Abstract
Over a century ago, the Nobel Laureate Elie Metchnikoff hypothesized that introducing lactic acid bacterium into the intestines might improve human health. The gut microbial dysbiosis has been implicated in several important gastrointestinal diseases. Epidemiological, clinical, and animal studies further provide evidence supporting the human health benefits of probiotics. This chapter provides an update on probiotic effects on gastrointestinal disorders and highlights possible challenges and opportunities to probiotic beyond tomorrow.
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Keywords
- Lactic acid bacteria (LAB)
- Gut microbiota
- Irritable bowel syndrome (IBS)
- Diarrhea
- Inflammatory bowel disease (IBD)
- colorectal cancer (CRC)
8.1 Introduction
8.1.1 Gut Health
The gastrointestinal tract is a digestive organ system within any metazoan from invertebrates to vertebrates. A growing large body of scientific evidence supports the critical role of gut for human health (Flint et al. 2015). It takes in foods, digests and absorbs nutrients and energy, and finally expels the remaining waste as feces. More recently, its importance in immune system was also increasingly recognized. However, it should be pointed out that a definition of gut health is still lacking (Bischoff 2011). It is usually evaluated based on the following aspects: (1) digestion and nutrition absorption, (2) immune response, (3) gastrointestinal disorders, and (4) gut microbiome composition and functionality.
8.1.2 Gut Microbes
The gastrointestinal tract is an extremely complex dynamic ecosystem (Maccaferri et al. 2012). It is widely accepted that the trillions of gut microbiota colonize human intestinal tract. From a taxonomic viewpoint, gut microbiota mainly includes fungi, bacteria, archaea, and viruses. All gut microbiota might generate a biomass of more than 1.5 kg, and their combined genomes might be 100-fold of the human’s genome (Gerard 2016). Of note, gut microbiota study has so far been focused on bacteria which might be roughly divided into three categories: beneficial bacteria, neutral bacteria, and harmful bacteria.
Emerging evidence indicated a pivotal role of gut microbes in host physiology. Gut microbiota might naturally enhance food safety by suppressing food-borne illness, destroying naturally occurring toxins, and lowering allergic reactions (Hooper et al. 2002; Bäckhed et al. 2005). Gut microbiota might low the risk of certain infectious diseases by antagonizing pathogenic bacteria infection or inducing antibacterial substances. Beyond these, they also involve in biosynthesis of short-chain fatty acids (SCFAs) and certain vitamins. More recently, gut microbes have been identified as a “new organ” which might communicate with and/or complement our own organs.
It is widely accepted that the gut microbiota composition is generally stable within health adult individuals (Palmer et al. 2007). The gut microbial dysbiosis has been recently implicated in various diseases, either inside or outside the gastrointestinal tract. Various external factors such as foods, drugs, and even lifestyles were reported to profoundly affect the gut microbiome as well as host health (Faith et al. 2013; Courtney et al. 2008; Dethlefsen and Gordon 2011; Scott et al. 2013). If gut bacteria are making you ill, can swapping them makes you healthy? To answer the question above, intestinal micro-ecology has become one of the hottest research areas in biomedicine in the past 20 years (Quigley 2013).
8.1.3 Probiotic Lactic Acid Bacteria
Lactic acid bacteria are a group of gram-positive, catalase-negative, and nonsporulating, aerotolerant bacteria which might ferment carbohydrates to lactic acid (Hugenholtz and Smid 2002). They are widespread in nature ever in our gastrointestinal tracts (Vlieg et al. 2011; Stolaki et al. 2012). Although lactic acid fermentation is among the oldest forms of food preservation, accumulating evidence clearly indicates that to extend food shelf-life is only the start of which lactic acid bacteria has done to affect our life. For example, fermented foods have long had a reputation for human health benefits. Multimillion-dollar industry runs by the concept that introducing lactic acid bacteria into gut might improve our health (Patrick et al. 2014). Application of fermented foods has also been well-documented in folk medicines, but it often relies on traditional beliefs rather than sciences.
Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” So far, the literature on the health benefits of probiotics has often focused on lactic acid bacteria. The original theory of probiotics is generally attributed to the Nobel Laureate Elie Metchnikoff, who hypothesized that the longevity of people in the Balkans might due to the bacteria in yogurt in 1908. Unfortunately, Metchnikoff’s hypothesis remained dormant for nearly a century. Over the last two decades, interests in probiotic lactic acid bacteria have been rekindled for their potential benefits against various gastrointestinal diseases such as bacterial infection, diarrhea, irritable bowel syndrome, inflammatory bowel disease (IBD), and even tumorigenesis (Kitazawa et al. 2015). Although the molecular underpinnings remain largely elusive, probiotic lactic acid bacteria might confer human health benefit, at least partially, by remodeling gut microbiota to be a disease-free state (Table 8.1). Taken together, it may, therefore, be possible to prevent and/or treat gastrointestinal disorders by probiotic LAB.
