - Hydrogen production via (HBT). - Patient global assessment (PGA). - Safety assessments: adverse events (AEs) and serious adverse events (SAEs).	- Study reported decreased H₂ excretion with ingesting RP-G28 in comparison to the placebo group. - Improved symptoms of abdominal pain, cramping, bloating, and flatulence. - Common adverse events such as headache, dizziness, nausea, upper respiratory tract infection, nasal congestion, and pain were mild or moderate. - No serious adverse events. - Changes observed in clinical evaluations were not significant.
Azcrate-Peril et al., 2017		Investigating the possibilities of shifting fecal microbiota in lactose intolerant population when treated with Galacto-oligosaccharides (GOS).	Randomized, double-blind, parallel-group, placebo-controlled trial	- Hydrogen production via the (HBT). - Lactose intolerance symptoms assessment (abdominal pain, flatulence, cramping, bloating, and diarrhea) - DNA isolation and subsequent microbiome analyses. - T-RFLP analysis. - 16S rRNA gene amplicon sequencing. - High throughput qPCR detection.	- Study reported symptoms alleviation in 71% of treated individuals after GOS ingestion. - Symptom alleviation in 69% of treated individuals with dairy reintroduction. - No bifidogenic response was recorded in symptomatic responders, while symptomatic non responders demonstrated a bifidogenic response.
Chey et al., 2020		Determination of safety, efficacy, and tolerability of RP-G28 dosages in subjects with reported severe and moderate lactose intolerance profiles.	Multi-center randomized, double-blind, placebo-controlled, parallel group clinical trial	- Lactose intolerance symptom assessments. - BH₂ excretion. - Gut microbiome analysis, 16S rRNA amplicon sequencing. - Safety analyses using summary statistics.	- Study reported reduction of symptoms effectively with ingesting RP-G28 alongside improved patient satisfaction. - Safety of RP-G28 along its well tolerance. - No significant gastrointestinal side effects. - Gut microbiome was enhanced with RP-G28 ingestion in terms of increased Bifidobacteria, Lactobacillaceae, as well as lactose-fermenting Roseburia species.

The data mentioned in Table 2 were dedicated to categorizing the common methods used in assessing the outcomes into their implicatory aspects, i.e., the aspect for which each assessment was first carried out. This led us to sixteen common assessment methods in five main categories. For each fecal β-glycosidase, 16S rRNA amplicon sequencing, DNA isolation, t-REIP analysis, and high-throughput qPCR were used to determine the abundance of lactase-producing and lactose-fermenting bacteria in one way or another. While conducting BHT, fecal pH, VFA, and lactic acid concentration testing indicate the incidence of microbial fermentation in the gut, its outcome, and the extent of its occurrence. The number of stools, fecal weight, orofecal transit time, and carbohydrate outputs were used to reflect data about gut motility and both its digestive and absorptive efficiency and can in turn indirectly indicate the incidence of diarrhea. Symptoms score tests were used to indicate symptom severity. The measures of osmotic gap and osmolality indicated the incidence of osmotic diarrhea or malabsorption.

Table 2. Common parameters used for assessment in the analyzed publications.

Prebiotic		Lactose		Lactulose			GOS - RP-G28
Author, year		Hertzler and Savaiano, 1996	Briet et al., 1997	Florent et al., 1985	Flourie et al., 1993	Szilagyi et al., 2001	Savaiano et al., 2013	Azcrate-Peril et al., 2017	Chey et al., 2020
Assessed aspect	Method of assessment	Hertzler and Savaiano, 1996	Briet et al., 1997	Florent et al., 1985	Flourie et al., 1993	Szilagyi et al., 2001	Savaiano et al., 2013	Azcrate-Peril et al., 2017	Chey et al., 2020
Abundance of lactase producing and lactose fermenting bacteria	Fecal β-glycosidase	+	+	+	+	+
	16S rRNA amplicon sequencing								+
	DNA isolation							+
	T-REIP analysis							+
	High throughput qPCR detection							+
Microbial fermentation incidence and outcome	BHT	+	+	+	+	+	+	+	+
	Fecal pH		+	+	+
	VFA			+	+
	Lactic acid concentration			+	+
Digestive/absorptive efficiency and gut motility	Number of Stools		+
	Fecal weight		+	+	+
	Orofecal transit time		+		+
	Carbohydrates outputs			+	+
Symptoms severity	Symptoms score test	+	+		+	+	+	+	+
Incidence of osmotic diarrhea or malabsorption	Osmotic Gap		+
Incidence of osmotic diarrhea or malabsorption	Osmolality			+	+

