Michael D. Crowell

Human gut microbiota in obesity and after gastric bypass

Recent evidence suggests that the microbial community in the human intestine may play an important role in the pathogenesis of obesity. We examined 184,094 sequences of microbial 16S rRNA genes from PCR amplicons by using the 454 pyrosequencing technology to compare the microbial community structures of 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery. Phylogenetic analysis demonstrated that although the Bacteria in the human intestinal community were highly diverse, they fell mainly into 6 bacterial divisions that had distinct differences in the 3 study groups. Specifically, Firmicutes were dominant in normal-weight and obese individuals but significantly decreased in post-gastric-bypass individuals, who had a proportional increase of Gammaproteobacteria. Numbers of the H2-producing Prevotellaceae were highly enriched in the obese individuals. Unlike the highly diverse Bacteria, the Archaea comprised mainly members of the order Methanobacteriales, which are H2-oxidizing methanogens. Using real-time PCR, we detected significantly higher numbers of H2-utilizing methanogenic Archaea in obese individuals than in normal-weight or post-gastric-bypass individuals. The coexistence of H2-producing bacteria with relatively high numbers of H2-utilizing methanogenic Archaea in the gastrointestinal tract of obese individuals leads to the hypothesis that interspecies H2 transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons. The large bacterial population shift seen in the post-gastric-bypass individuals may reflect the double impact of the gut alteration caused by the surgical procedure and the consequent changes in food ingestion and digestion.

Design of treatment trials for functional gastrointestinal disorders.

This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.This document summarizes recent progress and regulatory guidance on design of trials to assess efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo controlled parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively a sham procedure and control intervention with similar expectation of benefit but lacking the treatment principle are recommended. Investigators should be aware of and attempt to minimize expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition, or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location prior to initiation, and results should be published regardless of outcome.

Gut Microbiota and Its Possible Relationship With Obesity

Obesity results from alterations in the bodys regulation of energy intake, expenditure, and storage. Recent evidence, primarily from investigations in animal models, suggests that the gut microbiota affects nutrient acquisition and energy regulation. Its composition has also been shown to differ in lean vs obese animals and humans. In this article, we review the published evidence supporting the potential role of the gut microbiota in the development of obesity and explore the role that modifying the gut microbiota may play in its future treatment. Evidence suggests that the metabolic activities of the gut microbiota facilitate the extraction of calories from ingested dietary substances and help to store these calories in host adipose tissue for later use. Furthermore, the gut bacterial flora of obese mice and humans include fewer Bacteroidetes and correspondingly more Firmicutes than that of their lean counterparts, suggesting that differences in caloric extraction of ingested food substances may be due to the composition of the gut microbiota. Bacterial lipopolysaccharide derived from the intestinal microbiota may act as a triggering factor linking inflammation to high-fat diet-induced metabolic syndrome. Interactions among microorganisms in the gut appear to have an important role in host energy homeostasis, with hydrogen-oxidizing methanogens enhancing the metabolism of fermentative bacteria. Existing evidence warrants further investigation of the microbial ecology of the human gut and points to modification of the gut microbiota as one means to treat people who are over-weight or obese.

Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction.

A standardised inventory of stressful life events and a bowel symptom questionnaire were administered at three month intervals for one year to 383 women who were unselected with respect to bowel symptoms. A NEO Personality Inventory was given initially to assess neuroticism. Subjects who satisfied restrictive diagnostic criteria for irritable bowel syndrome were compared with those who complained of abdominal pain plus altered bowel habits but who did not meet restrictive diagnostic criteria (functional bowel disorder) and with controls without bowel dysfunction. The irritable bowel group showed significantly higher levels of stress than the other two groups even when the confounding effects of neuroticism were statistically controlled for. Time lagged correlations showed that stress in one three month interval was significantly correlated with bowel symptoms in the subsequent three month interval for all groups. The slope of the regression line relating stress to bowel symptoms was significantly steeper for the irritable bowel group than for the other two groups at three and six months, suggesting that subjects with irritable bowel syndrome show a greater reactivity to stress. Stress scores were also significantly correlated with the number of disability days and the number of medical clinic visits for bowel symptoms.

Evidence for exacerbation of irritable bowel syndrome during menses

Many women report that bowel symptoms are associated with menstruation, but neither the prevalence of these complaints nor their physiological basis is known. This study aimed to estimate prevalence, to determine whether patients with irritable bowel syndrome are more likely to make such complaints, and to determine whether bowel complaints during menstruation are attributable to psychological traits such as increased somatization. To estimate prevalence, 369 clients of Planned Parenthood of Maryland were asked whether gas, diarrhea, or constipation occurred during menstruation. These subjects were compared with women referred to a gastroenterology clinic and found to have irritable bowel syndrome or functional bowel disorder (abdominal pain plus altered bowel habits but not satisfying restrictive criteria for irritable bowel syndrome). Thirty-four percent of 233 Planned Parenthood clients who denied symptoms of irritable bowel syndrome or functional bowel disorder reported that menstruation was associated with one or more bowel symptoms. Gastroenterology clinic patients with irritable bowel syndrome were significantly more likely to experience exacerbations of each of these bowel symptoms, but especially increased bowel gas. Self-reports of bowel symptoms during menstruation were not associated with psychological traits or with menses-related changes in affect.

