Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1

Glucose galactose malabsorption (GGM, OMIM #606824) is a rare autosomal recessive disorder of intestinal monosaccharide transport that results in lifelong, diet-induced diarrhea. Loss-of-function mutations of the sodium-glucose/galactose cotransporter (SGLT1/SLC5A1) result in the inability to transport the monosaccharides, glucose, and galactose, across the apical border of the intestinal epithelium, resulting in bloating, cramping, flatulence, and a dose-dependent osmotic diarrhea [1‐3]. Following hydrolysis by specific enzymes, complex carbohydrates and disaccharides containing glucose and galactose, such as sucrose (glucose/fructose), lactose (glucose/galactose), and maltose (glucose/glucose), are also malabsorbed. The monosaccharide fructose is selectively transported across the apical membrane-facilitated transporter (GLUT5/SLC2A5), and its function is retained in GGM.

The standard of care for patients with GGM is lifelong restriction of dietary glucose and galactose. During infancy, the primary nutrition is a fructose-based formula, either as a Ross Carbohydrate-Free formula (Abbott Nutrition) with fructose supplementation, or a ready-made formula containing only fructose (Galactomin 19, Nutricia). Generally, by four to six months of age, low-carbohydrate foods, such as fruits and vegetables, can be introduced. Eventually, more carbohydrates may be incorporated, and some studies suggest improved tolerance to glucose and galactose with age [4‐6]. The nutrition management of GGM during infancy has been well-described [6, 7], but long-term dietary follow-up is limited [5].

The aim of this study was to perform a meaningful dietary assessment on a cohort of patients with GGM to gain insights into consumption patterns within the population, while also drawing comparisons to the typical Western diet. This assessment not only forms a foundation for prospective nutritional studies in patients with GGM and other disorders of carbohydrate malabsorption, but also provides a practical resource for providers caring for patients with GGM.

To the best of our knowledge, this was the first detailed cross-sectional cohort analysis of dietary intake of infant, children, and adult patients with GGM. Our data suggest that a high-fat and high-protein/low-carbohydrate diet is followed by patients of all ages with GGM. This is consistent with a prior study of Amish children with GGM that also reported a high-fat and high-protein GGM diet [5]. Not surprisingly, fructose was the major source of sugar in the GGM diet because of the lifelong restriction to glucose and galactose. As shown, however, there was a shift in sugar intake toward more glucose and less fructose with increasing age—albeit at significantly lower levels when compared to age-matched national intake data. While the proportion of glucose in the diet was higher over time, the actual amount remained limited. Meanwhile, galactose intake was marginal throughout life.

In our GGM cohort, several trends were observed in the individual food group preferences as well as the macronutrient distribution. Within the fruits, there was a pattern of apples, pears, and mangos in the diet, all of which are high fructose containing fruit [8]. In the dairy group, there was a trend toward hard and aged cheeses, specifically cheddar and Swiss, because they are lower in lactose due to breakdown of lactose into lactic acid during the aging process. These trends reflect the natural affinity of the GGM group toward foods with less glucose and galactose to improve their gastrointestinal symptoms.

Total fat consumption within the GGM cohort was high compared to the US population. This was not surprising given the need to omit carbohydrates, specifically glucose and galactose, in GGM. The dietary fat included a mixture of specific types of fat, including polyunsaturated, monounsaturated, saturated, and trans fats. The polyunsaturated fat intake within our GGM cohort was 9% calories, within the target 10% calories recommended by the National Heart, Lung, and Blood Institute (NHLBI) to reduce cardiovascular risk in pediatric patients, while the monosaturated fat intake was 21% calories, exceeding the target 10–15% calories [9‐11].

Next are the saturated fats, found mostly in animal-based foods and even some plant foods, like nuts and palm oil. Mean saturated fat intake within our cohort was 15% calories, above the 8–10% recommended by the NHLBI and the Dietary Guidelines by Americans [9, 10]. It remains to be seen whether the health protective effects of high poly- and monounsaturated fat intake offset the potentially harmful consequences of the high saturated fat intake.

The final type of fat is trans fat, considered the most deleterious to cardiovascular health [12]. Trans fat intake in our cohort was minimal. Supplementary Table 2 displays the US daily nutritional goals and recommendations for various sex-age groups [9‐11, 13].

Protein consumption was excessive in the GGM cohort, much greater than the amount necessary to meet the nutrient needs according to the Recommended Dietary Allowance [13] (Supplementary Table 2). Protein intake was also high relative to US consumption patterns because of the need for carbohydrate restriction in GGM. Protein is essential for growth and neurocognitive development, but it may also lead to glomerular hyperfiltration and accelerate kidney damage if the load exceeds kidney’s excretory capabilities [14]. Although the kidneys are usually unaffected in GGM, impaired renal function associated with nephrolithiasis as a result of chronic dehydration has been documented in multiple case reports [4, 15]. The single case of nephrolithiasis in our cohort (patient 4) was deemed by the medical team at the time to be more likely a result of dehydration than excessive protein consumption. Monitoring for complications associated with high-protein intake will be important for the long-term care of patients with GGM.