To narrow the scope even further (Table 3), only the parameters that directly reflected the gastric distress status of the participants and their relative extent of alleviation were assigned. Parameters such as decreased BH₂ excretion, decreased fecal pH, increased fecal β-galactosidase activity, decreased abdominal pain, decreased diarrhea, and decreased flatulence/bloating were sorted in the table to make the final data clearer and more accessible.

Table 3. Summary of the general impact of the tested prebiotics on lactose intolerance alleviation reported in the analyzed publications.

Prebiotic	Lactose		Lactulose			GOS - RP-G28
Author, year Alleviation Parameter	Hertzler and Savaiano, 1996	Briet et al., 1997	Florent et al., 1985	Flourie et al., 1993	Szilagyi et al., 2001	Savaiano et al., 2013	Azcrate-Peril et al., 2017	Chey et al., 2020
Decreased BH₂ excretion	+	+	+	+	+	+
Decreased Fecal pH		+	+	+
Increased Fecal β-galactosidase activity	+	+	+	+	+
Decreased abdominal pain		+				+	+	+
Decreased diarrhea				+	+		+
Decreased flatulence/bloating	+	+		+		+	+	+

According to the literature screened in our review, multiple studies have aimed to determine the optimum treatment for lactose intolerance. To achieve this goal, several prebiotics have been studied, from which we selected the most thoroughly investigated ones, in comparison to the body of literature available on the topic, as mentioned above. With respect to the use of naturally occurring lactose in dairy products as a prebiotic, lactase expression generally cannot be upregulated or induced in humans, unlike in some rodent models (Szilagyi and Ishayek, 2018); rather, tolerance is suggested to be indirectly induced through microfloral adaptation (Labrie et. al., 2016). It was proven in previous literature that this metabolic shift in the gut microbiota, which in turn leads to adaptation, decreased BH₂ test outcomes, and an increase in the incidence of lactose intolerance symptoms (Hertzler and Savaiano, 1996; Hertzler et. al., 1997).

In contrast, the normal intake of lactose was found in some cases to influence the lactase persistent population, with full functional lactase in terms of validity and sufficiency, where they can encounter up to 8% indigested segments of a lactose dosage, as reported by (Bond and Levitt, 1976), where at the same time, (Deng et. al., 2015) stated that lactose intolerance symptoms can only be spotted in the case of lactase activity below 50% in the gut.

(Briet et. al., 1997) confirmed the incidence of metabolic adaptation alongside decreased records of all symptoms except diarrhea. However, the study did not attribute this decrease to adaptation; rather, it was attributed to acclimatization to the process. Hence, the study suggested the avoidance of ingesting large doses of lactose following a fasting state. (Hertzler and Savaiano, 1996) showed that lactose ingestion led to metabolic adaptation as well as an unexpected outcome in which subjects tolerated a large dose of lactose (800:1500 ml of milk). Accordingly, suggesting that colonic adaptation can be a cost-effective approach for dealing with lactose-intolerant populations. Additionally, due to the elevated tolerability, the study indicated that regular lactose ingestion should be considered among the reasons why the BH₂ test should not be considered an accurate indicator for diagnosing lactose intolerance alongside severe diarrhea and recent antibiotic ingestion (Hertzler and Savaiano, 1996).

