Chapter 3.15
Lactose malabsorption and nutrition
Pascale Gerbault, Anke Liebert, Dallas M. Swallow and Mark G. Thomas
University College London, London, UK
The consumption of milk and dairy products varies
considerably in different regions of the world.
Indeed, according to the statistics of the Food and
Agriculture Organization of the United Nations
(FAO), in 2007 the consumption of milk and dairy
products averaged 240 kg and 360 kg per capita in
the UK and Sweden, respectively, while in China it
was about 29 kg per capita. Milk is a complex and
nutrient-dense food [1] that may have positive or
negative effects on adult health [2]. The major carbohydrate component in milk is lactose, a disaccharide whose concentration in bovine milk has been
reported to range between 45 and 55 g/L [2–4].
Lactose needs to be digested by the small intestinal
enzyme lactase into its constituent monosaccharides, glucose and galactose, before transport across
the epithelial cell membranes.
Lactase activity is therefore essential for the development of young mammals, since their sole source of
nourishment is their mother’s milk. In most mammals,
including most humans, lactase expression decreases
after the weaning period is over [5]. In humans, this
condition is termed lactase non-persistence and is
observed in around 65% of adults worldwide [6,7].
Lactase non-persistent individuals are sometimes
described as having primary adult hypolactasia and are
lactose maldigesters, while adults who have the genetically determined trait of lactase persistence (LP) and
continue to produce lactase throughout life are termed
lactose digesters.
The range of timing of lactase downregulation
varies from one population to another; for example,
most Chinese and Japanese become lactase non-
persistent between 1 and 5 years old, while on average lactase non-persistence does not manifest in
Finns and Estonians until somewhat later [8]. Even
though the mechanisms of developmental lactase
downregulation are not well understood, it is clear
that it is not reversible [9,10]. Lactase production
can also be lost through non-genetic mechanisms;
this is called secondary hypolactasia and it can
occur, for example, after any condition that damages the small intestinal mucosa brush border [11].
Adults with either primary or secondary hypolactasia are lactose malabsorbers and may exhibit symptoms of lactose intolerance after ingestion of
lactose. Genetically determined lactase non-persistence is quite normal in the majority of humans
worldwide and is distinct from congenital alactasia,
the absence of lactase from birth. This, in contrast,
is an extremely rare and potentially fatal condition.
A number of mutations that affect the structure of
the protein, and consequently its function, have
been identified in Finnish patients suffering from
this condition [12,13].
Two types of tests are available for determining
lactase production status at the phenotypic level.
Duodenal or jejunal biopsies can be taken by endoscopy and allow direct determination of lactase
activity. A lactase assay is usually combined with
routine histology and an assay of another enzyme
such as sucrase, so that secondary deficiency of
lactase can be readily identified. This procedure is
the most accurate available, but it is invasive and
performed routinely only if a pathological condition
such as coeliac disease is indicated. Other methods
Advanced Nutrition and Dietetics in Gastroenterology, First Edition. Edited by Miranda Lomer.
© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.
3.15 Lactose malabsorption and nutrition
involve lactose ingestion after an overnight fast to
inform indirectly on lactase activity [14]. For the
glucose test, an increase in blood glucose is indicative of LP as lactase cleaves lactose into glucose and
galactose. Although less commonly used for identifying LP, a urinary galactose test can also be performed, which also involves giving alcohol to block
galactose uptake by the liver. Alternatively, the
breath hydrogen test measures hydrogen production
by colonic bacteria; in lactase non-persistent individuals, undigested lactose reaches the colon and
hydrogen is released after fermentation by hydrogen-producing colonic bacteria, while in persistent
individuals lactose is cleaved before reaching the
colon. These tests require a baseline measurement
of glucose, galactose or breath hydrogen before
ingestion of the lactose load, and further measurements of the same at about 30-min intervals for 2–3 h.
It should be noted that these indirect tests are not
100% accurate (error rates are discussed in Mulcare
et al. [15]) and cannot distinguish primary from secondary hypolactasia. For example, there are some
individuals who do not have colonic bacteria that produce hydrogen, and therefore do not show a hydrogen
rise irrespective of their lactase production status.
