Answer by Tirumalai Kamala:
Simpler question is what isn’t. Gut bacteria influence our entire physiology from the basic such as what and how much we eat to the synthesis of essential vitamins, from our immune function and metabolism to even our mood. The study of microbiota, much of it mouse model data, has exploded over the past decade. Instead, I specifically highlight human data from peer-reviewed scientific studies.
Antibiotic usage, diet, hygiene and lifestyle shape our microbiota, particularly gut microbiota. In turn, they shape our immune and metabolic function.
Let’s start from first principles. Food. How do microbes control our eating behavior?
From 2. I highlight human data in purple.
- They influence our reward pathway. After all, our enteric (gut-associated) nervous system is the major source of dopamine and serotonin (3, 4).
- They modulate our taste perception (5).
- They play on our vagus nerve as a musician plays his instrument (6, 7). What’s the importance of the vagus nerve? It’s the main nerve communication between our gut and brain.
- Our gut microbiota is exquisitely adapted to our diet.
a) One of the most compelling examples is of a gut bacterium found in the Japanese. Bacteroides plebeius has a horizontally transferred gene from the marine bacterium Zobellia galactanivorans that gives it the capacity to digest seaweed polysaccharides (8). In fact, human-associated bacteria have a 25-fold higher rate of gene transfer compared to bacteria in other environments (9), implying host-microbe association imposes stringent selection pressures on our microbiota.
b) Obese have altered gut microbiota with reduced diversity and greater variability (10, 11, 12, 13).
c) US population microbiome appears adapted for a high-fat, high-protein diet while that of people living in rural Malawi and the Amazonas in Venezuela for breaking down complex carbohydrates (14).
Gut microbes influence every aspect of our physiology
What about the rest of our body functions? Even surprising ones such as metabolism and behavior are profoundly influenced by our microbiota.
Our metabolome refers to the variety of metabolites present in our blood circulation. About a third of our metabolome is estimated to be of microbial origin. Using our circulation system as their communication network, animal model studies show that our microbial products can reach every part of our body (16, 17, 18), and influence the metabolism and physiology of distant organs and each other. For example, people with symptomatic atherosclerosis have altered gut microbiota (19). A potential mechanism by which our gut microbes could jeopardize cardiovascular health is through conversion of dietary phosphatidylcholine into the proatherosclerotic metabolite, trimethylamine (20), a result that needs to be independently verified.
Possible Gut-Brain communication mechanisms
- Short-chain fatty acids (SCFA). Colonic gut microbes digest dietary carbohydrates to generate SCFA such as acetate, butyrate and propionate (22). Signaling through G protein coupled receptors such as (GPRs), GPR41 and GPR43, SCFA induce colonic motility, regulate appetite (23) and even suppress colon cancer (24) in human colon cancer cell lines. While colon cells (colonocytes) use butyrate as an energy source, acetate and propionate enter the blood stream and thence to other organs (25, 26). These SCFAs can stimulate the sympathetic nervous system (27).
- Gut microbiota can also modulate neurotransmitters within the gut. This includes acetylcholine, gamma-aminobutyric acid, histamines, melatonin and serotonin. Gut microbes can express and secrete neuropeptide-like molecules that could influence behavior and emotion (28, 29).
- Tryptophan is an essential amino acid we only get from our diet (30), and is the precursor of serotonin (31), most of it synthesized by our gut enterochromaffin cells and enteric nerves (32, 33, 34).
- Gut microbes synthesize vitamins essential for nervous system function. For example, Lactobacillus reuteri is a major source of Vitamin B12 or cobalamin (35), a vitamin important for the development of the nervous system (36).
GI diseases and psychiatric comorbidities
Cause and effect or correlation?
- While that’s still debatable, up to 80% of patients with GI diseases (IBS, Irritable Bowel Syndrome; IBD, Inflammatory Bowel Disease) also have psychiatric illnesses such as depression and anxiety (37, 38, 39). Changes in psychological activities are seen both before and after diagnosis of IBD.
- Serum cortisol, a marker of elevated anxiety, was reduced in patients who consumed probiotics, Lactobacillus helveticus and Bifidobacterium longum (40) while healthy subjects showed significantly less psychological distress compared to the placebo group in a double- blind, placebo-controlled, randomized parallel group clinical trial with the same probiotic mixture for 30 days (41).
- Treatment with a probiotic- containing milk drink resulted in improved mood and cognition in healthy subjects when compared to the placebo group (42).
- There are signs of cognitive impairment in IBS patients (43).