8.2 Irritable Bowel Syndrome
8.2.1 Epidemiology, Signs, and Symptoms
Irritable bowel syndrome (IBS), one common gastrointestinal disorder, might affect 10–15% of the general population worldwide (Didari et al. 2015). IBS not only negatively affects the patients’ quality of life but also often incurs significant healthcare costs. Its primary symptoms are abdominal pain, diarrhea, constipation, and a change in bowel habits (Soares 2014).
8.2.2 Histological and Molecular Pathogenesis
It should be pointed out that IBS is currently defined by symptom criteria. So far, the etiology of IBS is still unclear as it occurs sometimes even without any obvious histopathological abnormalities (Levesque et al. 2015). The associated risk factors include genetic factors, stress, food sensitivity, small intestinal bacterial dysbiosis, and gastroenteritis infection. For example, about 33% of IBS patients have family history. More importantly, IBS patients from a same family even share a very similar signs and symptoms. Notably, stress and anxiety might trigger or aggravate symptoms of IBS. In this regard, abnormal levels of several endocrine hormones (e.g., 5-hydroxytryptamine, vasoactive intestinal peptide, somatostatin, glucagon, and prostaglandin E2) have been observed. Although IBS is a non-communicable disease, its risk might be significantly increased once the intestinal tract infection. In addition, IBS has been associated with the genetic defects in innate immunity.
8.2.3 Gut Microbiota and Probiotic Intervention
More recently, several investigations suggest that gut microbiota might functionally mediate IBS. Although gut microbial dysbiosis has been observed in IBS, it remains to be determined whether such alternations are a cause or a consequence of IBS (Collins 2014). Of note, certain probiotics (e.g., Bifidobacterium infantis 35624) might greatly improve its clinical outcomes (Table 8.2). In this regard, probiotics might act through diverse mechanisms such as directly enhancing the intestinal mucosal barrier, reducing intestinal permeability, lowering bacterial translocation, modulating the gut immunity, and even affecting the intestinal nervous system and brain signals (Andrade et al. 2015; Barberi et al. 2015; Canfora et al. 2015; Chichlowski and Rudolph 2015; Kianifar et al. 2015; Martinez-Augustin et al. 2014; Mazurak et al. 2015; Meini et al. 2015; Moayyedi et al. 2010; Owaga et al. 2015; Stevenson et al. 2014).
8.3 Infectious Diarrhea
8.3.1 Epidemiology, Signs, and Symptoms
Infectious diarrhea (gastroenteritis) is a condition of having at least three loose or liquid bowel movements each day. Infectious diarrhea might represent as a leading cause of mortality among children under the age of 5, especially in those developing countries (Dinleyici et al. 2012; Weichert et al. 2012). Worse, repeated infections might lead to malnutrition, increase the risk of serious infections, and ultimately negatively affect children growth and development (Vandenplas et al. 2011). Depending on its duration, it has been classified into three main types: acute (<14 days), persistent (14–29 days), or chronic (≥30 days). The primary symptoms of infectious diarrhea include diarrhea, vomiting, and abdominal pain.
8.3.2 Histological and Molecular Pathogenesis
The primary causes of infectious diarrhea include viruses (rotavirus), bacteria (e.g., Escherichia coli, Campylobacter, Salmonella, Bacillus cereus, etc.), parasites (e.g., Giardia, Cryptosporidium, and Cyclospora), and fungi. Of note, antibiotic-associated diarrhea is often related with Clostridium difficile. Compared with adult, children are more predisposed to infectious diarrhea as they are less likely to practice good hygiene habits as well as normally under development of immunity.
8.3.3 Gut Microbiota and Probiotic Intervention
Infectious diarrhea is normally an acute and self-limiting disease. It does not require medication unless patient with dehydration or particularly severe symptoms (Gareau et al. 2010). In nature, infectious diarrhea is a condition caused by gut microbial dysbiosis (Sanders et al. 2013). Accordingly, probiotics have long been proposed for infectious diarrhea management. Although probiotics (e.g., Saccharomyces boulardii, Lactobacillus rhamnosus GG) show some promise in infectious diarrhea (Canani et al. 2007; Islek et al. 2014; Saavedra et al. 1994; Saavedra 2000; Szajewska et al. 2006; Szajewska and Kolodziej 2015), the overall results have been mixed (Table 8.3). Moreover, such approaches might not for those critically ill hospitalized patients.
