Diarrhea and the role of microbiota

The relationship between the microbiota and diarrhea

Diarrhea can involve various mechanisms (table 1), and the majority of them are related to the role of microbiota:

• Protection of the microbial balance, this state, known as eubiosis, is fundamental for the health of the human body because it prevents and slows down the expansion of pathogens. Disturbance of the balance between the main microbial strains, known as dysbiosis, can increase susceptibility to infections and contribute to diarrhea. The literature generally indicates that diarrhea represents a major dysbiosis and that the degree of dysbiosis is related to the etiology and the stage of diarrhea [6]. Following acute diarrhea, the taxonomy of the microbiota changes a lot. In early stages of diarrhea, facultative fastgrowing anaerobes such as Proteobacteria (mostly Enterobacteriaceae/Escherichia coli) and Streptococcus (mainly Streptococcus salivarius and Streptococcus gallolyticus) dominate and favor the drastic disappearance of obligate anaerobic gut commensals (Blautia, Prevotella, Faecalibacterium, Lachnospiraceae, Ruminococcaceae, etc.) [2, 3]. The consequence is that short-chain fatty acid (SCFA) also decreases, and the integrity of the intestinal barrier starts to be under threat, possibly leading to gut permeability. In the recovery phase after diarrhea, a proposed model shows that in the midstage, there is an abundance of Bacteroides (the 7th day since disease onset). At the same time, in the late-stage Prevotella and SCFA-producing Firmicutes dominate [4, 5].
   
• Protection against pathogenic invaders. The microbial community of the gut microbiota competes for resources, produces antimicrobial substances, and acts as a barrier against enteropathogens. Beneficial bacteria in the gut, such as certain strains of Bifidobacteria and Lactobacilli, have been demonstrated to have beneficial effects on infectious diarrhea caused by rotavirus in young children. However, there are no clinical trials to demonstrate it [6]
   
• Regulating the immune system. The gut microbiota helps educate and modulate immune responses, promoting tolerance to harmless substances and defending against pathogens. Dysregulation of the immune response due to microbiota imbalances can contribute to inflammation and diarrhea. After antibiotics for Clostridioides difficile-induced diarrhea, such as vancomycin, a reduced relative abundance of Bacteroidetes and Firmicutes is observed, while Proteobacteria and Fusobacteria increase and leading to a decrease in SCFA propionate, creating premises for inflammation [7]
   
• Maintenance of gut function and metabolism. Beneficial bacteria ferment dietary fibers to produce short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. SCFAs contribute to maintaining a healthy intestinal lining, promote water absorption, and provide an energy source for colonocytes. Imbalances between bacterial strains may impact these functions, leading to functional diarrhea due to decreased SCFA production. Increasing its production enhances colonic fluid absorption. [8]

Diarrheal illnesses and microbiota management

Infectious diarrhea

Bacterial, viral or parasitic gut infections cause acute diarrhea and are frequently spread through contaminated water. Most cases of diarrhea are improved in a few days, but severe diarrhea can lead to serious dehydration and can become lethal [9].

Rotaviruses remains the primary cause of diarrhea-associated deaths in children [11], and management of this viral disease generally involves oral or intravenous hydration, tailored to the severity of dehydration [12]. Furthermore, based on the latest conclusions from the ESPGHAN committee (2023) [13], healthcare providers might suggest certain probiotic strains for acute gastroenteric episodes in children, acknowledging their potential (certainty of evidence: low; grade of recommendation: weak) to decrease the duration of diarrhea, and/or hospital stay, and/or volume of fecal discharge. However, a randomized, double-blind, controlled trial of Bolivian children with acute rotavirus diarrhea demonstrated a decreased duration of diarrhea by using an oral rehydration solution plus a mixture of probiotics by comparison with simple rehydration solution [11].