Aside from lactose, there has been a growing body of evidence regarding lactulose’s beneficial effect on the gut microbiome when it is ingested in combination with other regimens for treating other complications. On a chemical basis, lactulose is a synthetic disaccharide consisting of D-galactose and D-fructose that can only be synthesized using the milk sugar lactose at relatively high temperatures (Hertzler and Savaiano, 1996; Nooshkam et. al., 2018). In addition to its multiple applications in the food technology sector, it has various applications in the medical field. These include the treatment of chronic constipation, portal systemic encephalopathy, and other intestinal and hepatic disorders. (Mayer et. al., 1996). Additionally, it was found to have a similar impact on the gut microbiota to that of lactose when ingested chronically (Hertzler and Savaiano, 1996; Hertzler et. al., 1997).

Similarly, in studies addressing lactulose, (Florent et. al., 1985) confirmed a potential modification in the microbial fermentation pathway as a result of frequent lactulose load ingestion. Subsequently, a greater abundance of lactic acid-fermenting bacteria was induced, which can also be attributed to the decreased pH of the cecal contents. (Flourie et. al., 1993) suggested that the symptoms induced by lactose ingestion are caused by the small intestine rather than the fermentation processes occurring in the colon. Moreover, this study supported the notion of improved microbial fermentation due to regular lactulose ingestion. In addition, we suspect that colonic motility and altered microbial fermentation pathways might have a synergistic relationship. Additionally, the study attributed the acknowledged decrease in the incidence of diarrhea to the reduction in the colonic osmotic load as well as the elevated absorption of organic acids (Flourie et. al., 1993). Later, (Szilagyi et. al., 2001) claimed that both lactose and lactulose are likely to have the same effect and mechanism of action while leading to microbial alterations in the colon, which has been supported by the recorded nonsignificant doubling of fecal β-galactosidase. The consideration of lactulose as a therapy for lactose-intolerant populations is recommended by previous studies (Szilagyi et. al., 2001).

For the articles in the literature dedicated to investigating the use of the galacto-oligo saccharide (GOS, RP-G28) approach for enhancing the alleviation of symptoms due to lactose intolerance and gastric-distress-causing diseases, we found RP-G28 to be a proprietary product that is greater than 95% galacto-oligosaccharide. Its empirical formula is C_(n+2)6 H_22 + 10n O_(n+2)5 (Savaiano et. al., 2013). Generally, GOSs reach the colon in an intact form, where they start their action in stimulating lactose-fermenting gut microbiota to grow and flourish; this in turn leads to the abundant bacteria (Lactobacillus and Bifidobacterium) obtaining enhanced β-galactosidase activity, thus utilizing GOS (Silk et. al., 2009; Depeint et. al., 2008). Subsequently, the fermentation rates of lactose into galactose, glucose, and SCFAs increase, and the rates of gas production decrease. Eventually, this leads to alleviated symptoms of lactose intolerance (Jiang et. al., 1996). For instance, one of the screened studies that addressed GOSs revealed gradational alterations in specific types of β-galactosidase enzymes as a result of implementing GOSs and dairy products in the diet (Azcarate-Peril et. al., 2017). This, in turn, suggests that the gut microbiome has shifted toward non-gas-forming lactose-fermenting microbiota. The same study suggested that gastric distress symptoms are negatively correlated with Bifidobacterium but positively correlated with the species Coprobacillus/ Rickenellaceae. Thus, the use of GOS may enhance beneficial microbiome abundance while decreasing the population of the microbiome, which has a negative effect on lactose intolerance (Azcarate-Peril et. al., 2017). Recently, it was indicated by (Chey et. al., 2020) that RP-G28 has a high safety profile while alleviating lactose intolerance symptoms, which leads to an increased tolerable upper limit of dairy intake and enhances the abundance and quality of the gut microbiota. This study also revealed a very important concern regarding the possible effect of RP-G28 on gastrointestinal symptoms in patients with IBS, as RP-G28 is a component of FODMAPs, which are known for negatively affecting gastrointestinal symptoms. No records of increased gastrointestinal symptoms were observed during the study (Chey et. al., 2020). Moreover, although RP-G28 is still not approved by the FDA for this purpose (Szilagyi and Ishayek, 2018), (Savaiano et. al., 2013) agreed that RP-G28 treatment affects the functional pain associated with lactose intolerance, which is mostly a key symptom that drives other symptoms of gastric distress.

