"All disease begins in the gut."
This often-referenced quote from the father of medicine is well-known, and with good reason. Over 2000 years of medical research and practice since the days of Hippocrates continues to confirm his observation that the health and function of the digestive tract profoundly influences overall health and the pathogenesis of disease. Particularly in the past decade, as investigation of digestive health and immune function has focused on the gut microbiome, this vast ecosystem has increasingly been recognized not only as an influencer of local digestive function, but as a part of the bidirectional communication network connecting the brain, immune, and endocrine systems.
We now understand that inflammation in the digestive tract is a critical link between digestive and many systemic inflammatory diseases, and data demonstrate that gut dysbiosis directly mediates this inflammation.1 Thus, probiotics hold unique potential to influence this observed chain of events, correcting dysbiosis locally and thus influencing systemic inflammation and disease.
The Intestinal Barrier in a Healthy State
The digestive tract is the largest mucosal surface in the body, a selective interface between self and non-self, and a central hub of immune activity (the gut-associated lymphoid tissue, or GALT). The four primary components of the intestinal barrier are: 1) the gut microbiota, 2) a mucin layer that acts as a buffer between gut bacteria and intestinal epithelial cells, 3) a single-cell layer of epithelial cells connected by tight junctions, and 4) innate and adaptive immune cells that form GALT.2 When functioning optimally, the gut microbiota is diverse and replete with beneficial, commensal bacteria that displace pathogens, while tight junctions strictly limit the passage of bacteria, metabolites, and other material from external to internal environments.
The Role of Gut Microbiota in Intestinal Inflammation
Diet, medications such as antibiotics, infection, and genetic susceptibility can dramatically shift gut microbial composition and alter barrier function.3 Inflammatory diseases of the gut are associated with a significant decrease in microbial diversity and a shift from a predominance of Gram-positive bacteria to a state of Gram-negative dominance.3 This dysbiotic composition disrupts the mucosal barrier, increasing intestinal barrier permeability and resulting in penetration of bacteria from mucosal biofilm in the gut lumen into direct contact with epithelial cells and tight junctions.4 This direct contact triggers immune inflammatory responses, such as are seen in inflammatory bowel diseases (IBD). The cell walls of these largely Gram-negative bacteria express endotoxic lipopolysaccharides (LPS), which are highly pro-inflammatory.5 That LPS contributes to the pathogenesis of many systemic inflammatory diseases has been well demonstrated in clinical and pre-clinical studies.
Intestinal Inflammation in Systemic Inflammatory Disease
Gut inflammation with resulting increases in intestinal permeability has consequences that extend beyond the digestive tract. A number of systemic inflammatory diseases, including those discussed below, are associated with, if not triggered by, inflammation in the gut.
Multiple sclerosis (MS) is a chronic, typically progressive disease in which lymphocytes of the immune system inappropriately mount an inflammatory attack of the myelin sheath around the brain and spinal cord. It has long been suspected that infection with bacterial pathogens could trigger MS. A growing body of research now implicates the gut microbiota as the primary inducer of autoimmunity, and it has even been proposed that MS patients may have characteristic alterations to their microbiome.6,7 In one study, the microbiomes of MS patients revealed specific bacterial taxa, when compared with healthy controls, i.e., Akkermansia muciniphila and Acinetobacter calcoaceticus were significantly associated with MS. Both of these organisms were found to induce proinflammatory responses in human peripheral blood mononuclear cells. In contrast, Parabacteroides distasonis, reduced in the microbiomes of MS patients, was found to stimulate an anti-inflammatory response.8
Alzheimer's disease (AD) is another chronic, progressive illness where inflammation is an established etiologic element.9 New research now demonstrates that gut dysbiosis contributes to the pathogenesis of dementia by triggering low-grade peripheral inflammation.10 Cattaneo and colleagues assessed the role of gut microbiota in AD pathogenesis by studying the association of brain amyloidosis with specific gut microbiota taxa, pro- and anti-inflammatory activity, and occurrence of peripheral inflammation in cognitively impaired patients.11 AD patients with amyloidosis showed higher levels of pro-inflammatory cytokines compared with both controls and with amyloid negative patients. In addition, patients with amyloidosis showed higher abundance of inflammatory Escherichia/Shigella taxa compared with both healthy controls and amyloidosis negative patients.
Obesity and Related Diseases
Evidence from human and animal models demonstrates plasma elevations of gut-derived endotoxin (LPS) as a driving factor behind the low-grade systemic inflammation associated with obesity, Type II diabetes, metabolic syndrome, and cardiovascular disease. The pro-inflammatory environment in obesity is well enough established to have earned its own name: "metabolic endotoxemia."12 To directly study the influence of LPS on adiposity, Cani and colleagues injected low dose LPS (300 μg/kg/day) in lean mice on a normal chow diet.13 These injected mice had similar outcomes to diet-induced obesity (i.e., weight gain, tissue specific inflammation, hepatic lipid deposition, and insulin resistance). However, lean mice lacking LPS co-receptors were resistant to these changes, indicating LPS is a mediating factor in obesity-related comorbidities.