Carbohydrates were limited in the GGM cohort as a result of glucose and galactose restriction. Fructose was the primary sugar in the diet. Fruits and vegetables accounted for most of the fructose in the GGM cohort, while sugar-sweetened beverages and grains, especially refined grains from processed foods, contributed the bulk of the fructose in the contemporary Western diet [16]. Added sugar intake among the GGM cohort was minimal at < 1% calorie intake, far below the recommended < 10% calorie intake by the Dietary Guidelines by Americans. Meanwhile, fiber intake was within the age-specific recommendations for most patients because of the high fruit and vegetable intake [13] (Supplementary Table 2).

Consistent with prior reports suggesting increased tolerance to glucose with time [4‐6], our data showed an incremental decline in fructose consumption, alongside a tempered increase in glucose consumption, with age. Although the mechanisms underlying the age-dependent tolerance is unknown, one study noted that the administration of Lactobacillus acidophilus seemed to help to accelerate tolerance, suggesting possible intestinal flora adaptations over time [3]. Other studies speculate an increased colonic absorption from microbiota with age [17], genotype/phenotype variations in sugar tolerance [2], and presence of other glucose or galactose transport mechanisms besides SGLT1. GLUT2, once thought to be a glucose, galactose, and fructose transporter only on the basolateral membrane of the intestinal epithelium, however, had been shown in rat models to be an important apical transporter at very high luminal glucose concentrations [18], providing an alternative way to transport sugar across the brush border membrane. However, because the proposed mechanism by which GLUT2 inserts onto the apical membrane is contingent on SGLT1, it is unlikely to do so since the majority of the GGM variants in SGLT1 results in improper targeting to the apical membrane [2, 19]. In another study in mice, data showing that SGLT1 null mice survived well on a glucose and galactose-free diet, but lost weight and eventually died after transitioning to a standard diet, further suggest that SGLT1 may be the primary apical transporter mediating glucose and galactose uptake [20]. Additionally, the presence or absence of GLUT2 did not seem to have any significant effect on glucose absorption in another study [21]. Based on our own experience, we hypothesize that the greater amounts of dietary glucose and galactose observed with older age may be the result of a higher functional reserve capacity of the gastrointestinal tract, smaller gastrointestinal caloric load (kcal/kg), and perhaps higher clinical tolerance to gastrointestinal symptoms (at the expense of a more liberalized diet). Collection of fecal output data in subsequent studies may help differentiate whether the increasing glucose consumption with advancing age is the result of poor dietary compliance or truly improving tolerance. Nonetheless, as our data demonstrated, the increasing amounts of glucose and galactose in the diet were only marginal.

While the present study represents the most comprehensive dietary analysis of patients with GGM to date, the results should be interpreted in light of several limitations. The first limitation is the use of a self-reporting dietary assessment. Although a food record is validated instrument for the assessment of energy and nutrients, the method is prone to measurement error and bias. However, this study employed several strategies to reduce bias, including the use of prospective tracking over a three-day period and follow-up telephone interviews with a trained dietician to review the dietary details. The second limitation is the small sample size, an inherent challenge in the study of rare diseases. GGM is extremely rare, with approximately several hundred people diagnosed worldwide [22]. Like most other published studies on GGM which consist of single person to small group case reports, our study reported only six participants, limiting generalizability to this patient group as a whole. Our study, however, had the added advantage of including older children and an adult patient with GGM, which, to our knowledge, is the first-time patients beyond the toddler age has been evaluated from a nutritional standpoint. Because of the small sample size and experimental design, a final limitation is that this study cannot draw conclusions about the effects of diet on health outcomes within the GGM population. However, based on our dietary analysis, we suspect that patients with GGM, compared to their non-GGM counterparts, are less likely to suffer obesity-related metabolic disease because of their dietary choices, which we believe may be a more important predictor for health than the macronutrient and caloric content of the diet itself. Although micronutrient intakes were not evaluated in this study, a prior study showed that patients with GGM consume more vitamin A, vitamin D, iron, and zinc compared to those without GGM [5]. Future research requires a larger GGM cohort and longer-term follow-up to better understand how the individual foods and both the macro- and micronutrient components of the GGM diet impact health.

In conclusion, patients of all ages with GGM consume a high-fat and high-protein/low-carbohydrate diet that is rich in fruits and vegetables but limited in dairy and added sugar. Avoidance of dietary glucose and galactose is key, but increased intake of these sugars develops over time by an unclear mechanism that requires further investigation. Fructose, although consumed in higher quantities relative to glucose and galactose, makes up a smaller proportion of the GGM diet compared to the standard Western diet. More importantly, the fructose in the GGM diet comes primarily from fruits and vegetables, as opposed to sugar-sweetened beverages and processed food in the Western diet. Future studies should investigate the effects of the GGM diet on intestinal transport mechanisms, gut microbiome, and long-term growth and health.