Probiotics with an anti-inflammatory effect may reduce abdominal pain and hours of hospitalization in adult patients with acute uncomplicated diverticulitis

The link between the gut microbiota and acute diverticulitis has been underestimated

Diverticulitis is a type of diverticular disease in which an inflammation of one or more diverticulum in the colon occurs, which affects approximately 4% of patients with the presence of diverticula. Associated with the presence of severe and prolonged abdominal pain, fever and leukocytosis, a subset of patients with acute diverticulitis will be treated with antibiotics and rest without developing complications. However, about 15% of patients with acute diverticulitis may require hospitalization and even surgery if the diverticula ruptures.

While the pathogenesis of diverticulitis is thought to have multiple origins, the role of fecal transplants, antibiotics and probiotics in reducing symptomatology by affecting inflammatory markers and changing the levels of gut bacteria suggests a link between the gut microbiota and diverticulitis that is largely underestimated.

It seems that changes in the gut microbiota in patients with acute diverticulitis can fuel mucosal inflammation that, in turn, favor abdominal symptoms’ development

On the involvement of the gut microbiota in acute diverticulitis, Veronica Ojetti from Università Cattolica del Sacro Cuore and Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome (Italy) explained to GMFH editors via a phone interview that changes in gut microbiota composition observed in patients who develop acute diverticulitis consist with an increase of bacteria with inflammatory action and a decrease in bacteria with anti-inflammatory activity.

It seems that changes in the gut microbiota in patients with acute diverticulitis can fuel mucosal inflammation that, in turn, favor abdominal symptoms’ development.

Are probiotics helpful for diverticulitis?

The modulation of the gut microbiota through antibiotics has been used in patients with acute diverticulitis for managing systemic manifestations of infection. However, the side effects of antibiotics include a disruption to gut microbiota diversity, an increase in antibiotic-resistant bacteria and the flourishing of C. difficile infection. In addition, 2015 guidelines from the American Gastroenterological Association for treating acute uncomplicated diverticulitis recommend using antibiotics selectively, rather than routinely, in inpatients with uncomplicated diverticulitis (strength of recommendation: conditional; quality of evidence: low). That recommendation has its roots in the importance of inflammation over infection in acute diverticulitis, paired with the negative effects of overconsuming antibiotics.

Probiotics are also a widely used gut microbiota-targeted intervention for preventing infectious diseases (e.g., antibiotic-associated diarrhea and upper respiratory tract infections) and avoiding many of the side effects of antibiotics. In particular, the probiotic properties that make them a potential therapeutic approach for acute diverticulitis include anti-inflammatory functions, their support for balancing the gut microbiota, their intestinal mucosa-strengthening function and their exclusion of pathogens in the gut.

Efficacy and safety of Limosilactobacillus reuteri ATCC PTA 4659 in acute uncomplicated diverticulitis

One of the most widely studied probiotics for managing gastrointestinal diseases is Lactobacillus reuteri. In particular, the Limosilactobacillus reuteri ATCC PTA 4659 strain (formerly known as Lactobacillus reuteri ATCC PTA 4659) has been shown in in vitro and animal findings to have anti-inflammatory effects in the intestine that are worth considering in the context of diverticulitis.

Two recent clinical trials showed L. reuteri ATCC PTA 4659 at a dose of 5 x 10⁸ colony-forming units for 10 days might help manage acute uncomplicated diverticulitis and reduce hospitalization periods in adults admitted to the emergency department, either as an adjuvant to the standard antibiotic therapy or alone.

• The first randomized double-blind placebo study studied the supplementation with reuteri ATCC PTA 4659 as an adjuvant to the standard antibiotic treatment for diverticulitis (ciprofloxacin and metronidazole) in adult patients with acute uncomplicated diverticulitis. On day 10, the probiotic supplemented group showed an 8.1-point reduction in grade of abdominal pain from day 1, compared to 6.7 reduction in the placebo group receiving only antibiotics. Although both groups showed a significant reduction in inflammatory marker C-reactive protein in the first 3 days of treatment, mean reduction in the probiotics group was markedly bigger. That translated into a 20-hour reduction in the hospitalization period of patients supplemented with the probiotic.
• In the second randomized double-blind placebo trial, adult patients with acute uncomplicated diverticulitis were supplemented with reuteri ATCC PTA 4659 or placebo, together with fluid replacement and bowel rest. Compared to placebo, C-reactive protein and calprotectin levels were significantly more decreased in the probiotics group at 72 hours from hospital admission. The probiotic group and the placebo group that only received fluid replacement and bowel rest reduced abdominal pain to the same extent. Yet, those receiving the probiotic showed, on average, an 8-hour reduction in hospitalization compared to the placebo group.