8.4 Inflammatory Bowel Disease
8.4.1 Epidemiology, Signs, and Symptoms
Inflammatory bowel disease (IBD), a group of chronic inflammatory disorders of the intestinal tract, mainly includes Crohn’s disease (CD) and ulcerative colitis (UC) (Kabeerdoss et al. 2015). They might affect the quality of life of 1.4 million individuals in the United States. The most common symptoms of IBD are abdominal pain, diarrhea, bloody stools, and weight loss. Compared with healthy individuals, patients suffering long-term IBD might increase the risk of colorectal cancer.
8.4.2 Histological and Molecular Pathogenesis
The etiology of IBD is incompletely understood yet. IBD is widely recognized as a complex disease which is trigged by the interaction between genetic and environmental factors (Saad et al. 2013). Compared with others, Caucasian descent especially those in developed countries are more predisposed to IBD. The dysregulation of innate immune mechanisms (e.g., TNFα, IL10, and ATG16L1 signaling pathways) has been implicated in the pathogenesis of IBD (Corthe et al. 2006).
8.4.3 Gut Microbiota and Probiotic Intervention
IBD management is currently relied on nonspecific immunosuppressive agents (such as steroids) and tumor necrosis factor (TNFα)-targeted therapy. However, these treatments are not effective in all patients. Worse, side effects have dampened enthusiasm for their long-term use.
Emerging evidence suggested a causal role of gut microbial dysbiosis in IBD (Hardy et al. 2013). IBD patients are different from healthy individuals, either in the community membership or abundance of gut microbiota. Probiotic use in IBD management has also been successful in multiple animal studies (Ahl et al. 2016). Although highly expected by either mechanistic or animal studies (Sartor 2008; Shanahan and Collins 2010), the clinical outcomes of probiotic use in IBD have been mixed (Table 8.4). Most likely, upon rational utilization, certain probiotics (e.g., Faecalibacterium prausnitzii, Bacteroides fragile, Bifidobacterium longum BB536, E. coli Nissle 1917, and Clostridium species) might be helpful in IBD treatment (Kato et al. 2004; Christensen 2006; Macfarlane et al. 2006; Saad et al. 2013; Takeda 2009). One potential proposed approach is to induce rapid clinical remission by corticosteroid and/or anti-TNFα therapy followed by probiotic interventions to sustain remission. Of note, fecal microbiota transplant might be another useful therapeutic strategy in IBD management. Mechanistically, probiotic might enhance clinical outcome by modulating intestinal mucosal barrier, reducing intestinal permeability, and suppressing pathogenic bacteria translocation (Sartor 2004).
8.5 Necrotizing Enterocolitis
8.5.1 Epidemiology, Signs, and Symptoms
Necrotizing enterocolitis (NEC) is the death of tissue in the intestine. Despite all modern advances in medical and surgical efforts, NEC still represents as a major cause of neonatal morbidity and death, especially in premature and low-birth-weight infants (Neu and Walker 2011; Zani and Pierro 2015). Currently, the mortality of NEC is around 30%. Worse, even upon success treatment, the survival infants often suffer malnutrition, growth retardation, and even neurologic abnormalities. As to NEC’s symptoms, they mainly include feeding intolerance, vomiting, bloating, diarrhea, and even bloody stools.
8.5.2 Histological and Molecular Pathogenesis
The exact etiology of NEC remains unclear, but growing evidence indicated that it is a multifactorial disease. The potential risk factors for NEC include premature birth, congenital heart disease, poor oxygen and blood supply, intestinal mucosal immaturity, and bacterial infection (Akin et al. 2014; Bajwa et al. 2011; Cotten et al. 2009; Cummings 2015; Mai et al. 2011; Mercado-Lubo and McCormick 2010; Nabi et al. 2006; Niemarkt et al. 2015). Compared with normal infants, the premature and/or low-birth-weight infants are more predisposed to NEC as their gut are normally under development of immunity and thus prone to inflammation as well as loss of epithelial integrity.
