Probiotics. Part 2/2

Probiotics have extensive potential for therapeutic use, and we continue to discover their specific actions. The previous article looked at classification and the role of probiotics with regards to immune function and digestion, including autoimmunity, atopic skin reactions, and respiratory conditions. This article will focus on the composition of healthy versus dysbiotic microbiomes, and on the effects of probiotics on metabolic markers and the microbiota-gut-brain intercommunication.

Microbiota Composition

Our microbiota composition is established and affected by events early in life such as gestational age, modes of birth (vaginal v. C‑section), feeding (breast milk v. formula), diet, antibiotic use, and stressors, among others.¹ Once established, the composition remains quite stable throughout adulthood. Small differences are seen with the elderly having a higher level of Bacteroides and Clostridium genera versus younger adults with a predominance of Firmicutes.² The idea of enterotypes involves the classification of human microbiota into three dominant genera: Bacteroides (enterotype 1), Prevotella (enterotype 2), both in phylum Bacteroidetes, and Ruminococcus (enterotype 3) in the Firmicutes phylum.³ Much research has identified changes in gut microflora in relationship with diet. For example, a Western diet tends to have a greater proportion of Bacteroides spp. in the gut microbiota compared with plant-based diets, which are associated with higher amounts of Prevotella spp.⁴ As a reminder, the Firmicutes include Lactobacillus and Bacillus, among others, so we can see the benefits of supplementing these probiotics. Diets high in red meat promote an overgrowth of sulfate-reducing bacteria which are associated with changes that could increase risk of colorectal cancer, and fibre-rich diets increase the production of short-chain fatty acids (SCFAs) such as butyrate, which is beneficial for having antitumor properties.⁵ There is great potential to shift the variety and composition of the microflora with diet and probiotics.

Dysbiosis

A variety of types of dysbiosis have been identified. In putrefactive dysbiosis, an increase in putrefactive bacteria (mainly Bacteroides) typically results from a diet rich in fat and meat and low in fibre.⁶ Fermentive dysbiosis is often related to antibiotic use and can result in irritable bowel syndrome (IBS). Susceptibility dysbiosis is associated with a loss in tolerance of the microbiota, leading to abnormal immune responses and inflammatory bowel disease (IBD). Typically, there are decreases in the “good” and increases in the “bad” bacteria with altered motility and inflammation of the bowel.⁷ Lastly, fungal dysbiosis involves the overgrowth of Candida and other fungal species, which results from a diet high in sugars and low in fibres.⁸ Changes in diet and pre- and probiotic supplementation have shown improvements in the microflora environment and promote a homeostatic balance for health and disease prevention.

Metabolic Conditions

Obesity is associated with increased Bacteroidetes over time and a decrease in Firmicutes.⁹ Also, patients with type 2 diabetes (DM2) have significantly reduced Firmicutes, and a similar pattern is observed with autoimmune diseases, such as type 1 diabetes.¹⁰ Metabolic syndrome involves a dysregulation of blood sugar, cholesterol, inflammation, abdominal fat, and blood pressure, as well as an increased risk of cardiovascular diseases including DM2. Multiple meta-analyses have found probiotic supplementation to have a positive effect on blood glucose and insulin levels along with improving blood pressure. ^11,12,13 Five more meta-analyses repeatedly found improvements in total cholesterol (TC) and LDL cholesterol levels, but with no significant effects on triglycerides (TGs) or HDL cholesterol.^{14,15,16,17,18}The length of probiotic use was important, showing that > 4 weeks was more effective at decreasing cholesterol levels,^19,20 and another meta-analysis showed TGs to be significantly reduced with > 8 weeks of probiotic use.²¹ Also, subjects with mildly high cholesterol levels showed greater results than those with normal cholesterol levels.²² Specific strains, such as L. acidophilus, B. lactis, and L. plantarum, significantly lowered TC,^23,24 and L. plantarum and L. reuteri significantly reduced LDL cholesterol. While TGs were not often changed, marked beneficial effects in TGs were seen with consumption of a synbiotic food containing L. sporogenes (aka Bacillus coagulans) and inulin.²⁵ Decreases in both systolic and diastolic blood pressure were also seen with probiotic supplementation,^26,27,28 and BMI was improved in obese patients.²⁹ L. gasseri with galactomannan and/or inulin fibres showed weight-reduction and anti-inflammatory effects.³⁰Specifically, L. gasseri BNR17 showed properties of inhibiting the increase in adipocyte tissue, which in turn decreases leptin secretion.³¹ L. rhamnosus CGMCC demonstrated significant weight reduction in obese women and was associated with an increase in satiety, a decrease in food cravings, a decrease in Beck Depression Inventory (BDI) score, and an improved body image, which touches on mental-emotional effects.³² Saccharomyces boulardii supplementation with superoxide dismutase (SOD) showed similar results, with significant weight loss as well as decreases in BMI, insulin, and fat mass in obese patients compared to placebo.³³Research on prebiotics showed that they could lower the risk of cardiovascular disease by reducing the inflammatory elements, noting that galacto-oligosaccharides (GOS) could reduce cholesterol and that the combination of fructo-oligosaccharides (FOS) with L. rhamnose had lipogenic effects due to the production of acetate, butyrate, and propionate.³⁴ Overall, probiotics and prebiotics seem beneficial for many signs and symptoms of metabolic syndrome including blood pressure, glucose, insulin, cholesterol, BMI, and inflammation.