On the whole, the findings show supplementation with L. reuteri ATCC PTA 4659 strain might help adult patients with acute uncomplicated diverticulitis with managing abdominal pain and reducing hospitalization time by reducing inflammatory markers. The findings do not translate into other probiotic strains administered alone or in the form of synbiotics, highlighting the importance of recommending probiotics at strain level to patients to achieve health benefits.

While previous studies support the rationale of using probiotics to modulate the gut microbiota in patients with symptomatic uncomplicated diverticular disease, Veronica Ojetti, involved in both trials, acknowledges that these two randomized clinical trials are the first evidence on the use of probiotics during the acute phase of uncomplicated diverticulitis.

The findings show supplementation with L. reuteri ATCC PTA 4659 strain might help adult patients with acute uncomplicated diverticulitis with managing abdominal pain

Veronica Ojetti explained to GMFH editors that in young patients (30-55 years old) with a mild acute diverticulitis, specific probiotics coupled with fasting, fluid therapy and an anti-inflammatory drug can help recovering patients with acute uncomplicated diverticulitis. On the other hand, old patients (more than 60 years old) with fever, high levels of C-reactive protein and comorbidities (e.g., diabetes and cardiovascular disease risk factors) might benefit from adding a probiotic to the mainstream antibiotic treatment.

Take-home messages

• The gut microbiota appears to be altered in diverticulitis and contributes to a state of inflammation and abdominal pain seen in patients with the condition.
• Probiotics emerge as a new gut microbiota-related intervention that might help manage acute uncomplicated diverticulitis by reducing inflammatory markers seen in patients with diverticulitis.
• Supplementation with probiotic strain reuteri ATCC 4659, whether with standard antibiotics for diverticulitis or alone, has been proven to be effective in reducing abdominal pain, inflammatory markers and accelerate recovery.

References:

Piccioni A, Franza L, Brigida M, et al. Gut microbiota and acute diverticulitis: role of probiotics in management of this delicate pathophysiological balance. J Pers Med. 2021; 11(4):298. doi: 10.3390/jpm11040298.

Stollman N, Smalley W, Hirano I, et al. American Gastroenterological Association Institute Guideline on the management of acute diverticulitis. Gastroenterology. 2015; 149(7):1944-1949. doi: 10.1053/j.gastro.2015.10.003.

Guo Q, Goldenberg JZ, Humphrey C, et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019; 4(4):CD004827. doi: 10.1002/14651858.CD004827.pub5.

Hao Q, Rong Dong B, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev. 2015; (2):CD006895. doi: 10.1002/14651858.CD006895.pub3.

Liu Y, Fatheree NY, Mangalat N, et al. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-B signaling in the intestine. Am J Physiol Gastrointest Liver Physiol. 2012; 302(6):G608-617. doi: 10.1152/ajpgi.00266.2011.

Petruzziello C, Migneco A, Cardone S, et al. Supplementation with Lactobacillus reuteri ATCC PTA 4659 in patients affected by acute uncomplicated diverticulitis: a randomized double-blind placebo controlled trial. Int J Colorectal Dis. 2019; 34(6):1087-1094. doi: 10.1007/s00384-019-03295-1.

Ojetti V, Saviano A, Brigida M, et al. Randomized control trial on the efficacy of Limosilactobacillus reuteri ATCC PTA 4659 in reducing inflammatory markers in acute uncomplicated diverticulitis. Eur J Gastroenterol Hepatol. 2022. doi: 10.1097/MEG.0000000000002342.

Lahner E, Bellisario C, Hassan C, et al. Probiotics in the treatment of diverticular disease. A systematic review. J Gastrointestin Liver Dis. 2016; 25(1):79-86. doi: 10.15403/jgld.2014.1121.251.srw.