Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Dear Editor,
We have read the article entitled “Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease ” by Hui KY et al (Sci. Transl. Med. 10, eaai7795 (2018)). We want to congratulate the authors, and make some contributions.
The conclusion states that, like in Parkinson’s disease (PD), variants of LRKK2 are associated with Crohn’s disease CD and mentions « a potential biological basis for clinical co-occurrence ».
This sentence could puzzle clinicians who extremely rarely face patients with combined CD and PD and who know that these two groups of patients harbour different microbiota (1).
In addition, the prevalence of Helicobacter pylori (HP) is low in CD and high in PD (2, 3). Gases measured with breath tests are specific and different between CD (4) and PD (5). Ulcerative colitis (UC), as opposed to CD, could be clinically associated with PD (6).
Since the impact of microbiota may overcome the consequences of the mutations, a strong focus on genes could be misleading in clinical practice.

Since the diagnosis of CD is sometimes difficult, since microbiota differ between ileum and colon, and since colonic CD is more and more considered as a specific disease (7), it could be valuable in further works to study confirmed CD (granuloma histologically confirmed) strictly limited to the small gut.
It could also be of interest to investigate the presence or not of HP or other infectious agents (e.g. Mycobacterium avium which could be more frequent in CD and in PD (8, 9, 10)). Gas measurements could check for the lack of recent antibiotic therapy or essential oils intake which could modify the gut flora and the severity of the disease and therefore skew the evaluation of the influence of the mutations in diseases control.

In our experience, patients with CD (67 patients) have rarely severe dental cavities before 10 years of age (4%), Propionibacterium acnes on the tongue (0%), Helicobacter pylori (0%) and medical history of acne (1.5%).
On the contrary patients with colonic CD (20 patients) or UC (85 patients) have frequently severe dental cavities before 10 years of age (respectively 65 and 86%), Propionibacterium acnes on the tongue (respectively 45 and 68%), Helicobacter pylori (respectively 45 and 30%) and medical history of acne (respectively 40 and 42%) [p<0.05 for all variables]
Patients with PD (14) are very close UC and different from CD (respectively 57%, 57%, 29% and 36%) [p<0.05 in comparison with CD for all variables].

Patients with CD have a very low level of methylacetate in exhaled breath (1.8 ppm +/- 1.8) versus high levels in colonic CD (4.4 ppm +/- 4.7), in UC (5.9 ppm +/- 4.9) or in PD (5.0 ppm +/- 3.5) [p<0.05].

Microbiota could be a relevant confounding factor and should therefore be taken into consideration in further works.

1. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65 (2010).
2. Castaño-Rodríguez N, Kaakoush NO, Lee WS, Mitchell HM. Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis. Gut. 66, 235-249 (2017).
3. Shen X, Yang H, Wu Y, Zhang D, Jiang H. Meta-analysis: Association of Helicobacter pylori infection with Parkinson's diseases. Helicobacter. 22, e12398 (2017).
4. Patel N, Alkhouri N, Eng K, Cikach F, Mahajan L, Yan C, Grove D, Rome ES, Lopez R, Dweik RA. Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study. Aliment Pharmacol Ther. 40, 498-507 (2014).
5. Bach JP, Gold M, Mengel D, Hattesohl A, Lubbe D, Schmid S, Tackenberg B, Rieke J, Maddula S, Baumbach JI, Nell C, Boeselt T, Michelis J, Alferink J, Heneka M, Oertel W, Jessen F, Janciauskiene S, Vogelmeier C, Dodel R, Koczulla AR. Measuring Compounds in Exhaled Air to Detect Alzheimer's Disease and Parkinson's Disease. PLoS One. 10, e0132227 (2015).
6. Villarán RF, Espinosa-Oliva AM, Sarmiento M, De Pablos RM, Argüelles S, Delgado-Cortés MJ, Sobrino V, Van Rooijen N, Venero JL, Herrera AJ, Cano J, Machado A. Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson`s disease. J Neurochem. 114, 1687-700 (2010).
7. Subramanian S, Ekbom A, Rhodes JM. Recent advances in clinical practice: a systematic review of isolated colonic Crohn's disease: the third IBD? Gut. 66, 362-381 (2017).
8. Liverani E, Scaioli E, Cardamone C, Dal Monte P, Belluzzi A. Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn’s disease, cause or epiphenomenon? World Journal of Gastroenterology : WJG. 20, 13060-13070 (2014).
9. Dow CT. M. paratuberculosis and Parkinson's disease--is this a trigger. Med Hypotheses. 83, 709-12 (2014).
10. Donatini B, Le Blaye I. Mycobacterium avium paratuberculosis (MAP) and Cytomegalovirus (CMV) are frequently detected in the saliva of patients recently diagnosed with Crohn Disease (CD) whereas oral Propionibacterium acnes (PA) or methylacetate (MA) in their breath is rare. J Biosciences Med. 3, 13-18 (2015).