Probiotics as Therapy
As previously noted, gut bacteria influence both local and systemic inflammatory processes. This suggests that beneficial probiotic bacteria might be useful in mitigating inflammation.14 Investigations of this theory have focused primarily on inflammatory bowel disease (IBD). However, newer animal and human clinical data suggest probiotic influence on systemic disease as well.
In IBD, a meta-analysis of twenty-three clinical trials comparing probiotics with controls, administration of an eight-strain probiotic combination consisting of four strains of Lactobacillus, three strains of Bifidobacterium, and Streptococcus thermophilus with a total of 900 billion viable bacteria, significantly increased remission rates in patients with active ulcerative colitis compared to placebo.15 In another clinical trial, this same probiotic mixture was shown to lower levels of mucosal inflammatory cytokines compared to placebo when given to patients with Crohn's disease within 30 days after ileocolonic resection surgery.16
In a clinical trial, 54 diabetic patients were randomly assigned to take either a multispecies probiotic consisting of Lactobacillus acidophilus (2 × 109 CFU), L. casei (7 × 109 CFU), L. rhamnosus (1.5 × 109 CFU), L. bulgaricus (2 × 108 CFU), Bifidobacterium breve (2 × 1010 CFU), B. longum (7 × 109 CFU), Streptococcus thermophilus (1.5 × 109 CFU), and 100 mg fructo-oligosaccharide or placebo for eight weeks.17 Group comparisons revealed that probiotic consumption prevented a rise in fasting plasma glucose and that mean changes in serum high-sensitivity C-reactive protein were significantly different between the two groups. From these data, the researchers concluded that multispecies probiotic supplementation directly and positively impacts the endocrine and inflammatory mechanisms underlying diabetes.
Although inflammation is a normal and important response to the presence of damaged and/or harmful cells, pathogens, or toxins, an excessive or prolonged inflammatory response can cause or exacerbate disease. Dysregulated inflammatory responses originating in the gut due to dysbiosis and resulting increases in intestinal permeability are now recognized as being determinative of disease pathogenesis. An increasing number of clinical trials now demonstrate probiotics as an effective therapeutic intervention. Further controlled clinical trials are urgently needed to clarify organisms, dose, mechanisms of action, and therapeutic targets. Restoring homeostasis in the digestive tract through multispecies probiotic supplementation should be considered a primary therapeutic intervention for both local and systemic inflammatory diseases.
1. D'Amelio P, Sassi F. Gut microbiota, immune system, and bone. Calcif Tissue Int. 2018 Apr;102(4):415-25.
2. Viggiano D, et al. Gut barrier in health and disease: focus on childhood. Eur Rev Med Pharmacol Sci. 2015;19(6):1077-85.
3. Im E, et al. Elevated lipopolysaccharide in the colon evoke intestinal inflammation, aggravated in immune modulator-impaired mice. Am J Physiol Gastrointest Liver Physiol. 2012 Aug;303(4):G490-7.
4. Vindigni SM, et al. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions. Therap Adv Gastroenterol. 2016 Jul;9(4):606-25.
5. Gnauck A, Lentle RG, Kruger MC. The characteristics and function of bacterial lipopolysaccharides and their endotoxic potential in humans. Int Rev Immunol. 2016 May;35(3):189-218.
6. Berer K, Krishnamoorthy G. Commensal gut flora and brain autoimmunity: a love or hate affair? Acta Neuropathol. 2012 May;123(5):639-51.
7. Chen J, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016 Jun;6:28484.
8. Cekanaviciute E, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci USA. 2017 Oct;114(40):10713-8.
9. Aisen PS, Davis KL. Inflammatory mechanisms in Alzheimer's disease: implications for therapy. Am J Psychiatry. 1994 Aug;151(8):1105-13.
10. Alkasir R, et al. Human gut microbiota: the links with dementia development. Protein Cell. 2017 Feb;8(2):90-102.
11. Cattaneo A, et al. Associate of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017 Jan;49:60-8.
12. Cani PD, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008 Jun;57(6):1470-81.
13. Boutagy NE, et al. Metabolic endotoxemia with obesity: is it real and is it relevant? Biochimie. 2016 May;124:11-20.
14. Fontana L, et al. Sources, isolation, characterization and evaluation of probiotics. Br J Nutr. 2013 Jan;109 Suppl 2:S35-50.
15. Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn's disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis. 2014 Jan;20(1):21-35.
16. Fedorak RN, et al. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease. Clin Gastroenterol Hepatol. 2015 May;13(5):928-35.
17. Asemi Z, et al. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab. 2013;63(1-2):1-9.
Keegan Sheridan, ND, is a naturopathic physician and graduate of Bastyr University. Since 2006, she has worked in the natural/organic food, beverage, and dietary supplement industries as a technical marketing expert and natural health strategist. Keegan is a scientific consultant for SFI USA, which manufactures the Klaire Labs brand of dietary supplements. She lives in San Diego, California. For more information, visit www.keegansheridan.com.