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Misselwitz et al recently reviewed the multifactorial aspects of lactose intolerance (LI).1 Their work highlights the known effects of genetic makeup and dietary patterns in the occurrence of gastrointestinal symptoms in LI individuals. The authors define LI as the occurrence of gastrointestinal complaints on lactose exposure and discuss the wide variety of symptoms among LI patients.1 Regarding lactose metabolism, Misselwitz et al mention the influence of the gut microbiome, in particular that Bifidobacterium or other lactose-fermenting bacteria are reported to affect the levels of lactose in the gut. However, the impact of the gut microbiome on the occurrence of gut-related LI symptoms remains unclear.
We previously observed that the Bifidobacterium abundance in the adult human gut depends on the interaction between LI genetic variants and dairy intake.2 This observation complements other findings indicating a mutual relationship between the gut microbiome and host lactose metabolism.3–8 However, these earlier analyses did not consider the occurrence of gastrointestinal symptoms. This inspired us to investigate whether the interplay of dairy consumption and Bifidobacterium affects the occurrence of gastrointestinal complaints in LI individuals.
We analysed data on gut complaints, genetics, gut microbiome and diet in 959 participants of the Lifelines-DEEP Dutch population cohort. We classified LI genetic status based on the presence of the functional variant rs4988235 associated with LI in Caucasian populations, as described earlier,2 and we found the LI recessive genotype (G/G) in 81 individuals (8.4% of the cohort). We investigated microbiome composition using shotgun metagenomic sequencing of faecal samples2 and selected the relative abundance of the Bifidobacterium genus for our analysis. Dietary intake, including milk and other dairy products, was assessed using a food frequency questionnaire. Total dairy consumption, in grams per day, was retrieved using the Dutch Food Composition tables.9 Notably, there were no reports of complete avoidance of dairy consumption among patients with LI. Lastly, gut complaints were assessed via a 7-day questionnaire where participants were asked to rank (from 1 to 5) their daily level of gastrointestinal discomfort in six categories: ‘abdominal discomfort’, ‘bloating’, ‘burping’, ‘abdominal pain’, ‘flatulence’ and ‘nausea’. The sum of the mean daily scores from each category was used as the overall score of gastrointestinal complaints.
As reported previously, an increased Bifidobacterium abundance was observed in LI individuals compared with non-LI individuals (pWilcox=4.56×10-9) (figure 1A) and was positively correlated with dairy intake in the LI group (R=0.22, p=0.05) but not in the non-LI group (R=0.02, p=0.48). No significant difference in dairy consumption was found between the LI and non-LI groups (pWilcox=0.31). In LI individuals, we observed a positive correlation between Bifidobacterium abundance and total gut complaints score (R=0.33, p=0.003) (figure 1B). Of the six specific gut complaints, Bifidobacterium abundance was positively correlated with abdominal pain, discomfort and bloating (figure 1C–E) but not with any other complaints (all p>0.26). We then performed a mediation analysis to address how dairy intake and Bifidobacterium abundance would influence the occurrence of symptoms in LI individuals. Interestingly, we found that the association between dairy intake and gastrointestinal complaints was partially mediated by Bifidobacterium abundance (Propmediated=43%, p=0.054) (figure 2).
Our results provide evidence that specific gut symptoms, experienced by LI patients, might be the result of Bifidobacterium abundance in the gut, rather than a direct effect of lactose intake. This work supports initial reports where metabolic products of lactose-fermenting bacteria may be related to LI symptom occurrence.7 8 10
We thank Katherine McIntyre for editing this letter. The researchers participated in this project are supported by Netherlands Heart Foundation (IN-CONTROL CVON grant 2012–03 and 2018–27); the Netherlands Organisation for Scientific Research (NWO) (NWO-VIDI 864.13.013 to JF, NWO-VIDI 016.178.056 to AZ and NWO Spinoza Prize SPI 92–266 to CW); the NWO Gravitation Netherlands Organ-on-Chip Initiative to JF and CW, the NWO Gravitation Exposome-NL (024.004.017) to JF, AK and AZ; the European Research Council (ERC) (FP7/2007-2013/ERC Advanced Grant 2012–3 22 698 to CW, and ERC Starting Grant 715 772 to AZ). TS holds scholarships from the Junior Scientific Masterclass, University of Groningen.
Contributors AK and AZ formulated the concept and design of the study. MFBG performed the data analysis. MFBG, TS, AVV, JES, LAB and AK were involved in the interpretation of the results. The data for the study was collected by RKW, JF, CW and AK. MFBG, AZ and AK have written the manuscript, with assistance and revision by all coauthors. All coauthors have critically revised this letter and approved the final version for publishing.
Funding The researchers participated in this project are supported by Netherlands Heart Foundation (IN-CONTROL CVON grant 2012–03 and 2018–27); the Netherlands Organisation for Scientific Research (NWO) (NWO-VIDI 864.13.013 to JF, NWO-VIDI 016.178.056 to AZ and NWO Spinoza Prize SPI 92–266 to CW); the NWO Gravitation Netherlands Organ-on-Chip Initiative to JF and CW, the NWO Gravitation Exposome-NL (024.004.017) to JF, AK and AZ; the European Research Council (ERC) (FP7/2007-2013/ERC Advanced Grant 2012–3 22 698 to CW and ERC Starting Grant 715 772 to AZ). TS holds scholarships from the Junior Scientific Masterclass, University of Groningen.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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