The passage of lactose into the colon in nonlactase producers can lead to GI symptoms, such as
bloating, flatulence, abdominal pain and diarrhoea.
These symptoms are described as ‘lactose intolerance’. Lactose intolerance should be distinguished
from milk allergy; while the former is a non-toxic
and non-immune adverse reaction to undigested
lactose, milk allergy involves an immune response,
usually to milk protein.
After an individual has been diagnosed as lactase
non-persistent, dairy products are often removed
from the diet. This may have serious nutritional disadvantages, such as reducing the intake of calcium,
phosphorus and vitamins, and may be associated
with decreased bone mineral density [2,16,17],
while lactose-free milk products intake would avoid
symptoms and be nutritious. In contrast, milk powder (which does contain lactose) has been used for
famine relief in undernourished populations where
the frequency of LP is often very low [18,19] and
for whom symptoms of intolerance can potentially
exacerbate diarrhoeal disease and mineral deficiency [18,20,21].
203
3.15.1 Lactase persistence
This section briefly summarises what is known
about the genetics and evolution of the LP trait, but
further details and references can be found in
Gerbault et al. [22] and on the global lactase persistence database website (www.ucl.ac.uk/mace-lab/
resources/glad).
The global distribution of lactase
persistence
Figure 3.15.1 shows an interpolated map of the
frequency of LP in indigenous populations worldwide. LP is particularly common in northern
Europe, with frequencies of around 89–96% in the
British Isles and southern Scandinavia; a declining
gradient towards the south and east is seen in the
rest of Europe. On other continents LP is not
evenly distributed geographically. Indeed, in
Africa and the Middle East it is often found at very
different frequencies in neighbouring populations,
such as 64% in the Beni Amir (pastoralists) and
23% in the Dounglawi (non-pastoralists) in Sudan.
LP frequency has been shown to correlate strongly
with a tradition of pastoralism [23].
The genetics of lactase persistence
Lactase persistence is inherited in an autosomal
dominant manner. A single gene (LCT) codes for
lactase. Several single nucleotide changes have
been found in a lactase gene regulatory region
(so-called enhancer, which is located in the
adjacent gene MCM6), one of which occurs at
high frequency in Europe. Estimates of the age
of these changes range between 2,188 and 20,650
years ago [24] and between 7,450 and 12,300
years ago [25] for the −13,910*T allele associated
with LP in Europe and southern Asia, and between
1200 and 23,200 years ago for the −14,010*C
allele, one of the major LP-associated variants in
Africa [26]. These date estimates bracket those
for the domestication of milkable animals and the
spread of agriculture and herding obtained from
archaeological data (cave paintings, distributions
of animal bones and dairy fat residues in pots).
Figure 3.15.1 Interpolated map of LP phenotype distribution in the ‘Old World’. Data points (dots) were taken from the literature (for
details see Ingram et al. [6]). The key shows the frequency of the LP phenotype, black being used for the lowest frequency while white is
used for the highest. Source: Itan et al. [7]. Reproduced with permission from BioMed Central Ltd.
3.15 Lactose malabsorption and nutrition
Natural selection and evolution of
lactase persistence in humans
A low frequency or absence of −13,910*T in early
Neolithic central European farmers [27] and early
Neolithic farmers from north-east Iberia [28], middle Neolithic Scandinavian hunter-gatherers [29]
and late Neolithic farmers from southern France
[30] suggests that dairying was practised before LP
arose or became common. The age estimates for the
LP-associated variants are remarkably young for
alleles found at such high frequencies in multiple
populations, suggesting that their spread has been
boosted by natural selection. The strength of natural
selection estimated for the LP-associated alleles
is very high (1.4–19% [23] and 5.2–15.9% [31]
for −13,910*T, and 1–15% for −14,010*C [26]),
amongst the highest for any human genes in the last
30,000 years.