Overall, against the bluntly misinformed belief that dairy products should be avoided in the case of lactose-intolerant patients, several authors have proven this approach wrong by studying some observed sequences of colonic microbiota adaptation after repeatedly reporting that chronic milk consumption, especially in developing countries’ school feeding programs, increases the extent to which lactose can be tolerated without causing symptoms (Johnson et. al., 1993; Hertzler and Savaiano, 1996). Admittedly, the colon has an elevated capacity for SCFA absorbance (Ruppin et. al., 1980; Høverstad et. al., 1982), which suggests that the more capable the gut microbiota is of fermenting lactose, the more it will positively affect the lactose intolerance symptom profile. However, this thought was not supported by (He et. al., 2006) in his study, as rather than attributing the distress commonly to the residual lactose, relying on the fact that the residual lactose is more prone to being hydrolyzed into glucose and galactose either by lactase in lactose-tolerant populations or by the gut microbiota to a sufficient extent in others. He suggested that the accumulated end products of microbial metabolism in specific parts of the colon affect its osmotic load, causing alterations in intestinal motility and colonic hypersensitivity that subsequently also lead to intolerance symptoms (He et. al., 2006). This drives us to a legitimate assumption that if a suitable rate of SCFA absorbance could be attained or regulated in the gut to reach a state of SCFA production/absorbance synchronicity, then all the leads, even the contradictory ones, will agree on the possibility of attaining an enhanced symptom profile that can further be applied to treatment regimens for lactose intolerance and other gastric distress-triggering diseases.

Current results are very promising regarding the use of the three investigated prebiotics equally despite lactose being more easily ingested (when used as a prebiotic) within its normal food matrix. However, the effect of pop-health claims on the public leads to false-positive BHT results in patients with self-reported lactose intolerance. Known for reporting symptoms right after ingestion of dairy rather than after 50:100 minutes, which is the estimated proper period of time for the substrate to enter the colon and inflect it (Deng et. al., 2015).

In conclusion, lactose intolerance variations (i.e., congenital lactase deficiency, developmental lactase deficiency, adult-onset hypolactasia, and secondary lactase deficiency) are highly individualized concerns for which a firm protocol for diagnosis should be developed to overcome the vast spread of misdiagnosis either by self-reporting or by insufficient testing methodologies, i.e., HBT, which in turn can lead to the spread of dietary patterns that compromise skeletal system health. Further clinical trials and cohort studies are needed to develop more solid evidence-based practices aimed at setting firm guidelines for proper dosage specifications for the aforementioned prebiotics rather than just investigating whether they have an actual impact on the lactose intolerance profile. Taking into consideration individual differences between subjects, it might be useful to implement various techniques in creating a proper management regimen/protocol for lactose-intolerant populations, including targeting lactose ingestion in terms of doses, combining specific proportions of each prebiotic to reach the most regulated rates of lactose fermentation metabolite formation/ disposal, and investigating the possibility of reaching the aforementioned hypothetical SCFA production/absorption rate synchronicity in the gut.

Nevertheless, it is advised that the implementation of lactose challenge testing should be combined with one or more diagnostic techniques for the following to achieve a proper, efficient outcome: 1) blood sugar testing after lactose ingestion, where the dosage failure to raise blood sugar above 1.1 to 1.4 mmol/L can be interpreted as maldigestion; 2) detection of the stool pH, where a lower outcome indicates a greater incidence of malabsorption; 3) HBT combined with methane production testing to increase its reliability; 4) genetic mutation detection; and/or 5) mucosal biopsy for lactose activity detection (Szilagyi and Ishayek, 2018).

Conflicts of Interest:

The authors have no relevant financial or non-financial interests to disclose.

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contribution

R. A. performed the database search, selected the reviewed publications, screened the publications, extracted the data for review, and wrote the draft of the review.V. K. helped develop the manuscript’s outline, guided the methodological approach selection, guided the publication selection process, and revised the extracted data from the selected publications.Both authors revised and approved the final manuscript.

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Prebiotics Ingestion in Relevance to Lactose Intolerance Alleviation

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