The Gut-Brain Axis

The concept of a microbiota-gut-brain axis is a new area of study, and we often see intestinal distress involving symptoms of anxiety and depression, and vice versa. Many mechanisms have been proposed for this bidirectional gut-brain communication pathway including immune activation, vagus nerve signaling, changes in tryptophan metabolism, and production of microbial neuroactive metabolites.³⁵ There is a relationship between dysbiosis and depression, and it has been shown that abnormal microbial exposure during childhood and perinatal stress influence the maturation of the microbiota and immune system, contributing to depression.³⁶ Antibiotic use can profoundly decrease the diversity of gut bacteria and has been found to increase the risk of developing anxiety later in life.³⁷ Also, patients with major depressive disorder (MDD) were found to have significantly lower Bifidobacterium and Lactobacillus counts than controls,³⁸ and the use of antipsychotics was associated with weight gain and a decreased ratio of Bacteroidetes to Firmicutes, further complicating the issue.³⁹

Depression and Anxiety

Looking at the research on specific probiotics, L. plantarum DR7 reduced symptoms of stress,⁴⁰ and L. plantarum 299v decreased kynurenine and improved cognitive performance in patients with MDD.⁴¹ Kynurenine is a metabolite of tryptophan associated with depressive symptoms, and imbalances in the breakdown of kynurenine and its ratio with tryptophan are found in schizophrenia, bipolar disease, and Alzheimer’s, among others.

L. rhamnosus showed anxiolytic effects in rodents and changes in GABA receptors in regions of mice brains.⁴² Another study, using L. rhamnosus during pregnancy, found significant decreases in prevalence of symptoms of depression and anxiety postpartum.⁴³L. helveticus with B. longum showed mixed results, and even taken for eight weeks, there was no significant effective in treating depression, stress, and anxiety.^44,45 A different study, using L. helveticus and B. longum with galacto-oligosaccharides (GOS), found significant decreases in the BDI score and in the kynurenine-tryptophan ratio.⁴⁶ Using just the prebiotic GOS, salivary cortisol awakening response was significantly reduced whereas FOS showed no effects.⁴⁷ A few other studies showed significant improvements in mood, depression, and mental health using mixtures of probiotics including L. acidophilus, L. casei, B. bifidum, B. lactis, L. brevis, L. salivarius, and Lactococcus lactis.^48,49,50 L. casei Shirota showed significant decrease in anxiety in patients with chronic fatigue syndrome,⁵¹ and while B. longum showed no effect on anxiety, there was a reduction in depression at 10 weeks, increased quality of life scores, and a decreased response to negative emotional stimuli seen in multiple brain areas (reduced limbic activity).⁵² Improvements in sleep and stress symptoms, including significant reduction in anxiety, were seen with L. gasseri CP2305,⁵³and L. casei also helped sleep quality during a period of increased stress in healthy adults.⁵⁴

Autism

Autism (ASD) is closely associated with dysbiosis and gastrointestinal (GI) disturbances, with findings of high Clostridium spp. and low Bifidobacterium in feces,^55,56,57 as well as increased microflora but decreased diversity.⁵⁸ Interestingly, the use of vancomycin, an antibiotic not absorbed by the gut that covers gram-positive bacteria such as Clostridium, improved symptoms of ASD.⁵⁹ Prebiotics, and specifically L. reuteri alone,⁶⁰ showed significant improvements in social behavior scores in children with ASD.⁶¹ L. plantarum showed an improvement in school records as well as attitude towards food, which is often challenging in ASD.⁶²

Another effect of probiotics on the gut-brain access is regulation of mood towards rewards and addictive behaviour by L. acidophilus.⁶³ From a preventative perspective, a study on children at risk of neurodevelopmental disorders suggested that Asperger’s syndrome and ADHD could be avoided when pregnant mothers were given L. rhamnosus four weeks before delivery and continued for six months after.⁶⁴ In Alzheimer’s disease, there was a significant improvement in Mini Mental State Examination score in the probiotic group, and C‑reactive protein was also reduced.⁶⁵

Conclusion

The microbial-gut-brain access is a fascinating area of research for probiotics, with a new term emerging, calling them “psychobiotics.” There is much known about the benefits of probiotics on immune regulation, digestion, skin, and respiratory conditions, and we are beginning to understand the specific effects on inflammation, metabolism, autoimmune disease, anticancer activity, and neurological communication. A naturopathic and whole-person perspective sees much overlap and intercommunication between these health concerns, and although generalized probiotic mixtures may often be beneficial, it is important to understand the distinctive actions probiotics provide. Factors that involve microbiota colonization early in life provide a basis for disease prevention, and knowing a person’s enterotype and dysbiosis type helps individualized treatment. Lastly, the functions of specific probiotic species and strains, and the type of prebiotic “food” that supports their growth, provide a specialized therapeutic benefit.