8.5.3 Gut Microbiota and Probiotic Intervention
The management of NEC has currently relied on bowel rest therapy, orogastric tube, intravenous fluids, and intravenous antibiotics. Accumulating evidence indicates an association between NEC and gut microbiotal alternations. In this connection, a decreased Firmicutes and increased Gammaproteobacteria were found in the gut microbiota of infants with NEC. Most likely, such gut microbial dysbiosis might be link with the antibiotic usage. Breastfeeding and probiotic uses have been strongly recommended to lower the risk of NEC (Lin et al. 2008; Sharma and Shastri 2016; Reali et al. 2015). Indeed, certain probiotics (e.g., Bifidobacterium, Lactobacillus, and Saccharomyces) show promise in improving clinical outcomes for NEC (Table 8.5). The gut of the newborn baby is generally accepted as sterile, and thus the timing administration of probiotic might help them to establish rather normal gut micro-ecology. Mechanistically, probiotic might reduce the incidence and mortality of NEC by targeting pathogenic bacteria infection via their metabolic productions such as extracellular polysaccharide, lactic acid, short-chain fatty acids (SCFA), and bacteriocin (Bird et al. 2010; Fleming et al. 2015; Gorelnikova and Karpunina 2015; Hevia et al. 2015; Lim et al. 2015; Roy et al. 2006).
8.6 Colorectal Cancer
8.6.1 Epidemiology, Signs, and Symptoms
Colorectal cancer (CRC) is a malignant tumor that occurred in the colon or rectum. It represents the third most common noncutaneous malignancy and affords the third leading cause of cancer-related death (Brenner et al. 2014a, b). Despite the recent improvements in preventive strategies, screening techniques, and development of surgery and chemotherapy, the median survival period for metastatic colorectal cancer patients is only 24 months. The common symptoms of CRC might include bloody stools, a change in bowel habits, body weight loss, and fatigue (e.g., extreme tiredness or lack of energy).
8.6.2 Histological and Molecular Pathogenesis
During colorectal carcinogenesis, the transition from normal mucosa to adenoma and final carcinoma is a protracted event as well as a multifactorial process (Baert-Desurmont et al. 2016). The potential risk factors of CRC include family history, obesity, lack of physical activity, high-fat diet, low dietary fiber intake, high red meat intake, and smoking and alcohol use (Botteri et al. 2008; Crockett et al. 2011; Declercq et al. 2015; Gallagher and LeRoith 2011; Germansky and Leffler 2011; Fedirko et al. 2011; Han et al. 2015; Hannan et al. 2009; Odegaard et al. 2011; Pajares and Perea 2015; Raufman et al. 2015; Wani et al. 2014). Molecular analyses of colorectal carcinomas have led to a genetic model of colon carcinogenesis which stemmed from the accumulation of a number of genetic alterations (e.g., APC, p53, and K-Ras) and oncogenic protein overexpression (e.g., COX-2 and EGFR).
8.6.3 Gut Microbiota and Probiotic Intervention
It is well-known that both high-fat diet and low dietary fiber intake might increase the risk of CRC. Considering the fact that both of them greatly affect the composition of the intestinal microbiota, gut microbial dysbiosis has long been suspected to functionally mediate CRC development (Louis et al. 2014; Sears and Pardoll 2011). Compared with healthy ones, CRC patients have a lower gut bacterial diversity but more Fusobacterium nucleatum and Escherichia coli (Castellarin et al. 2012). Further studies confirmed that they might potentiate intestinal tumorigenesis by modulating the tumor-immune microenvironment. Certain probiotics show some promise in CRC management (Table 8.6), but it still leaves much to be desired (Ishikawa et al. 2005; Ma et al. 2010; Pearson et al. 2009; Pala et al. 2011; Rafter 2002; Rafter et al. 2007; Rowland et al. 1998; Rowland 2009). It is worth noting that probiotics might reduce side effects of radiation therapy (Ciorba et al. 2012) while potently enhancing cancer immunotherapy (Chitapanarux et al. 2010; Moreno de LeBlanc and Perdigón 2010; Vétizou et al. 2015).
8.7 Probiotic Lactic Acid Bacteria: To the Future and Beyond
8.7.1 Challenges to Probiotic Intervention
Accumulating data suggested the implication of gut microbial dysbiosis in multiple gastrointestinal diseases. If gut bacteria are making you ill, can swapping them make you healthy? Accordingly, gut microbiota is proposed as one promising molecular target for gastrointestinal disorder management. People reasoned that probiotic intervention might remodel a disease-prone microbiota pattern into a disease-free state. Indeed, probiotics have shown some promise in several gastrointestinal disorders such as irritable bowel syndrome, infectious diarrhea, inflammatory bowel disease, and even colorectal cancer, but the following bench-to-bedside translation remains to be a big issue (Klein et al. 2010; Floch et al. 2011).