Travelers diarrhea

More than 60% of the adults from developed countries who travel to developing countries experience acute diarrhea, also known as traveler’s diarrhea (TD). The most frequently identified pathogens implicated in traveler’s diarrhea episodes are Escherichia coli, Campylobacter jejuni, Salmonella species and Shigella species. Thus, the recommended treatment strategies include antibiotic therapy with azithromycin or fluoroquinolones for moderate to severe cases [14]. However, antibiotics are not recommended to prevent TD, due to insufficient evidence of their prophylactic efficacy and partially due to the risk of antibiotic resistance [15].

There is conflicting data regarding the efficacy of probiotics in preventing traveler’s diarrhea [16]. One systematic review and meta-analysis compared the efficacy of rifaximin and probiotics in preventing TD. [15].

Antibiotic-associated diarrhea

Antibiotics are one of the most prescribed medications and represent an effective treatment for several infectious pathologies [17]. One of the complications associated with antibiotic therapy is antibiotic-associated diarrhea (AAD), which occurs in 5%-35% of the patients who receive antibiotherapy [18]. AAD can be defined as three or more watery or loose stools per day for at least two consecutive days, which is strictly related to antibiotics administration and no other cause [14]. The highest risk is attributed to aminopenicillins, cephalosporins and clindamycin, which primarily target anaerobes [19]. 

The lack of an infectious agent identified in AAD may be explained by the direct toxic effect of the antibiotics on the intestinal mucosa, which may cause diarrhea. Due to their beneficent properties, probiotics are now being researched and used for both treatment and prophylaxis of AAD [16, 18].

Clostridium difficile associated diarrhea

Clostridioides difficile (CD) infection is the most common cause of nosocomial antibiotic-associated diarrhea in adults. Risk factors include age over 65 years, long hospitalization in intensive care, and administering antibiotics (fluoroquinolones, clindamycin, cephalosporins, and betalactams in particular) or proton pump inhibitors. During antibiotherapy, anaerobes that produce SCFAs may disappear due to antibiotic-induced alterations in the gut microbiota, which may also disturb the metabolism of carbohydrates and bile and cause an osmotic imbalance. Following antibiotic intake, all three intestinal barriers are affected: the epithelial intestinal cells, the mucus and antimicrobial peptides layer, and the immunoprotective layer composed of different immune cells and various biomolecules (figure 1). This event can interfere with the production of mucin, cytokines, and antimicrobial peptides, dysregulating intestinal function and leading to other infections or even causing recurrent episodes of infections. The American Gastroenterological Association (AGA) conditionally recommends specific probiotics for preventing CD infection in individuals on antibiotics, noting that the quality of evidence is low [20].

Emerging discoveries and the future of diarrhea management

Recent breakthroughs in microbiota research, including metagenomic analysis and microbial transplantation, are revolutionizing our approach to diarrhea treatment (figure 2).

There is limited data regarding the prebiotics and fibers in treating diarrhea (table 2). Apparently, prebiotics are more prone to prevent and treat the recurrence of diarrhea. At the same time, fibers, mainly the viscous ones, are more indicated during acute episodes due to their water-retaining capacity. Other therapeutic options involve, in some cases, the probiotic administration and (table 3), in severe cases, the use of fecal microbiota transplantation (FMT).

The fascinating journey of FMT discovery has roots in ancient China, where Ge Hong treated patients with severe diarrhea using a “yellow soup” consisting of feces suspension. In modern times, Dr. Ben Eiseman used fecal enemas from healthy individuals to treat pseudomembranous enterocolitis back in 1958. Nowadays, there is growing interest in fecal microbiota transplantation (FMT) as a treatment for recurrent Clostridioides difficile infection (CDI), which points out its utility [22]. Research is ongoing regarding its efficacy towards inflammatory bowel disease, diabetes, cancer, liver cirrhosis, and brain diseases such as Parkinson’s [23]. The benefits of using FMT in patients with diarrhea are based on the idea that the healthy microbial flora introduced via FMT has the ability to outcompete pathogens and restore the composition of a healthy gut microbiome (figure 3).