0070

Digestive disorders in Cystic Fibrosis: Transit, Motility and MRI Signs of Small Intestinal Bacterial Overgrowth

Neele S Dellschaft^1,2, Christabella Ng³, Caroline Hoad^1,2, Luca Marciani^2,4, Robin Spiller^2,4, Penny Gowland^1,2, Alan Smyth^2,3, and Giles Major^2,4
¹Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, United Kingdom, ²Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom, ³Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, United Kingdom, ⁴Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, United Kingdom

Synopsis

Cystic Fibrosis (CF) is a genetic disease leading to sticky mucus. We used MRI to characterise the effect of CF on gastrointestinal function, comparing people with CF to matched healthy controls. People with CF had slower orocaecal transit times. No change in gastric emptying rate was apparent but more free water was present in their small bowel with reduced small bowel motility and a reduced gastro-ileal reflex. Some images suggested increased bacterial load in the small bowel. CF colons were larger. These findings are consistent with sticky chyme impeding ileal emptying into the colon, causing obstruction to flow, and constipation.

INTRODUCTION

Cystic Fibrosis (CF) is a life-limiting genetic disease affecting the chloride channel CFTR, leading to dry, sticky mucus secretion. The respiratory and digestive systems are the main systems affected since they both rely heavily on secretions. Digestive disorders present a significant burden in CF. Up to 90% of people with CF are affected by obstruction of the pancreatic duct, which prevents enzymes reaching the small bowel and therefore causes malabsorption of food and reduced growth. Nearly 50% report constipation and up to 20% report gastrointestinal complications, such as gastro-oesophageal reflux, distal intestinal obstruction syndrome and rectal prolapse¹. The relief of gastrointestinal symptoms in CF has recently been identified as a research priority².
MRI can be used to evaluate various aspects of gut function^3–6 but has not yet been used to investigate CF. We therefore hypothesised that MRI could provide new information about altered GI function in CF, and could ultimately provide a new method of clinical assessment and management of GI function in this patient group in the future.

METHODS

We conducted a pilot study of 12 people with CF and 12 healthy controls matched for age (12-36 years) and gender (7/12 male in both groups). People with CF had reasonable lung health (≥40% predicted forced expiratory volume in 1 second). Subjects underwent 11 sets of MRI scanning (1 fasting, 10 post-prandial) at intervals of 30-60 minutes using a 3T Ingenia (Philips) scanner. Standardised meals were given after the initial fasting scans (meal A: rice pudding with cream and jam, orange juice, water; 2176 kJ) and after the 9^th scanning set (meal B: macaroni cheese, cheesecake, water; 4213 kJ). Our GI MRI protocols were adapted to accommodate young people with lung disease who required shorter breath holds. The primary outcome was orocaecal transit time, assessed by visual identification of arrival of the food bolus in the caecum (dual-echo gradient echo sequence; TR 110 ms, TE 1.15 and 2.30 ms, FA 60°). Other outcomes included time to empty gastric contents (transverse turbo spin echo sequence; TR 508 ms, TE 60 ms, FA 90°), small bowel water content (heavily T2 weighted HASTE sequence; TR 1263 ms, TE 400 ms, FA 90°)³, small bowel motility (balanced turbo field echo cine MRI in six coronal slices; TR 2.1 ms, TE 1.03 ms, FA 50°, 1 minute of free breathing)^6,7, and colonic volume (dual-echo gradient echo sequence as above).

RESULTS

Scan procedures were acceptable to all study participants. The primary outcome, orocaecal transit time, was longer in CF than in controls (Figure 1; median 330 minutes vs 210 minutes, Χ² 4.1, P=0.04). There was no difference in the time to empty gastric contents between the groups (median time 240 minutes in both groups). Small bowel motility was significantly lower in CF than in healthy controls, both fasted and as assessed by area under the curve in response to meal A (Figure 2; fasted P=0.034, AUC T0-T60 Wilcoxon P=0.041). Healthy subjects showed the normal fall in small bowel water content in response to the second meal reflecting ileal emptying (Figure 3; median -164 ml in controls) but in CF patients it did not change (median -20 ml; P=0.005). Total colon volume throughout the day was higher in CF (AUC 99 L.min (IQR 72-123 L.min) in controls v 147 L.min (IQR 133-164 L.min) in CF, P=0.049; Figure 4). A third of CF patients were also noted to have changes in the small bowel content MRI signals; these were similar to changes in CT imaging seen in small bowel obstruction⁸, due to the overgrowth of bacteria (faecalisation) in the small bowel (Figure 5).

DISCUSSION

Novel, non-invasive MRI methods can be used to provide serial assessment of multiple aspects of GI tract function in people with CF, including young people and dyspnoeic patients. The difference in orocaecal transit (and the similarity in gastric emptying time) was consistent with previous data using other methods⁹. For the first time, we showed reduced small bowel motility, a difference that could previously not be detected in CF patients using cruder methods¹⁰. MRI has also identified signs of bacterial overgrowth in the small bowel. In future we will compare this with breath tests, an indirect test of bacterial overgrowth in the small bowel often leading to inconclusive results^11,12.
Striking differences in transit, motility and intestinal content between people with CF and controls were identified. These changes are consistent with chyme that is stickier, changed in consistency due to malabsorption, altered ileocecal transit and constipation.