A success in clinical trial mainly depends on two factors: an effective and safe drug and a selectively responsive subpopulation. In precision medicine, one trend is rational drug design, which is largely based on a definite molecular target. The first and most important question is how gut microbiota affect host physiology. Although altered gut microbiota have been associated with various gastrointestinal diseases, their causality remains to be further defined (Bäckhed et al. 2012). A better understanding of the etiology of gastrointestinal disorders as well as their cause-and-effect relationship among gut microbiota, microbe-derived gut metabolites, and host is thought to be an essential step forward.
The second question is how to design a clinical study on probiotics. Is it based on epidemiological data and/or evidence-based medicine (Sanders and Levy 2011)? Probiotic products are currently marketed as foods or dietary supplements, which are normally not regulated as disease management. Then, how do we conduct studies to test the potential health benefit of probiotic in healthy ones? If performed among a disease population, such kind of study should follow the standards of drugs. Efficacy of probiotic intervention might be dependent on the probiotic strains and/or dosage used. How the optimizing probiotic LAB strain, dose and even product formulation are weight and judged? As outcomes must be clear and measurable in a clinical study, what are the validated biomarkers used for targeted diseases? In addition, has the optimal target population been clearly defined? To this end, nutrition standards, dietary guidelines, and even genetic background of targeted populations must be considered.
Another issue is the safety of probiotics. Although probiotics are generally considered safe as they derived from traditional fermented foods or health gut, they might cause adverse health consequences in certain cases (Guarner et al. 2011). If gut bacteria are making you ill, can swapping them make you healthy? Please keep in mind, probably, the reverse is also true. For example, some probiotics might cause excessive immunity response, affect the metabolism of some drug, and even carry and spread antibiotic resistance genes. Although probiotic might sometimes rectify gut microbial dysbiosis, its administration in wrong way might further profound microbial dysbiosis and thereby causes serious side effects, especially on certain subgroup of populations. The suitability and safety of probiotic should be studied by randomized, double-blind, placebo-controlled trials.
Taken together, before a large-scale clinical trial can be discussed, all those basic information about the targeted populations as well as microbe used is required.
8.7.2 The Future of Probiotic Intervention
Recent studies clearly indicated that the gut microbiota play a critical role in host physiology. However, an understanding of how they affect the host health is only beginning to be elucidated. For example, beyond probiotic supplement, there are many factors (e.g., as age, genetics, drug, diet, and even stress) influencing the composition of human microbiome. As a saying goes, you are what you eat. Diet strongly affects human health, at least partially, by modulating gut microbiome. And long-term dietary interventions may allow modulation of an individual’s enterotype to improve health. To this end, the relationships among diet-microbe-host should be more thoroughly studied and elucidated in the future.
Tomorrow’s probiotics might probably move beyond the microorganisms commonly used as probiotics today. For example, despite the presence of fungal and viral members, studies in gut microbe so far have focused on the bacteria, and the probiotics available to consumers also solely belong to lactic acid bacteria. Actually, lactic acid bacteria itself is also a term which has no strict taxonomic significance. Not surprisingly, such paradigm might be changed. Upon recent progression and understanding of the gut microbiota, some specific strains (e.g., Akkermansia muciniphila, Bacteroides fragilis, and Faecalibacterium prausnitzii) might be the next-generation probiotics. Probiotic interventions outside the gastrointestinal tract (e.g., diabetes, obesity, the metabolic syndrome, liver diseases, etc.) are also increasingly recognized (Hojsak et al. 2010). Moreover, probiotics are normally nonpathogenic and noninvasive and non-colonizing bacterium, and thus recombinant probiotics may represent an interesting direction in the future, especially to deliver oral vaccine, improve natural immune responses, and restore antigen-specific tolerance (Takiishi et al. 2012). Advancements in this direction might largely lie in our better understanding of their genetic-metabolic networks.
In summary, probiotics might have a huge potential in clinical application. Although the overall efficacy of current probiotic intervention is still far to meet the standard of medical care required for evidence-based medicine and some data might be inconsistent or somewhat ever contradictory with each other, targeting gut microbial dysbiosis by probiotics opens a new avenue to gastrointestinal diseases management. Exciting times are definitely coming up for food microbiologist and gastroenterologists. Working together, we might create the next epoch in this area.
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Li, H., Fang, Z. (2019). Lactic Acid Bacteria and Gut Health. In: Chen, W. (eds) Lactic Acid Bacteria. Springer, Singapore. https://doi.org/10.1007/978-981-13-7832-4_8
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