Brain-gut connections in functional GI disorders: anatomic and physiologic relationships

Abstract  Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom‐attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the ‘mind‐body interaction’ may largely arise in this region. Finally, the limbic system is also involved in the ‘top down’ modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of ‘functional’ disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.

Overlapping Upper and lower gastrointestinal symptoms in irritable Bowel syndrome patients with constipation or diarrhea

OBJECTIVES:Distinguishing between irritable bowel syndrome (IBS) and functional dyspepsia can be challenging because of the variations in symptom patterns, which commonly overlap. However, the overlap is poorly quantified, and it is equally uncertain whether symptom patterns differ in subgroups of IBS arbitrarily defined by primary bowel patterns of constipation (IBS-C) and diarrhea (IBS-D). We aimed to determine and to compare the distribution of GI symptoms, both, upper and lower, among IBS-C and IBS-D patients.METHODS:A total of 121 consecutive patients presenting with a diagnosis of IBS were grouped according to primary bowel symptoms as IBS-C (58 women and 18 men, mean age 47 ± 17 yr) or IBS-D (26 women and 19 men, mean age 47 ± 15 yr). The Hopkins Bowel Symptom Questionnaire, which includes a brief Quality of Life assessment, and the Hopkins Symptom Checklist 90-Revised were completed by all patients at intake.RESULTS:IBS-C patients reported significantly more overall GI symptoms when compared to patients with IBS-D (6.67 vs 4.62, respectively, p < 0.001). Abdominal pain patterns differed in patients with IBS-C versus IBS-D (lower abdominal pain: 40.8%vs 24.4%p = 0.05 and upper abdominal pain: 36.8%vs 24.4%, respectively). Bloating was substantially more common in IBS-C patients (75%) than in IBS-D (40.9%). There were no significant differences in personality subscales by IBS subgroup; however, somatization was positively associated with multiple symptom reports and was negatively correlated with quality of life.CONCLUSIONS:Upper GI symptoms consistent with functional dyspepsia were more frequent in IBS-C. Although there was considerable overlap of upper and lower GI symptoms in patients with IBS-C and IBS-D, the former had more frequent lower abdominal pain and bloating.

Irritable bowel syndrome defined by factor analysis gender and race comparisons

To examine the applicability across subgroups of the Manning criteria commonly used to diagnose the irritable bowel syndrome, a 22-item symptom questionnaire was administered to male and female African-American and Caucasian adults (N=1344). Principal components factor analysis with varimax rotation was used to identify symptom clusters. Consistent with the findings of a previous factor analytic study, three of the six Manning symptoms (loose stools and more frequent bowel movements with onset of pain, pain relieved by defecation) formed a cluster corresponding to the irritable bowel syndrome in all subgroups. It is concluded that: (1) The three core Manning symptoms have equal applicability to both genders and to African-Americans as well as to Caucasians. They are useful symptom criteria for the diagnosis of IBS when used in conjunction with medical evaluation. (2) Three of the six Manning symptoms rarely correlate with the others; if confirmed in patient samples, this would indicate that these three symptoms are not useful for making a diagnosis of the irritable bowel syndrome.

Role of serotonin in the pathophysiology of the irritable bowel syndrome

The irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion, and sensation. Serotonin (5‐HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. 5‐HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. The enteric nervous system (ENS) comprises a semiautonomous effector system that is connected to the central autonomic network. Parasympathetic and sympathetic nerves modulate the ENS via afferent and efferent communications. Ongoing, bidirectional brain–gut interactions involving 5‐HT pathways occur that significantly influence the effector systems. Altered 5‐HT signalling may lead to both intestinal and extraintestinal symptoms in IBS. 5‐HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. 5‐HT modulates sensation and perception of visceral stimulation at peripheral and central sites. Therapeutic agents targeting altered 5‐HT signalling may provide new, effective treatments for patients with IBS.

Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity

Objective: The aim was to determine whether lower visceral pain thresholds in irritable bowel syndrome (IBS) primarily reflect physiological or psychological factors. Methods: Firstly, 121 IBS patients and 28 controls underwent balloon distensions in the descending colon using the ascending methods of limits (AML) to assess pain and urge thresholds. Secondly, sensory decision theory analysis was used to separate physiological from psychological components of perception: neurosensory sensitivity (p(A)) was measured by the ability to discriminate between 30 mm Hg vs 34 mm Hg distensions; psychological influences were measured by the report criterion—that is, the overall tendency to report pain, indexed by the median intensity rating for all distensions, independent of intensity. Psychological symptoms were assessed using the Brief Symptom Inventory (BSI). Results: IBS patients had lower AML pain thresholds (median: 28 mm Hg vs 40 mm Hg; p<0.001), but similar neurosensory sensitivity (median p(A): 0.5 vs 0.5; p = 0.69; 42.6% vs 42.9% were able to discriminate between the stimuli better than chance) and a greater tendency to report pain (median report criterion: 4.0 (“mild” pain) vs 5.2 (“weak” pain); p = 0.003). AML pain thresholds were not correlated with neurosensory sensitivity (r = −0.13; p = 0.14), but were strongly correlated with report criterion (r = 0.67; p<0.0001). Report criterion was inversely correlated with BSI somatisation (r = −0.26; p = 0.001) and BSI global score (r = −0.18; p = 0.035). Similar results were seen for the non-painful sensation of urgency. Conclusion: Increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity.