A short-term diet that mimics fasting significantly improved clinical symptoms and inflammatory biomarkers in adults with mild-to-moderate Crohn’s disease (CD) in a randomized controlled trial.

In the study, nearly 70% of patients assigned to the fasting-mimicking diet (FMD) achieved a clinical response compared with fewer than half of control patients following their usual diet.

In addition, about two thirds of patients in the FMD group achieved clinical remission compared with a little more than one third of the control group. The FMD also led to measurable reductions in gut inflammation.

The FMD has patients eat between about 700 and 1100 calories per day for 5 consecutive days per month and then following for their normal diet.

“We were very pleasantly surprised that the majority of patients seemed to benefit from this diet. We noticed that even after just one FMD cycle, there were clinical benefits,” said senior author Sidhartha Sinha, MD, assistant professor of gastroenterology and hepatology at the School of Medicine, Stanford University in Stanford, California.

“Fasting for any period of time can be challenging, but in our trial nearly 80% of participants adhered to all three 5-day cycles of the reduced calorie diet,” Sinha told Medscape Medical News.

“Given much lower rates of long-term adherence reported for other types of diets, which require more sustained changes to dietary patterns, we are encouraged by the relatively high level of adherence to FMD,” he said.

The study was published online in Nature Medicine.

Limited Management Options

CD is a chronic inflammatory bowel disease affecting about 5 million people worldwide. About 20%-30% of patients with CD have a milder disease course with limited endoscopic inflammation and no stricturing or penetrating complications. Management options for these patients remain limited; except for corticosteroids, there are no FDA-approved medical therapies for mild CD.

In healthy individuals, short cycles of a FMD have been shown to decrease systemic inflammatory markers and improve metabolic health. Yet the potential benefits of FMD have not been investigated in CD, until now.

Sinha and colleagues randomly allocated 97 adults (median age, 45 years) with mild-to-moderate CD to either a FMD or continuation of their baseline diet.

The 65 patients in the intervention group followed a plant-based, calorie-restricted FMD for 5 consecutive days per month over 3 months, consuming 1090 calories on day 1 and 725 calories on days 2-5, before resuming their usual diet for the remainder of each month. The 32 patients in the control group made no dietary changes and continued standard medical care.

Clinical response was the primary outcome, defined as a reduction in CD Activity Index (CDAI) of ≥ 70 points or CDAI of ≤ 150 points after the third 5-day diet cycle.

Among all, 45 patients (69.2%) in the FMD group met the primary outcome compared to 14 patients (43.8%) in the control group (P = .03). The median decline in CDAI was 105 points for the FMD group compared with 76 points for the control group (P = .02).

In addition, 42 patients (64.6%) in the FMD group achieved clinical remission (CDAI of ≤ 150) compared with 37.5% in the control group (P = .02). Improvements related to the FMD were observed early, with a majority of participants showing clinical benefit after a single 5-day cycle.

Sinha told Medscape Medical News that a notable aspect of the design was that it allowed for standard-of-care medical therapy to reflect real-world conditions. Many participants in both groups were on background IBD therapies, “yet the dietary intervention still outperformed control. And we also saw benefit in participants not on medical therapy at baseline (clinical response, 76.9% vs 33.3% in controls), which supports an effect that isn’t solely medication driven,” Sinha said.

In terms of biochemical markers of inflammation, the mean fecal calprotectin declined from baseline by 22.0% in the FMD group and increased by 8.0% in the control group (P = .03).

In post hoc analysis, 37.0% of patients in the FMD group achieved a ≥ 50% reduction in fecal calprotectin compared with 6.3% of patients in the control group (P = .01).

Mean C-reactive protein (CRP) decreased from baseline in the FMD group and increased in the control group; however, this finding did not reach statistical significance (-1.0% vs 36.9%; P = .06). No statistically significant difference was observed in the mean percentage change in erythrocyte sedimentation rate (10.7% vs 15.2%; P = .87).

Exploratory analyses demonstrated reductions in proinflammatory lipid mediators and immune-effector gene expression after the diet, “concordant with reduced CD activity,” the study team wrote.

The FMD was generally well tolerated. There were no significant changes in weight, and no participants in the diet group reported grade 3 adverse events.

In the FMD group, fatigue (52.3%) and headache (50.8%) were the most common adverse events, which were predominantly mild. Fourteen (21.5%) participants withdrew from the FMD group compared with three (9.4%) from the control group, but none of the withdrawals were due to adverse effects.

Ready for Prime Time?

The results suggest that a FMD may serve as a feasible adjunctive option for patients with mild-to-moderate CD, the authors concluded.

Sinha told Medscape Medical News that he believes the FMD can be explored under physician supervision in select patients.

“It should, however, be noted that our study used a very structured, time-limited intervention (5 consecutive days per month for 3 months) with active monitoring for adherence and safety (daily questionnaires during cycles and scheduled calls, including dietitian involvement),” he noted.

“Even in this supportive setting, some participants withdrew due to difficulty following the diet. So in practice, I’d advise doing this with clinician oversight, especially to screen out patients at higher risk (eg, malnutrition/low BMI, pregnancy, eating disorders, frailty, or those with unstable disease where delaying escalation would be unsafe),” Sinha said.

Reached for comment, Ashwin Ananthakrishnan, MBBS, MPH, gastroenterologist at the Massachusetts General Hospital and Harvard Medical School, Boston, said this is an “important and well done study” and there is “biologic plausibility” for why the FMD may be helpful in CD.

The FMD had a clinical benefit in some patients and “importantly, they also examined various biological mediators, demonstrating a beneficial effect that supports a true clinical benefit (rather than a false-positive result),” Ananthakrishnan, who wasn’t involved in the study, told Medscape Medical News.

“The unanswered questions that follow are how does this compare to other dietary interventions that have been studied (or other medical therapies), how durable is the benefit, is there an endoscopic healing effect (shown in a subset here, but very small numbers), and whether it will have a benefit either alone (or in conjunction with advanced therapies) for more severe disease,” Ananthakrishnan said.

The study had no commercial funding. Sinha and Ananthakrishnan had competing interests.