Several lines of evidence (genetics, anthropology
and archaeology) suggest that LP would not have
provided a selective advantage without a supply
of dairy products containing lactose to adults,
implying that these traits evolved as the result of a
co-evolutionary process involving both genes and
culture. A spatially-explicit computer simulation
study of this gene–culture co-evolutionary process
in Europe indicate that LP and dairying began
between 6856 and 8283 years ago in a region
around modern-day Hungary [31].
3.15.2 Implications for
diet today
Variable symptoms of hypolactasia
in adults
Symptoms of lactose intolerance can arise after an
individual with hypolactasia has ingested lactose.
Firstly, when undigested lactose passes into the
colon it creates an osmotic gradient across the GI
wall, driving an influx of water to re-equilibrate the
osmotic imbalance, which can lead to diarrhoea.
Secondly, the fermentation of lactose by colonic
bacteria can lead to the production of fatty acids and
various gases as by-products (including hydrogen),
potentially causing discomfort, bloating and flatulence
205
(reviewed in (Hammer et al. [32]). These symptoms
usually manifest within 1–2 h of ingestion, but vary
greatly from one individual to another.
The symptoms of lactose intolerance are a function of (1) the amount of lactose ingested at one
time, (2) gut transit time, which itself is influenced
by factors such as the presence and consistency of
solid foods and the temperature of the food [33],
and (3) the quantity of residual lactase expressed in
the small intestine and, (4) the spectrum of microbiota present in the colon. In fact, most lactase nonpersistent individuals can consume small amounts
of fresh milk (such as in coffee or tea) without
symptoms, and some can consume considerably
larger quantities. It has variously been reported that
lactose-intolerant individuals can tolerate daily
amounts of lactose ranging from no more than 12–15g
of lactose – the equivalent of a cup of milk [34,35] – up
to 40–70 g of lactose [19,36]. Also, a controlled
double-blind study showed a strong placebo effect
in the production of symptoms [37]. It thus appears
that lactase non-persistent individuals should not be
warned off fresh milk, except like all people, while
experiencing diarrhoea, but rather need to find their
own lactose tolerance threshold. Lactose is often used
as a bulking agent in pills. It is relevant to note that
administration of capsules containing either 400 mg of
lactose or a placebo failed to show any changes in H2
in breath exhalation or GI symptoms [33].
Some interindividual variation in lactose intolerance symptoms can be explained by the composition
of the GI microbiota. Lactase is not an inducible
enzyme [10] but it has been suggested that adaptation
can come from the GI microbiota when lactose
is continuously consumed [33]. The microbial
community within the human GI tract is diverse and
dynamic in species composition, large in mass and
complex in ecology [38]. Furthermore, its equilibrium composition can be shaped by diet [38]. Indeed,
both an alteration of the composition of the microbiota and an increase in fecal beta-galactosidase activity
have been observed after daily milk feeding and in
association with a reduction in lactose intolerance
symptoms [34,36]. There are also differences in the
production of gases (such as hydrogen), which cause
much of the discomfort in lactose intolerance. This
highlights the fact that milk and lactose-containing
products can often be consumed without provoking
206
SECTION 3: Gastrointestinal disorders
symptoms of intolerance, and that dietary tolerance,
rather than lactase expression, can be adaptive, as
has been observed in lactase non-persistent Somali
camel herders who often consume large quantities of
milk [19].
Dietary strategies
Many dairy products contain only small amounts of
lactose (Table 3.15.1), allowing their consumption by
most lactase non-persistent individuals. Bacteria and
yeast fermentation convert the lactose in milk into
various by-products, reducing the content of lactose
by 25–50% [33,39]. For example, yoghurt is made of
milk incubated with micro-organisms that contribute
to lactose hydrolysis both during the fermentation
process and sometimes after ingestion (discussed in
Montalto et al. [33]). Such micro-organisms are also
called probiotics, i.e. live micro-organisms that are
said to confer health benefits to the host when taken in
adequate quantities. Even though different microbial
species ferment lactose to different extents depending
on their morphological and physiological characteristics [2,33], fermented dairy products ultimately
contain less lactose, allowing consumption of dairy
products without ill effects [39,40].
