Relationships between IBD and DF suggest that rates of LM largely reflect ethnic backgrounds of patients. Activity of IBD and small bowel involvement in CD increases LM rates. Symptoms of LI during tests may not reflect daily DF reactions. Consequences of true or self perceived LI may impact on DF consumption which may have variable outcomes.
Lactose maldigestion in IBD
In the mid 20th century, milk protein allergy was considered a possible cause of UC [
64]. As well in the early 1960s reports emerged showing that intestinal lactase levels were diminished in UC and were accompanied by self-restricted and physician-advised reduction of DFs in IBD [
65,
66]. The impact of ethnicity was not yet proven.
The meta-analysis on LM rates does show a statistically significant increase in prevalence. However, analysis of CD and UC independently reveals that the outcome is driven by CD with small bowel CD involvement. Sub analysis of BT also follows the overall pattern suggesting that LM is either secondary to mucosal disease, motility disorder or bacterial overgrowth not necessarily genetics [
67]. In other cases ethnic distributions account for the frequency of LM. These results should be interpreted with some caution in light of moderate or high heterogeneity encountered.
The notion that IBD rates differ between LP and LNP populations rests on epidemiological correlations between IBD and population distributions of LP and LNP [
8]. The outcome of the meta-analysis suggests that LP and LNP persons may be equally affected by IBD.
There are only few studies examining possible risks of different lactase alleles in IBD. Eadala et al. evaluated C/T-13910 polymorphism in a group of patients from Wales and found a 6 % rate of CC (LNP) genotype among 165 Welsh IBD patients [
24]. This frequency is close to the national rate. Earlier reports were conflicting however. Buning et al. did not find any statistically significant differences in frequency of IBD among German patients with CC genotype [
68]. Elguezabal et al. could not confirm increased TT/CT genotypes in Spanish patients [
69]. However an earlier study from Spain [
70] and one from New Zealand [
71] did find increased prevalence of Crohn’s disease in TT genotype (LP phenotype) persons.
The current observations however can’t rule out different rates or delay in disease development between LP and LNP. For example IBD rates are different between Indigenous populations and Caucasians described both in Canada [
72] and New Zealand [
73]. In both areas Indigenous people are predominantly LNP and Caucasians are predominantly LP.
Symptoms of LI
It is no longer accurate to equate LI with LM. The reason for this is that studies of LI in patients with irritable bowel syndrome (IBS) showed similar frequency of symptoms whether they were LNP or LP phenotype [
74,
75]. Another reason is the ability of LNP persons to adapt to continued lactose consumption [
76]. Lactose in LNP/LI persons induces symptoms (LI) through a metabolic effect on the microbiome [
77]. In LNP persons, continued ingestion of sufficient lactose will lead to microbiome adaptation resulting in altered metabolomes as well as reduced test outcomes for BT [
78].
However ability to adapt to lactose in IBD is unclear and there are no formal trials. Using lactulose, a disaccharide with similar properties to lactose failed to show adaptation compared with healthy controls [
79]. Pironi et al. however may have detected microbial adaptation since despite increased LM status only 8 % of CD patients were also LI [
37].
There are two other factors which may alter symptoms to lactose/DFs. As in the case of the study by Nolan –Clark, DFs containing fats may actually be the prime cause of symptoms [
49], a possibility also stressed by Mishkin [
12]. As well, a role of FODMAPs driving food sensitivities needs to be considered [
80]. Restriction of these may reduce symptoms in IBD [
81], since irritable bowel syndrome is frequent in IBD even in remission [
82]. However, in this paradigm, genetics of lactase may not play a role. In studies reviewed, LI and LM were interchanged in several studies [
27,
30,
31,
33,
34,
36,
42] and Eadala introduced the concept of lactose sensitivity [
24]. They reported the highest symptom rate of any study, independent of genetic analysis and with discrepant outcomes with BTs [
24]. The reasons for these observations aren’t clear and the study was criticized on methodological grounds [
83]. This review in the end doesn’t allow a true estimate of the frequency of LI in IBD patients. Activity of disease, site in CD and surgical resections variably affected outcome. The overall impression is that self reported LI along with counseling led to DF consumption restrictions.
Specific impact of milk and DFs consumption on IBD has not been studied as extensively as on other diseases (reviewed in [
84]). In general there are 3 topics to consider: first is the relationship of DFs to risk of IBD, second DFs impact on IBD relapse rates, finally possible risks of dietary DFs restrictions.
While 2 epidemiological studies [
50,
51] suggested a positive correlation of increasing DFs intake with increasing incidence of IBD, remaining studies suggested possible protection by DFs [
52‐
55] or no effect on IBD [
56‐
59]. Further studies are needed to verify protective outcomes. However there is a hint that an ecological fallacy type relationship between DFs and IBD exists. In this situation, observed ecological relationships between disease and target variables are opposite to those expected at patient level studies. A similar paradigm occurs between DFs and colorectal cancer [
8,
85].
The second topic that DFs aggravate established IBD is not clear. One study reported that milk and DFs intake were associated with flares [
60] and this is supported in a study of food groups in patients with UC [
86]. However in a large review, of effects of general diets in IBD, no convincing evidence was found to show that any nutrient induced flares [
7]. The presence of IBS and role of FODMAPs contributing to symptoms may cloud the issue [
82].
The third topic is whether DF restriction has any negative impacts. In the general population, an NIH conference on LI concluded that the main health hazard is the improper withdrawal of DFs. Benefits from DFs were stressed [
87]. Among these, bone health, better control of hypertension [
88], weight gain [
89,
90] and a reduced risk for colorectal cancer either through calcium or vitamin D is oberved [
91].
In IBD, osteopenia and osteoporosis are consequences of chronic inflammation and medications [
92‐
94]. The role of calcium and DF intake in IBD-related bone disease is unclear [
95‐
97] or controversial [
98] but intuitively is still important.
Colorectal cancer is increased in IBD colitis and may be linked with chronic inflammation also [
99]. Calcium and vitamin D may be protective both for cancer [
100,
101] and provide anti-inflammatory effects [
102].
Risks of cardiovascular complications may be increased in IBD [
103] and calcium may contribute by reducing arterial stiffness [
88]. Evaluation of the specific impact of DFs in IBD require further evaluation.
There are limitations to this review. Conclusions from meta-analyses are as accurate as the papers reviewed. Although the quality of most studies was rated as adequate, the period spans 50 years with the majority of studies being older. The period of study includes 4 modalities of lactase assessment and conceptual changes in the genetics of lactase as well as concepts related to symptoms. These variations, as well as inclusion of different populations, and the few number of studies may well account for heterogeneity. However, in the studies reviewed for meta-analysis patients were always studied in parallel with healthy controls, and the outcome sought was an objective prevalence of LM in IBD regardless of method of ascertainment. To our knowledge, this is the only review to date which derives conclusions based on the available literature.