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As is the case for an increasing number of illnesses, the pathogenesis of pancreatic diseases is increasingly thought to be affected by the gut microbiome. And although the causal relationship is still largely unexplored, the intestinal milieu may prove to be significant clinically.

While gut dysbiosis is hypothesized to mediate chronic pro-inflammatory changes in the pancreas, targeted modulation of the microbiota could ultimately be a therapeutic option: "Evaluating the gut microbiome of patients at risk of pancreatic disease in prospective studies is necessary to better understand the role of gut dysbiosis in human pancreatic disease pathogenesis," wrote Michael G. Goggins of Johns Hopkins Medicine in Baltimore, and colleagues, in a review in .

And researchers have a lot to study since the human gastrointestinal tract harbors more than 100 trillion microorganisms – 80% to 90% of which are Firmicutes and Bacteroidetes – with more than 5,000,000 genes.

"While it was commonly believed that the pancreas was somehow a sterile organ, there is now evidence for migration into the pancreas of specific bacteria associated with pancreatic diseases, and of changes in the gut microbiome that might be causes or consequences of pancreatic diseases," Gabriele Capurso, MD, PhD, of San Raffaele University in Milan, who was not involved with the paper by Goggins et al, told MedPage Today.

As they explained, gut flora may affect the microbial milieu even in the normal pancreas, as well as play a role in acute and chronic To date, however, "there is still only limited evidence supporting a causal relationship between gut dysbiosis and pancreatic diseases."

Acute Pancreatitis

Patients with acute pancreatitis are more likely than healthy volunteers to have exhibiting higher populations of Enterobacteriaceae and Enterococcus populations and lower populations of Bifidobacteria.

Preclinical and human studies suggesting a role for intestinal dysbiosis in the pathogenesis and severity of acute pancreatitis raise the question of whether modulating the gut microbiome might be therapeutic. "Altering the 'acute pancreatitis-associated microbiota' with 'physiological gut microbiota' using broad-spectrum antibiotics and antimicrobial peptides might be expected to improve outcome," Goggins and co-authors wrote.

In addition, benign gut bacteria such as Lactobacillus and Bifidobacterium are thought to maintain gut barrier function and limit the growth of pathogenic flora. And while the potential value of probiotics in patients with severe acute pancreatitis has been evaluated in several heterogeneous randomized controlled trials and a Cochrane probiotics have shown neither significant benefit nor significant adverse effects in severe acute pancreatitis.

The 296-patient Dutch Probiotics in Pancreatitis Trial, for example, randomized 296 patients with predicted severe acute pancreatitis to two Bifidobacterium species, three Lactobacillus species, and one Lactococcus species versus placebo. While infectious complications were similar in both arms of the study, the probiotic group had a surprisingly (16% versus 6%) and a higher incidence of bowel ischemia (6% versus 0%). The heavy load of probiotics was the suspected cause of the greater number of deaths.

"The timing, dosage, and type of probiotic administration seem critical issues," Capurso said.

Chronic Pancreatitis

Small intestinal bacterial overgrowth (SIBO) has been frequently observed in chronic pancreatitis patients and is thought to arise from reduced pancreatic synthesis of antimicrobial peptides, impaired motility, and abnormal chyme formation in the ileal lumen, as well as from reduced alkalization due to reduced bicarbonate-rich pancreatic secretions.

SIBO can exacerbate pancreatic exocrine insufficiency, suggesting that treatment of these bacterial overgrowths would be beneficial for patients with this deficit. In a 2016 of heterogeneous studies, the mean prevalence of SIBO in chronic pancreatitis patients was 36%. A small 2017 found reductions in Bacteroidetes and increases in the ratio of Firmicutes to Bacteroidetes in chronic pancreatitis patients. Plasma endotoxin was detected in many of these patients and correlated negatively with glycemic status, indicating an association between dysbiosis and the metabolic alterations of chronic pancreatitis.

Cancer

In terms of malignancy, pancreatic cancer is expected to become the second leading cause of death in United States by 2030. "Since gut dysbiosis has been postulated to contribute to chronic pancreatic inflammation, it may also contribute to the pathogenesis of pancreatic cancer in the setting of chronic pancreatitis," Goggins and colleagues wrote.

Strong evidence supports an association between the oral microbiome alterations common in periodontal disease and the risk of this aggressive malignancy, Capurso noted. "As the gut microbiome is influenced by many factors associated with increased risk of pancreatic cancer such as smoking, obesity, and diabetes, it will be important to establish whether the microbiome somehow acts as a mediator of other pro-carcinogenic stimuli, or is per se a leading factor in this cascade of events."

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