Should people wish to consume more milk products than they can tolerate, exogenous beta-galactosidase represents a possible therapy for primary
lactase deficiency. Enzymes can be added in a liquid or solid (capsules or tablets) form together with
milk and dairy products. The efficacy of enzymes
extracted from distinct species has been assessed
and compared [33,40]. For example, the beta-Dgalactosidase from Aspergillus oryzae has shown
good properties in decreasing symptoms of lactose
intolerance for a relatively low dose of enzyme
[41]. Pretreated lactose-free products, which were
first introduced in Finland and the USA, are now
becoming more widely available.
As an alternative approach, Ritter Pharmaceuticals
has recently announced the successful completion
of a phase II trial of a potential treatment for lactose
intolerance, RP-G28, which is an orally administrated proprietary oligosaccharide that is claimed to
stimulate the growth of certain colonic lactosemetabolising bacteria (www.ritterpharmaceuticals.
com/product-platform/rpg28).
Table 3.15.1 Lactose content in different
type of products (adapted from Holland et al.
[53], with permission from the Royal Society
of Chemistry)
Product
Type
Milk
Cattle (whole milk,
pasteurised)
Cattle (semiskimmed milk,
pasteurised)
Cattle (skimmed
milk, pasteurised)
Human
Sheep
Goat
Whole milk,
plain
Greek style,
plain
Single
Double
Crème fraiche
Cheese spread
Fromage frais
Cottage cheese
Feta
Parmesan
Cheddar
Stilton
Cream cheese
Brie/Camembert
Edam/Gouda
Mozzarella
Yoghurt
Cream
Cheese
Butter
Chocolate
Ice cream
Milk
Plain
Dairy, vanilla
Lactose content
in g per 100 g
product
4.6
4.7
4.8
7.2
5.1
4.4
4.7
3.5
2.2
1.7
2.1
4.4
4
3.1
1.4
0.9
0.1
0.1
Trace
Trace
Trace
Trace
0.6
10.1
0.2
5.2
Pros and cons of dairy intakes
for lactose malabsorbers
Many studies have investigated both the benefits and
increased risks to health of dairy product consumption
among LP and lactase non-persistent individuals, such
as the risk of developing metabolic syndrome components [42–45], osteoporosis [46–49] and various cancers [50–52]. Results from these studies should be
3.15 Lactose malabsorption and nutrition
treated with caution since confounding effects such as
mixed ancestry, cryptic population structure or differences in diets are not always accounted for and can
yield contradictory results.
The concentration of calcium in bovine milk is
about 1 g/L and calcium intake from milk and
yoghurt accounts for about 50% of the total calcium
intake in Dutch people, though it accounts for only
about 15% of the total calcium intake in Austrians
[16,17]. This shows the importance of milk as a
calcium source but also that other dietary sources of
calcium can be used. It is nevertheless important to
be aware that lactose malabsorbers need not avoid
all milk and dairy products unnecessarily, and if
they do, they should not do so without adequate
advice.
3.15.3 Conclusion
Far from being a disease or a dysfunctional disorder,
lactase non-persistence – causing lactose intolerance – is the norm and it is the adult consumption of
milk that is the novel (cultural) variant. Nutritional
epidemiology studies, and the staggering selective
advantages that have favoured LP-associated alleles
over the last 10,000 years, clearly show that adult
milk consumption can be highly beneficial.
Lactase non-persistent individuals may or may not
exhibit symptoms of lactose intolerance after consumption of lactose, whose intensity depends on
both internal (amount of lactase still expressed in the
small intestine, GI microbiota, gut transit times) and
external factors (food consistency, the lactose content of the food, whether it contains probiotics or not,
and if so what probiotics they are). An individual’s
threshold of lactose intolerance should be assessed
before deciding to avoid dairy products, and alternative lactose intolerance management strategies exist,
including potential oligosaccharide-based treatments
and bacterial beta-galactosidase activity.
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