CONCLUSION

This MRI approach supports hypotheses about CF GI pathophysiology previously built from animal models using invasive methods¹³. The observed differences in intestinal function and contents underlie GI complications in CF such as distal ileal obstruction syndrome. We are now using MRI to determine if new CF medications can improve GI function in CF.

Acknowledgements

No acknowledgement found.

References

1. van der Doef, H. P. J. et al. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J. Cyst. Fibros. Off. J. Eur. Cyst. Fibros. Soc. 9, 59–63 (2010).

2. Rowbotham, N. J. et al. The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers. Thorax 73, 388–390 (2018).

3. Hoad, C. L. et al. Non-invasive quantification of small bowel water content by MRI: a validation study. Phys. Med. Biol. 52, 6909–6922 (2007).

4. Chaddock, G. et al. Novel MRI tests of orocecal transit time and whole gut transit time: studies in normal subjects. Neurogastroenterol. Motil. 26, 205–214 (2014).

5. Pritchard, S. E. et al. Fasting and postprandial volumes of the undisturbed colon: normal values and changes in diarrhea-predominant irritable bowel syndrome measured using serial MRI. Neurogastroenterol. Motil. 26, 124–130 (2014).

6. Khalaf, A. et al. Cine MRI assessment of motility in the unprepared small bowel in the fasting and fed state: Beyond the breath‐hold. Neurogastroenterol. Motil. 31, e13466 (2019).

7. Menys, A. et al. Dual registration of abdominal motion for motility assessment in free-breathing data sets acquired using dynamic MRI. Phys. Med. Biol. 59, 4603–4619 (2014).

8. Mayo-Smith, W. W. et al. The CT small bowel faeces sign: description and clinical significance. Clin. Radiol. 50, 765–767 (1995).

9. Gelfond, D., Ma, C., Semler, J. & Borowitz, D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig. Dis. Sci. 58, 2275–2281 (2013).

10. Hedsund, C., Gregersen, T., Joensson, I. M., Olesen, H. V. & Krogh, K. Gastrointestinal transit times and motility in patients with cystic fibrosis. Scand. J. Gastroenterol. 47, 920–926 (2012).

11. Posserud, I., Stotzer, P.-O., Björnsson, E. S., Abrahamsson, H. & Simrén, M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut 56, 802–808 (2007).

12. Riordan, S. M. et al. The lactulose breath hydrogen test and small intestinal bacterial overgrowth. Am. J. Gastroenterol. 91, 1795–1803 (1996).

13. Munck, A. Cystic fibrosis: evidence for gut inflammation. Int. J. Biochem. Cell Biol. 52, 180–183 (2014).

Figures

Figure 1: A) Orocaecal transit time was longer in CF (median 330 minutes vs 210 minutes in healthy volunteers, P=0.04), with 4/12 CF subjects having uncompleted orocaecal transit by T360. This is suggestive of transit being disturbed due to stickiness of the contents. B) Example image of head of meal arriving in the caecum.

Figure 2: A) Motility of the small bowel measuring both bolus and wall movements. Small bowel motility was lower in people with CF both fasted (Wilcoxon P=0.034) and in response to the first meal (AUC T0-T60, Wilcoxon P=0.041), consistent with the delayed small bowel transit (Figure 1). Data displayed as mean and SD. B) Example image with small bowel outlined in white and areas of highest motility shown in red.

Figure 3: A) Individual changes in small bowel water content before and after a high-fat meal (meal B). All healthy participants had a stark reduction in small bowel water due to the gastro-ileal reflex but the same drop was not seen in CF participants. This suggests that the emptying of the small bowel contents into the colon is disturbed due to the contents being too sticky. B) An example image of the small bowel water analysis.

Figure 4: A) Colon volumes in each segment and in total. Ascending and total colon volumes were larger in CF with high outliers representing megacolons. Slow transit, undigested fat and sticky secretions lead to compaction of colonic contents, typical for constipation. B) Example of ROIs describing the ascending (blue), transverse (red), descending (yellow) and sigmoid colon segments (green), and a rendering of the total volume across slices.

Figure 5: Altered appearance of small bowel in a dual-echo GRE sequence (out of phase). Usually, small bowel (marked in red, left) has a smooth appearance with a bright, mottled colon (marked in yellow). A third of CF participants (4/12) had bright, mottled areas in the small bowel (arrows, right), which may indicate overgrowth of bacteria in the small bowel. This growth may be caused by delayed small bowel transit, low small bowel motility, an ileocecal valve that is less effectively separating the small bowel and colon contents, or the altered composition of the chyme due to maldigestion.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)

0070