- After 4 weeks of treatment with a fermented milk product with probiotics, healthy women volunteers performed a specific cognition test faster (44). Analysis of their brain function indicated specific uptick in activity in regions innervated by serotonergic nerves.
- Neuroimaging studies suggest abnormal brain function in GI disorders. This includes thinning of the anterior cingulate and insular cortex, and increased activation of the thalamus, anterior cingulate and prefrontal cortex of IBS patients (45, 46).
- Lactobacillus and Clostridium species are reduced in stool samples from IBS patients (47, 48).
Deconstructing our Gut microbe-Brain connection
How to infer a connection between our gut microbiota and brain? We could if specifically targeting microbes affected our brain and/or behavior. Antibiotics directly and specifically target microbes. If antibiotic therapy also resulted in any change in brain function and/or behavior, it could be inferred as evidence of microbe-brain connection. As a direct effect, gut microbes synthesize vitamins essential for brain function.
In the first stages of liver disease, cirrhosis, the liver compensates to perform its functions. In later stages, it can no longer compensate. At this stage, there is attendant encephalopathy (degeneration of brain function). Several lines of evidence suggest a link between gut microbiota disturbance (dysbiosis), liver disease and brain function.
- Oral antibiotics can reverse encephalopathy in decompensated liver disease patients (49, 50, 51)
- Compared to healthy controls, encephalopathic cirrhosis patients have altered gut microflora (52, 53).
- In particular, reduced Alcaligenaceae and Porphyromonadaceae and increased Enterococcus, Megasphaera and Burkholderia correlate with poor cognition and increased inflammation in encephalopathic patients with cirrhosis and cognitive dysfunction (54, 55).
- Most children with Autism often experience a range of GI problems (56).
- Disease onset usually follows antimicrobial use in a high percentage of late-onset Autism (18–24 mo of age) children having a history of extensive antibiotic use. One study observed a 10-fold increase in certain clusters of Clostridium spp in stool samples from Autistic children compared with healthy controls. The authors speculated that exposure to trimethoprim/ sulfamethoxazole rather than exposure to other antibiotics could be linked to the diagnosis of late-onset Autism since the former are not effective against Clostridium spp, while oral vancomycin specifically targets Gram positive organisms which include Clostridium spp (57). Increased clostridial species in stool samples of Autistic patients was confirmed by another study (58). Indeed, oral vancomycin treatment showed a decrease in Autistic symptoms, while relapse occurred following cessation of treatment (59).
- Clostridia spores are also implicated in the high rates of Autism seen among siblings (60).
- Real time qPCR (61) and culture-based microbiota (57) profiling techniques suggest that alteration in microbiota may contribute to disease phenotype.
- Intestinal biopsy of late-onset Autism spectrum disorder (ASD) patients revealed reductions in Bifidobacterium spp. and the mucolytic bacterium Akkermansia muciniphila (62).
- Late-onset Autism patients have marked reduction in Bacteroides and Prevotella species and increase in Sutterella species compared to controls (63, 64, 65, 66).
- At least one study refutes differences in gut microbiota between Autistic patients and controls (67). Possible reasons for the different result could be they used a different approach for taking samples and used a different technique for microbiome analysis.
- Altered expression in the ileum of carbohydrate transporters such as hexoses and for enzymes such as disaccharidases suggest a role for carbohydrate malabsorption in Autism (68).
- Urine and fecal sample metabolites are different in Autism patients (69, 70, 71, 72).
- Casein- and gluten-free diets are reported to improve behavior of patients with Autism (73, 74, 75).
Problems with many Autism-GI disorder association studies
- They study different types of populations (possibly different diseases).
- Population sizes differ considerably between studies.
- Different studies use different controls.
- Do not control for the unique diets of the patients. Diet itself could be a reason for different gut microbe distribution in patients compared to controls.
A better controlled and more comprehensive US study (76) examined 589 patients with a history of familial ASD and their unaffected sibling controls. Separating ‘Full’ from ‘Spectrum’, they reported constipation (20%) and chronic diarrhea (19%) as the most common symptoms among those with ‘Full’ Autism. Another study of >140000 ASD patients showed higher prevalence of IBD (0.83% vs 0.54%) and other bowel disorders (11.74% vs 4.5%) compared to hospitalized controls (77).
This comprehensive table summarizes findings from various Autism-GI disorder association studies
Antibiotic associated behavior changes
- Sometimes antibiotics are associated with behavioral changes spanning insomnia, mood alteration (79, 80), to mania, particularly in elderly patients, (‘antibomania’) (81).
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